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Sierra College Bio 6 Human Physiology Lecture Outline Keri Muma SPRING 2016 2 TABLE OF CONTENTS Homeostasis 4 Chemistry 12 Cells & Membrane Transport 24 DNA Replication 31 Mitosis 31 Protein Synthesis 38 Energy Concepts 43 Cell Metabolism 51 Cell Communication 58 Neurophysiology 63 Sensory 73 Central Nervous System 80 Control of Body Movement 91 Autonomic Nervous System 93 Muscle Physiology 101 Endocrine System 114 Blood 126 Cardiac Physiology 131 Blood Pressure 140 Body Defenses / Immunology 146 Respiratory Physiology 156 Digestive Physiology 169 Renal Physiology 185 Reproductive Physiology 197 3 Homeostasis Study Objectives: 1. Define physiology and apply the definition to examples. 2. Distinguish between the teleological approach and the mechanistic approach to physiology. Be able to recognize examples of each. 3. Describe the six levels of organization found in the human body from simplest to most complex. 4. Define homeostasis and define the components of the homeostatic control mechanisms (variable, stimulus, receptor, input, control center, output, effector, compensatory response). Be able to identify examples of each component. 5. Discuss the “law of the maximum and minimum” and how it applies to maintaining homeostasis. 6. Distinguish between intrinsic (local control) and extrinsic control of homeostasis. Be able to recognize if an example would be considered intrinsic or extrinsic. 7. Compare and contrast negative feedback and positive feedback mechanisms and give examples of each. 4 Homeostasis Outline I. Physiology – the study of body functions; how the body carries out its lifesustaining activities. Physiology primarily focuses on the cellular and molecular levels. Example: how the stomach digests food and the chemical reactions taking place within the cell or organ. a. Associated Areas of Physiology i. Anatomy - structure determines function 1. Physiological mechanisms are only possible through structural design 2. A slight change in anatomy can have a significant effect on physiology For example if you have a ventricular septal defect (basically a hole between the chambers of the heart) it will no longer function properly as a pump. Therefore a change in structure will lead to a problem with the function. ii. Physics 1. Electrical currents 2. Blood pressure 3. Flow rates 4. Gas Laws iii. Chemistry 1. Acid / Bases 2. Osmolarity 3. Biochemistry II. Homeostasis - state of balance in which the body’s internal environment remains relatively stable despite changes in the internal and external environments. a. Mainly controlled by a process called negative feedback - the output or response of the effector counteracts the original stimulus, returning the variable to normal limits. 5 i. Internal values within the body may vary within narrow limits (for example: body temperature, pH, blood glucose levels, etc.) These are called variables. ii. However, a stimulus can cause these variables to deviate from their stable condition. This will trigger a sequence of events (compensatory responses) that will counteract the change caused by the stimulus to bring the variable back into its normal limits. iii. Tends to be stabilizing iv. Can be a short-term immediate response to a stimulus or a longterm adaptation to a constant stimulus. a. Example: Heart’s response to exercise i. Short term response: increased heart rate ii. Long term adaptation: increased stroke volume b. Law of Maximum and Minimum – affects of various conditions on the functional efficiency of body processes. Refers to the value or range of the variable. i. Optimal range – range in which the body functions most efficiently ii. Range of tolerance –body can still function just may not be as efficient iii. Minimum or Maximum condition that the body can function at iv. Moving past the max or min condition may result in death v. PH example giving in lecture: The body functions most efficiently when blood pH is in the range of 7.38-7.42. The range of tolerance would be between 7.0 – 7.8. The body may still function but less efficiently. For example acidosis can depress the nervous system and the individual can become disorientated or comatose. Alkalosis can cause hyperexcitability of the nervous system resulting in muscle spasms and tetany. The minimum value would be around 7.0 and maximum would be 7.8 which moving beyond these values could result in death. c. Components of Homeostatic Control Mechanisms - Let’s look at some of the components involved in controlling homeostasis. I will define these components below and then I will apply these components of negative feedback to the example of maintaining a stable body temperature. 6 i. Components: 1. Variable: factor being regulated (in this example it would be body temperature) 2. Stimulus: produces a change in the variable (exercise could be one stimulus that would cause body temperature to increase) 3. Receptor: detects change in the variable. (in this example, thermoreceptors in your body monitor body temperature and they would detect that temperature is increasing) 4. Input: communicates the information from the receptor to the control center. (in this example your thermoreceptors and control center are both located within the same place the hypothalamus. Therefore, there isn’t a distinct input. However, if the receptors are in a different location then the control center your input would usually be the afferent nervous system but it depends on the example.) 5. Control Center: analyzes the information from the receptor and determines the appropriate response to the change. (in this example the control center would be a part of your brain called the hypothalamus that regulates temperature. It will decide that body temperature needs to be lowered and will send the information to the effector.) 6. Output – sends/communicates the response instructions from the control center to the effector. (in this example the output would be the efferent (motor) nervous system. It would be specifically the autonomic nervous system traveling to smooth muscle in the blood vessels and sweat glands.) 7. Effector: are organs or glands that carry out the response from the control center. (in this example the effector would be the sweat glands and the blood vessels in the skin. 8. Compensatory response: The action of the effector that will counteract the stimulus and bring the variable back to its normal value. (in this example it would be producing sweat to help cool the body and the dilation of the blood vessels in the skin that allow more heat to radiate away from the body. Both these responses will cool the body and bring the temperature back to normal). 7 **Listen to your audio lecture for other examples and in your post lecture assignment you will have an opportunity to apply these components to your own example. d. Sources of Homeostatic Controls – homeostasis can be controlled from outside the organ or tissue through a reflex or it could be controlled completely within the organ/tissue where the change occurs. i. Extrinsic control - from outside the organ/tissues 1. Accomplished by the nervous and endocrine systems. This is also called reflex control. 2. It involves several systems working towards a common goal 3. For example, let’s stick to our control of body temperature. This would be considered a reflex or extrinsically controlled because the change is detected in one part of the body (the hypothalamus) and than the response involves other areas such as the blood vessels of the skin and sweat glands which are located elsewhere and are controlled by the nervous system. In the audio lecture I also went over the sympathetic regulation of blood pressure. ii. Intrinsic control - from within the organ/tissue (a.k.a local control) 1. Self-serving the organ it occurs in 2. Example given in lecture: Decreased oxygen levels detected within skeletal muscle tissue can causes vasodilation of local blood vessels so that more blood flows into the active tissue. The low oxygen levels are detected and the response occurs all within the skeletal muscle tissue. Therefore, it is considered locally controlled and does not involve the nervous or endocrine communicating systems. iii. Positive Feedback - output of effector is amplified or the original stimulus is intensified 1. Variable moves further from set value 2. Tends to be destabilizing if it is not self limiting 3. Examples of Positive Feedback: Childbirth 8 iv. Feed forward mechanism– reflex that starts the response loop in anticipation of the stimulus or change 1. Examples of Feed forward mechanisms: Thought or smell of food triggers salivation and increased respiratory rate in anticipation of exercise III. Approaches to explaining physiology a. Teleological – explanation is based on purpose, meeting body needs i. Does not consider how it occurs. Focus on why. ii. Example: Why do we sweat? Answer: To cool down b. Mechanistic – in terms of cause and effect, sequence of events i. Example: Why do we sweat? Answer: 1. Thermoreceptors in hypothalamus detect temperature change 2. Motor pathways activated to stimulate sweat glands 3. As sweat evaporates it takes heat with it and the body temperature decreases c. Activity: Why do red blood cells transport oxygen? i. Write down a teleological explanation to this question: ii. Write down a mechanistic explanation to this question: IV. Physiology as an integrative science - integrates function across many levels of organization and information from different body systems a. Levels of Organization i. ii. iii. iv. v. vi. Chemical level Cellular level Tissue level Organ level Organ system level Organism 9 b. Emergent properties – properties that cannot be predicted based only on the knowledge of individual systems i. Important to look at the human body as a whole and how the different systems work together and affect each other 1. Example: how blood pressure influences kidney function ii. Physiological responses depend on numerous factors both internal and external. 1. Example: Think of all the factors that can affect just blood pressure. Diet, exercise, genetics, temperature, dehydration, loss of blood, and the list can go on and on! 10 Post-lecture Practice Homeostasis The purpose of this exercise is to give you an opportunity to see if you can apply the concepts of homeostasis you learned about in lecture to a real life example. You may find it helpful to discuss your assignment with your classmates but each individual should try to come up with their own example written in their own words. In this assignment you will pick a specific example of negative feedback in our body and describe how it maintains homeostasis. You can use your book, the internet or other sources to find an example of a negative feedback loop. The only exception is you cannot pick body temperature. Define negative feedback and homeostasis in your own words. You need to define the role of all the components of a homeostatic control mechanism and then identify theses components in your specific example. Components to include: o Variable o Stimulus o Receptor o Input o Control center / integrator o Output o Effector o Compensatory response Hypothetically, describe how the “laws of maximum and minimum” apply to your variable? o Define optimal range, range of tolerance, max and min value and how it specifically applies to your variable. o You may have to do some research to find these specific values. 11 Chemistry Study Objectives: 1. Define the terms matter, elements, and atoms 2. Differentiate between ionic, covalent, and hydrogen bonds 3. Differentiate between polar and non-polar molecules: how do they interact? 4. Describe the unique properties of water and their importance to the human body 5. Distinguish between inorganic and organic compounds 6. Describe acids and bases, and explain the concept of the pH scale 7. Explain the importance of buffer systems and how they work 8. Describe the building blocks, structure, and functions of carbohydrates: monosaccharide, disaccharides, and polysaccharides 9. Describe the building blocks, structure, and functions of lipids: neutral fats, phospholipids, steroids, and eicosanoids 10. Describe the building blocks, structure, and functions of proteins: fibrous and globular 11. Explain how acidity and high temperature affect the functioning of globular proteins 12. Describe the building blocks, structure, and functions of nucleic acids: DNA and RNA 12 Chemistry Outline I. Matter - anything that occupies space and has mass a. Elements are substances that cannot be broken down into other substances b. Atoms - the smallest unit of matter that still retains the properties i. Structure of atoms - composed of subatomic particles 1. Protons - that are positively charged and are found in the nucleus (center) of an atom 2. Neutrons - are neutral or have no charge; are also found in the nucleus 3. Electrons - are negatively charged and exist in the orbits/shells around the nucleus. a. Maximum number of electrons per shell = 2 in the first shell; 8 in the other shells b. Number of electrons on the outer shell determines the atoms chemical behavior c. Chemical Bonds i. Ionic Bonds - formed between oppositely charged ions 1. When an atom loses or gains electrons, it becomes electrically charged 2. Ions are charged atoms ii. Covalent Bonds - form when electrons are shared between atoms 1. non-polar covalent bonds – electrons shared equally 2. polar covalent bonds – electrons are NOT shared equally iii. Hydrogen bonds – interaction between a hydrogen atom bound to an electromagnetic atom and another electromagnetic atom. 1. The polarity of water results in hydrogen bonds between neighboring water molecules 13 2. Gives water some unique vital properties: a. High heat capacity - requires a lot of energy to increase in temperature, and releases a lot of energy when it cool b. High heat of vaporization - as water evaporates it takes large amounts of heat with it c. Good solvent properties –dissolves chemicals, making it a good medium for transporting biological molecules i. Solution - is a liquid consisting of two or more substances evenly mixed 1. Solvent: is the dissolving agent 2. Solute: is the substance being dissolved ii. Hydrophilic – water soluble (likes water) 1. Polar molecules iii. Hydrophobic – does not dissolve in water (water fearing) 1. Non – polar molecules iv. Amphiphilic – molecules that is both hydrophilic and phobic 1. Polar and non-polar ends d. Chemical reactivity i. Hydrolysis – water breaks bond apart ii. Dehydration – removing water to form bonds e. Cohesion - stickiness of water molecules f. Cushioning II. Acid and Base Concepts a. Acid – a chemical compound that donates H+ ions to solutions i. HCl H+ + Cl- 14 b. Base - a compound that accepts H+ ions and removes them from solution i. NaOH Na+ + OH- c. pH scale - measures concentration of hydrogen ions i. Logarithmic scale – each pH unit is a tenfold change in H+ concentration 1. pH 7 = neutral 2. pH below 7 = acidic 3. pH above 7 = basic d. Buffers - substances that resist pH change i. They accept H+ ions from the solution when they are in excess ii. They donate H+ ions to the solution when they are depleted III. Biochemistry a. Organic molecules – large molecules containing carbon (macromolecules) i. Have a unique three-dimensional shape that defines its function in an organism ii. The molecules of your body recognize one another based on their shapes iii. Most macromolecules are polymers. Polymers are made by stringing together many smaller molecules called monomers (subunits) b. Four types of macromolecules found in cells i. Carbohydrates - includes sugars and starches 1. Contain carbon, hydrogen, and oxygen (1:2:1 ratio) 2. Monomer = monosaccharide 3. Classified according to size: a. Monosaccharides – one sugar, referred to as simple sugars b. Disaccharide - a double sugar 15 c. Polysaccharides - complex carbohydrates formed by long chains of monosaccharides i. Starch, cellulose (plants), glycogen (animals) ii. Lipids 1. Carbon and hydrogen outnumber oxygen 2. Lipids are hydrophobic 3. Functions: a. Energy storage b. Cushioning c. Insulation 4. Types of lipids: a. Neutral fats – mostly triglycerides i. A combination of glycerol and three fatty acids ii. Found in fat deposits (adipose tissue) iii. Source of stored energy and insulation iv. Cushions organs v. Unsaturated fatty acids - have less than the maximum number of hydrogen bonded to the carbons 1. Examples: Most plant oils; vegetable or corn oil vi. Saturated fatty acids - have the maximum number of hydrogen bonded to the carbons 1. Example: Most animal fats vii. What is trans fat then??? 16 b. Phospholipids – composed of phosphate head (hydrophilic) and two lipid tails (hydrophobic) i. Forms cell membranes and the myelin sheaths of neurons c. Eicosanoids – a 20 carbon fatty acid with a 5 or 6 carbon ring i. Examples: prostaglandins, leukotrienes, thromboxanes d. Steroids - the carbon skeleton is bent to form four fused rings i. Cholesterol is the “base steroid” from which your body produces other steroids ii. Example: testosterone, estrogen, cortisol, bile salts iii. Protein - a polymer constructed from chains of amino acid monomers 1. Contains C, H, O, N, and sometimes S 2. Monomer = Amino Acids a. There is 20 different amino acids b. The arrangement and combination of amino acids makes each protein different c. Amino acids are held together by peptide bonds 3. Types of Proteins a. Fibrous proteins i. Provides for construction materials for body tissues ii. Important role in structure iii. Examples: collagen, elastic fibers, myosin and actin 17 b. Globular Proteins i. Relies on complex folded structure to function ii. Plays a vital role in cell function iii. Act as enzymes, hormones, transport proteins or antibodies iv. Protein Shape - protein’s shape is sensitive to the surrounding environment 1. Primary structure – order of amino acids 2. Secondary structure -polypeptide folded into a helix or a sheet 3. Tertiary structure- sheets and helices folded into a 3-D globule 4. Quaternary structure - several tertiary units put together 5. A slight change in the primary structure of a protein affects its ability to function a. Example: sickle cell anemia 6. Denaturation - unfavorable temperature and pH changes can cause a protein to unravel and lose its shape iv. Nucleic Acids - information storage molecules 1. Monomer = nucleotides a. 5 carbon sugar b. Phosphate group c. Nucleic base 18 2. Types of Nucleic Acids a. Deoxyribonucleic Acid i. Composed of 4 types of nucleotides 1. Purines – Adenine (A) and Guanine (G) 2. Pyrimidines – Thymine (T) and Cytosine (C) ii. Organized by complimentary base pairing to form a double stranded helix 1. A = T 2. C = G iii. The nucleotides of the two stands are joined by hydrogen bonds iv. Contains a sugar-phosphate backbone b. Ribonucleic acid i. RNA is different from DNA in that: 1. Its sugar is ribose instead of deoxyribose 2. It has the base uracil (U) instead of thymine (T) 3. It’s single stranded c. Some other nucleotides: i. ATP used for cellular work ii. NAD and FAD, used as electron carriers in cellular respiration iii. GTP, cyclic AMP, ADP in cell signaling 19 Chemistry Post-Lecture Practice 1. List at least four vital properties of water and describe why this is important to the human body. 2. Draw two or three water molecules interacting with each other by accurately depicting where the hydrogen bonds would take place in your illustration. 3. Bicarbonate ions, HCO3- is an important ion in the body. It reacts in the following way: HCO3- + H+ H2CO3 a. Are bicarbonate ions acids or bases? _________________ b. Why? 20 4. HNO3 reacts in the following way when dissolved in water: HNO3 H+ + NO3a. Is HNO3 an acid or a base? ___________ b. Why? 5. How much more H+ is in a solution that has a pH of 3 when compared to a pH of 6? 6. How much OH- is in a solution with a pH of 11 when compared to a pH of 7? 21 Organic Molecules Name Monomers (subunits) List examples of: Monosaccharide biological function Carbohydrates Disaccharide Polysaccharide Neutral Fats Lipids Phospholipids Steroids Eicosanoids 22 Name Monomers (subunits) List examples of: Fibrous biological function Proteins Globular DNA Nucleic acids RNA 23 Cell Physiology & Membrane Transport Study Objectives: Cell Physiology 1. Explain the structure and functions of nucleus structures: nuclear envelope, nucleolus, and nuclear pores 2. Describe the structure and function of the following cell structures: cytoplasm, mitochondria, rough ER, smooth ER, golgi apparatus, lysosomes, peroxisomes, ribosomes, cytoskeleton, centrioles, cilia, flagella, microvilli. Membrane Transport 1.Describe the general structure of the plasma membrane and its overall functions: phospholipid bilayer, proteins (peripheral, integral), cholesterol, and glycocalyx 2. Explain Fick’s law and the factors that affect the rate of diffusion 3. Define these terms, be able to recognize examples of each, and apply them: passive transport vs. active transport, simple diffusion, facilitated diffusion, osmosis, hypertonic, hypotonic, isotonic, filtration, solute pumping (primary transport, secondary transport) exocytosis, and endocytosis (phagocytosis, pinocytosis, receptor mediated) 4. Explain the effects of hypertonic, hypotonic, and isotonic solutions would have on cells and the direction solutes and water would diffuse. 24 Cells & Membrane Transport Outline I. Cell Theory a. Cells are the smallest structural and functional units of life b. All living organisms are composed of one or more cells c. Cells arise from other cells II. Plasma Membrane - separates the living cell from its nonliving surroundings a. General Functions i. Barrier – separates extracellular fluid from intracellular fluid ii. Selective permeability – controls what enters and exits the cell iii. Cell markers and receptors – cell recognition, binds hormones, cell communication iv. Adhesion – between other cell membranes or extracellular materials b. Structure – fluid mosaic model (see figure 3-3 in textbook) i. Phospholipid bilayer 1. Hydrophilic heads orientate themselves towards the extracellular and intracellular fluid 2. Hydrophobic tails orientate themselves inward, away from the fluid 3. Sketch the arrangement of the phospholipid bilayer: ii. Cholesterol – stabilizes the membrane iii. Glycocalyx – serve as biological markers iv. Proteins 1. Peripheral – attach to inner or outer surface of the membrane 2. Integral – embedded in or span the membrane 3. Functions of membrane proteins: a. Transport i. Channel proteins – water filled pathways that allow select ions in/out of the cell ii. Carrier proteins- transport select substances across the membrane 25 b. Cell adhesion molecules – play a role in anchoring cells to each other and the cytoskeleton, responsible for stickiness of cells c. Receptors– cell recognition, cell signaling, binding of hormones d. Enzymes – facilitate chemical reactions on inner and outer membrane surfaces III. Plasma Membrane Transport – two types of transport passive vs. active a. Passive transport – does not require energy to move solutes across a membrane i. Diffusion – solutes move down their concentration gradient until evenly distributed throughout the solution 1. Simple diffusion – solutes diffuse across the membrane unassisted a. Small non-polar and lipid-soluble solutes b. Examples given in lecture: oxygen or carbon dioxide 2. Facilitated diffusion – proteins carry or assist solutes across the membrane a. Charged ions move through protein channels b. Large molecules such as glucose or amino acids are carried across by carrier proteins c. Carrier proteins (see figure 3-14 in textbook and watch the carrier-mediated animation posted on Canvas) i. Transports a specific substance (for example you have specific glucose transporters in the membrane of some cells) ii. Can reach saturation when all binding sites are occupied (Transport maximum) iii. Competitive inhibitor - other closely related compounds can compete for the same binding sight 26 3. Fick’s law of diffusion –factors that affect the rate of diffusion a. the magnitude of the concentration gradient i. if you increase the concentration gradient then would the rate of diffusion increase or decrease? b. the permeability of the plasma membrane to a substance. i. if you increase the permeability of the membrane to a substance then would the rate of diffusion increase or decrease? c. the surface area of the membrane across which diffusion takes place i. if you increase the surface area of the membrane to a substance then the rate of diffusion would increase or decrease? d. the molecular weight of a substance i. if you increase the molecular weight of a substance then would the rate of diffusion increase or decrease? e. the distance through which diffusion takes place i. if you increase the distance a substance must diffuse then would the rate of diffusion increase or decrease? f. Temperature i. if you increase the temperature then would the rate of diffusion increase or decrease? • See Table 3-1 in your textbook for a summary of factors influencing rate of diffusion. ii. Osmosis – diffusion of water across a membrane down its concentration gradient 1. Tonicity – ability of a solution to change the shape of a cell by altering its internal water volume, depends on concentration of non-penetrating solutes 27 a. Isotonic solution – contains equal concentration solutes as the cell i. What effect would this solution have on cell volume? b. Hypertonic solution – contains more solutes than the cell i. What effect would this solution have on cell volume? c. Hypotonic solution – contains less solutes than the cell i. What effect would this solution have on cell volume? *See figures 3-10, 3-11, 312, and 3-13 in your textbook to support these osmotic concepts. iii. Filtration – water and solutes are pushed across a membrane from an area of higher pressure to an area of lower pressure 1. Non-selective process, only large molecules cannot pass iv. Summary: Types of passive transport 1. Diffusion: simple or facilitated 2. Osmosis 3. Filtration b. Distribution of Solutes In Fluid Compartments i. Osmotic equilibrium – total amount of solutes per volume of fluid is equal ii. Chemical disequilibrium – some solutes are more concentrated in one fluid compartment than another (requires input of energy) c. Active transport – movement of solutes across the membrane requires energy (ATP). Occurs during movement of solutes against their concentration gradient or very, very large molecules i. Solute pumping – proteins use ATP to transport solutes against concentration gradient 28 1. Cotransporters – carrier proteins that transport two or more substrates across a membrane (See figure 3-17) a. Symport: moves two substrates in same direction b. Antiport: moves two substrates in opposite directions 2. Types of solute pumping: a. Primary active transport – energy is provided directly by the hydrolysis of ATP i. Example: Sodium-Potassium pump maintains a higher concentration of potassium inside the cell and a higher concentration of sodium outside the cell. Pumps 3 Na+ out and 2 K+ in. (See figure 316 for illustration) b. Secondary active transport – primary transport of one molecule creates an ion gradient used to drive another molecule against its concentration gradient (See figure 3-18 for illustration) ii. Exocytosis - moves material from cell interior to the extracellular space (Figure 2-5a) 1. Vesicles fuse with the plasma membrane expelling the contents out of the cell iii. Endocytosis- moves material from extracellular space into the interior of the cell (Figure 2-5b) 1. Phagocytosis – “cell eating” 2. Pinocytosis – “cell drinking” 3. Receptor mediated endocytosis – receptors bind specific substances and initiates endocytosis (See figure 2-8b) iv. Summary of Types of Active Transport: 1. Solute Pumping: primary or secondary 2. Exocytosis 3. Endocytosis: phagocytosis, pinocytosis, or receptor mediated *There is a helpful summary of membrane transport methods in Table 3-2 of your textbook. 29 Membrane Transport Post-lecture Practice 1. Circle all of the following factors that would increase a solute’s diffusion rate: a. Increasing temperature b. Decreasing surface area for diffusion c. Increasing the distance d. Lower molecular weight 2. Look at the following illustrations of solutions whose solute is indicated by small circles. A B C D E a. Solution A is hypertonic to solution(s) __________. b. Solution A is hypotonic to solution (s) ___________. c. Solution A is isotonic to solution(s) ____________. 3. A cell containing 4% NaCl is suspended in a solution that consists of 15% NaCl. Assume the sac is permeable to all substances: a. Which direction will water initially move? i. Into the cell ii. Out of the cell iii. It will not move b. Which direction will NaCl initially move? i. Into the cell ii. Out of the cell iii. It will not move Cell 4% NaCl Solution 15% NaCl 4. List four examples of active transport: 30 DNA Replication & Mitosis Study Objectives: 1. Describe the structure of DNA and where it is found. 2. Explain complimentary base pairing: A-T and C-G 3. Describe the steps involved in DNA replication. Include the enzymes involved and their functions. 4. Compare the replication of the leading strand vs. the lagging strand. 5. Explain why DNA replicates and when during the cell cycle it happens. 6. Describe the structure and function of a eukaryote chromosome. What is a chromosome? How many do you have? What are homologous chromosomes? 7. Explain why cells undergo mitosis. 8. Briefly describe the events that occur in each phase of interphase: G1, S, G2 9. Briefly describe the events that occur in each phase of mitosis: prophase, metaphase, anaphase, telophase. What is the final result of mitosis? Which types of cells undergo mitosis? 10. Define cytokinesis. 11. Compare and contrast the characteristics of normal cells vs. cancer cells 12. Describe factors that control cell division and the role they play in the development of cancer: proto-oncogenes, tumor suppressor genes, apoptosis (cell death), telomeres 31 DNA Replication Outline I. Review of DNA Structure a. Double stranded i. The chemical side groups of the nitrogen bases form hydrogen bonds, connecting the two strands. 1. Adenine forms two hydrogen bonds with thymine 2. Guanine forms three hydrogen bonds with cytosine ii. Sugar-Phosphate Backbones run antiparallel to each other 1. Each DNA strand has a 3’ end with a free hydroxyl group and a 5’ end with a free phosphate group (See figure 14- 6 in textbook) 2. One strand runs 5’ to 3’ and the other runs 3’ to 5’ 3. Sketch two DNA strands running antiparallel to each other and label the 5’ and 3’ ends. II. DNA Replication a. Purpose - before a cell divides it must replicate its DNA so each daughter cell has a full set of DNA b. Mechanism: Semiconservative – the two parent strands serve as a template for the synthesis of the new complementary strands (See figure 14.7 and 14.8) c. Steps in replication: i. Replication Origin - begins at special sites called origins of replication 1. There may be hundreds or thousands of origin sites per chromosome. 2. Strands separate forming a replication “bubble” with replication forks at each end. 3. The replication bubbles elongate as the DNA is replicated and eventually fuses with other replication bubbles 4. Enzymes Involved a. Helicase – unwinds and unzips the DNA helix at the replication forks b. Topoisomerases – relieves the torque from the unwinding DNA 32 ii. Elongation of new strand 1. Primase – constructs RNA primer complementary to the DNA templates 2. After formation of the primer, DNA polymerase III – elongates the new strand by adding nucleotides to the 3’end (~50 per second) 3. Replication always occurs in the 5’ to 3’ direction a. Leading strand – elongates toward the replication fork, continuous b. Lagging strand – elongates away from the replication fork i. Results in Okazaki fragments: discontinuous short segments c. Sketch your original template strands and then add your leading and lagging strands. Label your 5’ and 3’ ends on your template strands so you can determine your leading and lagging strand: 4. DNA polymerase I – replaces RNA primers with DNA nucleotides 5. Ligase – enzyme that joins fragments into a single DNA strand III. Proofreading and Repair a. Replication is extremely accurate i. 1 error per billion nucleotides b. DNA polymerase proofreads each nucleotide against the template and fixes any mismatches c. Causes of mistakes i. replication errors ii. physical and chemical agents **Note: DNA replication only occurs when the cell is preparing to divide. When the cell is NOT dividing DNA is used as a blueprint for protein synthesis. 33 Cell Division – Mitosis Outline I. Why do cells divide? a. To grow b. To repair damaged cells c. To replace lost cells d. To reproduce II. Chromosomes in Eukaryotes -long threads of DNA wrap around proteins called histones a. Chromatin -when a cell is not dividing the DNA is loose & unwound b. Chromosomes - when the cell divides the chromatin condenses into tightly c. Chromosome number – humans have 46 chromosomes (23 pairs) i. “n” is the number of different types of chromosomes 1. in humans n =23 ii. Humans are diploid (2n) therefore each somatic cell has two sets of chromosomes 1. in humans 2n = 46 iii. Homologous chromosomes - are matching pairs of chromosomes 1. 22 pairs of homologous (matching) chromosomes, called autosomes 2. 1 pair of sex chromosomes, XY or XX d. Before a cell divides, it must duplicates all of its chromosomes so that each new cell gets a complete copy of DNA i. A duplicated chromosome consists of 2 sister chromatids, which are identical molecules of DNA III. Phases of Cell Division a. The cell cycle consists of two phases: i. Interphase – cell carrying out daily functions or preparing to divide ii. Mitosis- division of the nucleus b. Phases of Interphase i. G1 phase – cell spends 90-95% of its time in this phase growing and carrying out its everyday functions ii. S-phase - DNA is replicated iii. G2 phase - final “check point”: make sure everything is ready for mitosis 34 c. Phases of Mitosis i. Prophase 1. Chromatin condenses into chromosomes 2. Centrioles migrate to opposite poles 3. Nuclear membrane breaks down 4. Mitotic spindles form ii. Metaphase 1. Sister chromatids are aligned in the center of the mitotic spindle iii. Anaphase 1. Mitotic spindles shorten pulling chromosomes to opposite poles 2. Sister chromatids separate becoming daughter chromosomes 3. The cell begins to elongate iv. Telophase 1. Chromosomes uncoil into chromatin 2. Spindle breaks down 3. Nuclear membrane reforms d. Cytokinesis – division of the cytoplasm i. Original cytoplasmic mass divides resulting in two identical daughter cells IV. Cell division out of control!!!! a. Cell division is usually under strict control in order to ensure appropriate proportions. When cell cycle regulation fails, cells start dividing uncontrollably and result in abnormal masses of dividing cells called tumors. b. Types of Tumors i. Benign – does not invade adjacent tissues, encapsulated ii. Malignant – invades adjacent tissues 1. Metastasize – cells break away from primary tumor and travel to other areas of the body c. Normal cells vs. Cancerous cells i. Characteristics of Normal Cells 1. Stop dividing after a certain # of divisions 2. Have contact inhibition 3. Differentiated (have a job) 4. Undergo apoptosis if DNA is damaged 35 ii. Characteristics of Cancer cells 1. Immortal, divide indefinitely 2. No contact inhibition, pile up on each other 3. Non differentiated (no job) 4. Large abnormal nuclei or chromosome numbers d. Factors that control cell division i. External signals from neighboring cells 1. Proto-oncogenes – produce proteins that turn on cell division a. Mutations in proto-oncogenes (now called oncogenes) may cause these genes to stay turned on and produce excess growth stimulating proteins resulting in uncontrolled cell division 2. Tumor suppressor genes – code for proteins that receive stop signals from neighboring cells. If mutated they cannot suppress cell division ii. Apoptosis – programmed cell death, back up system for cells with damaged DNA iii. Telomeres – regions at the end of chromosomes that become shorter each time the cell divides 1. Keeps cells from becoming immortal 2. Cancer cells have enzyme telomerase which repairs telomeres *Optional reading to better understand how cells become cancerous: the article “How Cancer Arises” posted on Canvas. 36 Mitosis Post-Lecture Practice 1. Draw and label the events occurring in the stages of cell division for a cell that is 2n = 4 and give a brief description for each event. Include the phases of interphase, mitosis (prophase, metaphase, anaphase, telophase), and cytokinesis. Other things you should include somewhere in your drawing is the labeling of chromatin, homologous chromosomes, sister chromatids, and daughter chromosomes. 37 Protein Synthesis Study Objectives: 1. Define what a gene is. 2. Describe the steps involved in transcription: initiation, elongation, and termination. Include enzymes involved and where the process occurs in the cell. 3. Describe the roles of mRNA, rRNA, and tRNA in protein synthesis. 4. Describe the post-transcriptional modifications of mRNA, rRNA, and tRNA 5. Describe the steps involved in translation: initiation, elongation, and termination Include enzymes involved and where in the cell the process occurs. 6. Describe the post-translational modifications of polypeptides 7. Define mutation and explain how the following mutations may affect the final protein: silent, point, and frame-shift mutations 38 Protein Synthesis Outline I. Gene Expression a. What is a gene? i. Gene = a segment of DNA coding for a RNA segment. These RNA segments will be used to produce a polypeptide (structural or enzymatic protein) ii. Each strand of DNA can contain thousands of genes iii. Each gene has a beginning and an end b. DNA is used as the blueprint to direct the production of certain proteins c. Genetic Code i. The DNA nucleotide sequence codes for the order in which amino acids are put together to form proteins ii. Every three nucleotides (codon) on the mRNA codes for a specific amino acid iii. There are 20 different amino acids but 64 possible codons iv. Some redundancy - more then one codon codes for the same amino acid v. The genetic code is universal in almost all organisms (See figure 15.5 for a copy of the code) II. Protein Synthesis a. Transcription - information is transferred from DNA to RNA i. Occurs in the nucleus ii. All three types of RNA are transcribed from DNA 1. Messenger RNA – carries the coded message from the DNA to the ribosome in the cytoplasm 2. Ribosomal RNA – reads the mRNA 3. Transfer RNA – transfers the correct amino acid to the ribosome iii. Overview of Transcription: the segment of DNA that contains the gene for a specific protein or RNA that the cell wants to produce will unwind and the complementary RNA strand will be made by incorporation the complementary RNA nucleotides 39 iv. Stages in Transcription 1. Initiation a. Each gene has a precise beginning known as the promotor region and an end known as the termination sequence b. Transcription factors bind to the promoter region (TATA box) of the DNA. c. RNA polymerase then initiates transcription by binding to the transcription factor. It: i. Unwinds the DNA ii. Elongates the RNA segment 2. Elongation of the RNA transcript a. RNA nucleotides are added in the 5’ to 3’ direction by RNA polymerase b. RNA nucleotides form temporary hydrogen bonds with the DNA template c. As the DNA helix reforms the RNA peels away 3. Termination a. At the end of the gene the termination sequence causes transcription to end b. The pre-RNA segment dissociates from the DNA 4. Post-transcriptional Modifications to mRNA a. 5’ cap – a guanine triphosphate is added that signals for ribosomal attachment in the cytoplasm b. 3’ poly A tail – polyA polymerase adds ~250 “A” nucleotides to the end. Protects RNA from being degraded by nucleases. c. Splicing - introns are cleaved out by snRNPs, and exons are spliced together i. Exons – coding region ii. Introns – noncoding region 5. Post-transcriptional modifications rRNA a. rRNA associates with proteins to form two subunits (40s and 60s) b. Leaves the nucleus and enters the cytoplasm 6. Post-transcriptional Modifications tRNA a. Folds into a three dimensional structure (clover shaped) 40 b. Translation - going from the mRNA nucleotide code to amino acid code i. Occurs in the cytoplasm ii. Overview: mRNA is read by a ribosome (rRNA) to determine the sequence of amino acids to produce a polypeptide iii. Players in Translation 1. mRNA strand 2. ribosomes (rRNA) a. rRNA has a mRNA binding site and three tRNA binding sites: i. A site (amino-acyl binding site) ii. P site (peptidyl binding site) iii. E site 3. tRNA a. Has an anticodon - three base sequence that is complementary to a codon on the mRNA b. 3’ end of the tRNA contains a binding site for the specific amino acid the tRNA carries iv. Stages of Translation 1. Initiation a. mRNA binds to the 40s ribosome subunit b. The initiator tRNA binds to the mRNA start codon (AUG) at the P site on the ribosome c. The anticodon on the tRNA matches with the codon on the mRNA strand d. The arrival of the 60s subunit completes the initiator complex 2. Elongation – of the polypeptide chain a. The next tRNA enters at the A site b. The enzyme peptidyl transferase forms a peptide bond between the amino acid on the P site and the new amino acid on the A site c. The ribosome then moves down the mRNA (this is called translocation) d. The tRNA that was at the A site is now at the P site and the empty tRNA that was at the P site now exits at the E site e. Charging of tRNA i. Amino acids are floating freely in the cytoplasm ii. The enzyme amino-acyl tRNA synthetase attaches the amino acids to the 3’end of the tRNA iii. Requires ATP 41 3. Termination of translation a. Elongation continues until a stop codon on the mRNA is reached (UAA, UAG, UGA) b. The polypeptide is then released from the ribosome by a release factor v. Polysomes - several ribosomes can simultaneously translate the same mRNA strand to make multiple copies of the same polypeptide vi. Post-translational modifications to the polypeptide 1. The start methionine is removed by the enzyme aminopeptidase 2. Proteins will under go folding or modifications a. Cleavage into smaller fragments or joined with other polypeptides b. Chemical modifications: addition of carbohydrates or lipids c. Transport to its final destination III. Mutations and their consequences a. Mutation = a change in the sequence of bases within a gene b. Caused by a mistake during DNA replication (rare) or due to environmental factors called mutagens c. Mutations can be somatic or germinal d. Types of Mutations i. Point mutations (substitutions) – change in a single nucleotide 1. Due to redundancy of the genetic code it may change the amino acid, it may not “wobble” 2. Silent mutations do not change the protein ii. Frame-shift mutation – caused by insertion or deletion of a nucleotide 1. Changes the reading frame of the codons, usually results in a non-functional protein e. Are all mutations bad? Although mutations are sometimes harmful….. i. They are also the source of the rich diversity of genes in the world ii. They contribute to the process of evolution by natural selection 42 Energy Concepts Study Objectives: 1. Define energy 2.Describe the 1st law of thermodynamics Compare kinetic and potential energy, be able to give or recognize examples of each 3. Describe the major forms of energy and explain how energy flows from one type to another: radiant, electrical, mechanical, chemical, and heat (2nd law of thermodynamics) 4. Describe the structure of ATP and explain the role of ATP in the body. How is it recycled? What organelle produces ATP? 5. Define the following terms: metabolism, catabolism, anabolism, synthetic reactions, decomposition reactions, reversible reactions 6. Describe the characteristics and function of enzymes. How do they work? 7. Describe the various factors that effect enzyme activity: concentrations, temperature, pH, inhibition, and allosteric regulation 43 Energy Concepts Outline I. Energy -the ability to do work or to put matter into motion A. 1st Law of Thermodynamics - conservation of energy i. Energy is not created or destroyed, it is only converted from one form to another B. Types of energy i. Kinetic- energy doing work, energy of motion ii. Potential- inactive or stored energy C. Forms of Energy i. Radiant - travels in waves Example: Light waves are essential for photosynthetic organisms; vision in animals ii. Electrical - flow of charged particles Example: Nerve impulses are created by the movement of Na+ and K+ ions iii. Mechanical - directly involved in moving matter Example: Muscle contraction iv. Chemical – potential energy stored in chemical bonds and is released when bonds are broken 1. Found in food, fuel, ATP II. Types of Reactions A. Synthesis reaction (A+BAB) i. Atoms or molecules combine to form larger molecules ii. Endergonic – reaction absorbs energy into the chemical bonds B. Decomposition reaction (ABA+B) i. Larger molecule is broken down into smaller molecules ii. Exergonic - chemical energy is released 44 C. Reversible reaction: (A + B C + D) i. Chemical reaction that can proceed in either direction ii. Direction of the reaction will shift depends on the concentration of the reactants and products III. Energy Conversions A. 2nd Law of Thermodynamics - Heat is a product of all energy conversions i. Heat= the kinetic energy contained in the random motion of molecules ii. Entropy = measure of disorder or randomness 1. Therefore, all energy transformations increase the entropy of the universe. 2. Living things are organized, therefore they have low entropy 3. To maintain low entropy, constant input of energy is needed 4. Where do we get this energy??? IV. ATP and Cellular Work A. The chemical energy in food is released in cellular respiration to make ATP in the mitochondria B. ATP is used to drive different types of cell work: i. active transport ii. muscle contraction iii. impulse conduction iv. we use 10 million ATP molecules per second 45 C. The Structure of ATP i. ATP (adenosine triphosphate) - chemical energy used by all cells ii. Consists of adenosine plus a tail of three phosphate groups iii. Energy is released by breaking high energy phosphate bond (-7.3 kcal/mol) D. ATP is always recycled… i. ATP ADP + P + Energy ii. Cellular work uses (spends) ATP so more must be made iii. ATP is recycled from ADP and phosphate through cellular respiration V. Metabolism - the sum of all the chemical reactions that occur in the body A. Two types of metabolic reactions i. Catabolic – breaking down molecules, releases energy which is captured in the bonds of ATP ii. Anabolic – uses energy from ATP to synthesize large molecules B. Enzymes i. Few metabolic reactions occur without the assistance of specialize proteins called enzymes ii. Enzymes are protein molecules that speed up the rate of chemical reactions (biological catalyst) iii. Enzymes lower the activation energy for chemical reactions 1. Activation energy is the energy required to trigger a chemical reaction iv. Characteristics of Enzymes 1. Each enzyme is very selective – it catalyzes specific reactions 2. Each enzyme recognizes a specific substrate 3. Enzymes can function over and over again (can be reused) 46 v. How an enzyme works 1. Each enzyme binds a specific reactant molecule (substrate) at its active site. 2. After the reactants are converted, the products are released and the enzyme remains unchanged. 3. Enzyme + Substrate Enzyme-substrate complex Product + Enzyme vi. Factors Affecting Enzyme Activity 1. Concentration a. Increase in substrate or enzyme concentration will increase the rate b. At some substrate concentrations, the active sites on all enzymes are engaged and has reached saturation 2. Temperature a. Increase in temperature, increases the rate of enzymatic reactions by increasing kinetic energy of molecules b. However, at a point the rate will drop off sharply due to denaturing of the enzyme at high temperatures 3. pH – enzymes work best at an optimal pH a. If it is more acidic or basic than the optimal pH the rate of enzymatic activity will decrease 4. Enzyme inhibitors or activators- can inhibit or activate a metabolic reaction a. Competitive inhibition - binds to the active site, as substrate impostors i. Can be reversible or irreversible 47 b. Noncompetitive - bind at a different site (allosteric), changing the shape of the enzyme’s active site 5. Allosteric Regulation a. Feedback inhibition – the accumulation of the end product turns off the metabolic pathway b. Most allosterically regulated enzymes are constructed of two or more polypeptide chains. c. The whole protein oscillates between two conformational shapes, one active, and one inactive. d. Binding of regulatory molecules can either inhibit or stimulate enzyme activity. 48 Post – Lecture Practice 1. Review Energy Concepts PowerPoint slides #1-10. Describe in your own words in a short paragraph what is happening in the diagram below. Include the specific types of energy and how the First and Second Law of Thermodynamics apply. (Act like I don’t know anything about this drawing and you are teaching me about the flow of energy ) 49 2. Explain how ATP is used as a source of energy for cellular processes. You can draw and describe a diagram OR use words to get your point across. Include in your answer: a. the general structure of ATP b. how is it used and recycled during cellular processes c. give examples of two specific mechanisms that you have learned about so far that use ATP 3. Describe the role enzymes play in living organisms. Include in your answer: a. Define enzyme, substrate, and product b. Describe the characteristics of an enzyme c. Give an example of two variables that can affect the activity of an enzyme and explain why these variables change the course of an enzymatic reaction. 50 Cell Metabolism Study Objectives: 1. Define oxidation and reduction. 2. Describe the mechanisms of ATP synthesis: substrate level phosphorylation vs. oxidative phosphorylation 3. Write the overall general equation for cellular respiration. 4. Describe the role of dehydrogenases and coenzymes NAD and FAD in cellular respiration. 5. Distinguish between anaerobic (lactic acid fermentation) and aerobic respiration in terms of when they occur and the total number of ATP produced per glucose molecule. 6. Describe the basic stages of aerobic respiration: glycolysis, transitional stage, Krebs cycle and Electron Transport System. For each stage include: What goes into each stage and what is produced in each stage? Where does each stage occur in the cell? Is it anaerobic or aerobic? 7. Define lipolysis and explain how glycerol and fatty acids are used for cellular respiration. 8. Define beta-oxidation, ketogenesis, ketosis, and ketoacidosis 9. Describe protein metabolism. Explain the role of proteases, deamination, and organic acids in utilizing proteins for cellular respiration. 10. Define glycogenolysis and gluconeogenesis. 51 Cell Metabolism Outline I. The big picture: a. The sun provides the energy that powers all life b. Animals depend on plants to convert solar energy to chemical energy c. This chemical energy is in the form of organic molecules which animals then eat to convert into ATP through cellular respiration II. Cellular Respiration a. Overview i. Cell respiration is the main way that chemical energy is harvested from organic molecules and converted to ATP ii. It involves a series of catabolic reactions iii. This is an aerobic process —it requires oxygen iv. OVERALL EQUATION: (write it below) b. Oxidation-Reduction Reactions (review these types of reactions on page 103 of your textbook). i. Reactions transferring electrons from one molecule to another ii. Molecules that lose electrons are said to be oxidized iii. Molecules that gain electrons are said to be reduced iv. Movement of electrons is usually associated with movement of hydrogen atoms v. Look at the overall equation above: which molecule is oxidized and which is reduced during cellular respiration? c. Enzymes Involved i. Dehydrogenases - enzymes that catalyze redox reactions by removing hydrogen ii. Most require coenzymes that are able to accept and carry the electrons (electron carriers) 1. Nicotinamide adenine dinucleotide (NAD+) – derived from niacin 2. Flavin adenine dinucleotide (FAD) – derived from riboflavin 52 d. Three overall stages of cellular respiration i. Glycolysis ii. Krebs Cycle (a.k.a. Citric Acid Cycle) iii. Electron Transport Chain e. Mechanisms of ATP Synthesis i. Substrate-level phosphorylation 1. Enzymes transfer a phosphate group from a substrate to ADP 2. Occurs during glycolysis and Krebs cycle ii. Oxidative phosphorylation 1. The phosphorylation of ADP is powered by a series of redox reactions that transfer electrons from organic molecules to oxygen 2. Produces the majority of the ATP molecules 3. In electron transport system III. Stage 1: GLYCOLYSIS a. Overview i. Occurs in the cytoplasm ii. Does not require oxygen (anaerobic) iii. Six carbon glucose molecule is broken down into 2 three carbon molecules of pyruvic acid iv. Produces 2 net ATP and 2 NADH (electron carrier) v. See figure 2-11 in your textbook for reaction b. The Fate of Pyruvic Acid (see figure 2-16) i. Depends on the availability of oxygen ii. In aerobic conditions pyruvic acid is converted to acetyl-CoA and enters the Krebs cycle iii. In anaerobic conditions NADH + H+ reduces pyruvic acid to form lactic acid c. Lactic Acid Fermentation i. Produces 2 ATP per glucose (less efficient) ii. When oxygen becomes available again lactic acid is oxidized back to pyruvic acid and enters the Krebs cycle IV. Stage 1½ : TRANSITION a. Pyruvic acid enters the mitochondrial matrix through facilitated diffusion b. There it is converted to Acetyl-Coenzyme A to enter Krebs cycle c. 1 CO2 and 1 NADH is produced in this stage per pyruvate 53 V. Stage 2: KREBS CYCLE a. Overview i. Occurs in the matrix of the mitochondria ii. Requires oxygen (aerobic) iii. Completes the breakdown of glucose to CO2 and harvests the energy as: 1. 2 ATP 2. 6 NADH 3. 2 FADH2 (Numbers based on per one glucose molecule) b. Events (see figure 2-12): i. Acetate joins the four carbon compound oxaloacetate to form the 6 carbon compound citrate ii. 2 decarboxylation events release 2 CO 2 iii. Four oxidation events generate 3 NADH and 1 FADH2 iv. 1 molecule of ATP is formed via substrate-level phosphorylation VI. Stage 3: Electron Transport Chain a. The hydrogen being delivered to the ETC by the coenzymes are split into electrons and H+ ions b. Electrons from NADH and FADH2 are passed down a chain of protein complexes embedded in the inner membrane of the mitochondria c. Electrons fall to lower energy levels as they are passed down the chain (releases energy) d. Oxygen is the final electron acceptor e. The negative oxygen binds to 2 H+ to form water f. Chemiosmosis (see figure 2-13) i. The energy released by electrons moving down the chain is used to pump H+ from the matrix to the intermembrane space ii. This creates a proton gradient (potential energy) iii. This gradient drives protons back in through a protein called ATPsynthase iv. This creates kinetic energy that ATPsynthase harnesses to catalyze ADP + P ATP (oxidative-phosphorylation) VII. Metabolic pool concept: any organic molecule can be used in respiration a. Lipid Metabolism i. Lipolysis – the hydrolysis of triglycerides into glycerol and fatty acids 1. Catalyzed by the enzyme lipase 54 ii. The glycerol 1. is converted into glyceraldehyde phosphate a glycolysis intermediate 2. then enters into Krebs cycle 3. complete oxidation of glycerol yields 18 ATP molecules iii. The fatty acid chains 1. Are broken apart into 2 carbon acetic acid fragments (Betaoxidation) 2. Coenzyme A is attached to the acetic acid fragments forming Acetyl CoA 3. Enters the Krebs cycle 4. Complete oxidation yields ~54 ATP iv. Ketogenesis 1. If Acetyl CoA production exceeds the capacity of the Krebs cycle to process it, the liver will convert it to ketone bodies which are released into the blood 2. Ketones can be used as an energy source in skeletal and cardiac muscle a. Examples of ketones: acetoacetic acid, Bhydroxybutyric acid, acetone 3. Ketosis - an increase in circulating ketone bodies a. Occurs when lipids are the primary energy source (starvation and diabetes mellitus) b. May lead to ketoacidosis – decreased blood pH c. Depresses nervous system, may become comatose d. Compensatory response to ketosis: increased ventilation and large amounts of ketones excreted in urine b. Protein Metabolism i. Proteins are hydrolyzed into individual amino acids by proteases ii. Amino acids are deaminated in the liver (amine group is removed) iii. Amine group is removed as ammonia iv. Combined with CO2 to form urea which is excreted by the kidneys v. Generates organic acids which can be converted to glucose or enter Krebs cycle to be oxidized for energy 55 c. Glucose Synthesis i. Aerobic metabolism of glucose is the most efficient way for cells to make ATP ii. It is the primary source of energy in cells and normally the ONLY source neurons prefer iii. There is multiple metabolic pathways for producing glucose to ensure that there is a continuous supply for the brain iv. Synthesis of Glucose 1. Glycogenolysis – the breakdown of glycogen to glucose a. The liver and skeletal muscle contains high concentrations of glycogen 2. Gluconeogenesis - synthesis of glucose from noncarbohydrates a. Can start with glycerol, lactic acid or various amino acids b. Occurs in the liver and kidneys 56 Post-lecture Practice Cell Respiration Worksheet 1. Overall equation for cellular respiration: + What you eat. + What you inhale. What you exhale. + What your cells use for energy! 2. Fill out the table below to organize the main ideas of cellular metabolism. (Assume per glucose molecule for number of electron carriers and ATP): Aerobic or Anaerobic? Location in cell Starting Molecule Ending Molecules # of Electron Carriers made Number of ATP made Glycolysis Transition stage Krebs Cycle (citric acid cycle) Electron Transport Chain Fermentation 57 Cell Communication Study Objectives: 1. Describe the different mechanisms of cell communication: direct contact vs. extracellular messengers. 2. Compare and contrast paracrine, autocrine, neurotransmitters, hormonal, and neurohormonal communication. 3. Discuss the general mechanism of hormone action and list the effects they can have on cellular activity 4. Distinguish between lipid soluble and water soluble hormones. Describe how they are transported in the blood and the type of receptors they bind to at the target cells. 5. Define and give examples of secondary messengers. 6. Describe the general mechanism of the cyclic AMP signal transduction pathway. 7. Describe the general mechanism of the calcium signal transduction pathway. 58 Cell Communication Outline I. Types of Cellular Communication (See figure 4-20) a. Direct contact between cells i. Gap junctions – cells are connected by tunnels formed by connexons 1. Allows ions and small water soluble chemicals to pass between cells 2. Examples: cardiac and smooth muscle ii. Cell to cell recognition – interaction of cell-surface molecules 1. Example: immune cells – recognize self vs. non-self b. Through extracellular chemical messengers - cells release ligands that bind to receptors on target cells to initiate a desired cellular response i. Local regulators 1. Paracrine – through diffusion, ligands affect cells in the local vicinity a. Examples: histamine, cytokines, prostaglandins 2. Autocrine – chemicals act on the cell that produced it 3. Neurotransmitters – secreted by neurons a. Diffuse across the synaptic cleft and target the adjacent cell (neuron, gland, muscle) b. Short-lived ii. Long-range (distant) regulators 1. Hormones – secreted into the blood by endocrine glands to travel to distant target cells 2. Neurohormones – neurons secretes hormones into the blood II. Cellular Effects of Chemical Signals a. Example of various effects chemical signals may have on the target cell i. Activate or inhibit enzymes ii. Direct protein synthesis through activation of transcription factors iii. Stimulate cell division iv. Alter membrane permeability – membrane potential or opening/closing of ion channels 59 b. How do hormones work? i. Hormones are chemical substances that travel through the blood to a target cell ii. Target cells must have specific receptors to which the hormone binds iii. These receptors may be intracellular or located on the plasma membrane iv. They trigger a change in cellular activity c. Types of Hormones/Chemical Signals i. Amines – amino acid derivatives 1. Examples: catecholamines (NE and E), T3, T4, serotonin, melatonin ii. Peptides – proteins 1. Examples: vasopressin (ADH), insulin iii. Steroids – cholesterol based 1. Examples: cortisol, aldosterone, estrogen, testosterone iv. Eicosanoids –derived from arachidonic acid 1. Prostaglandins, leukotrienes d. Transport of Hormones i. Hydrophilic (water-soluble) hormones – transported dissolved in the plasma 1. Examples: peptide and catecholamines ii. Lipophilic (lipid-soluble) hormones – circulate bound to plasma proteins such as albumin 1. Examples: steroids and thyroid hormones e. Mechanism of Signaling Molecules i. Lipid soluble hormones (see figure 4-28) 1. Move through the plasma membrane and bind to an intracellular receptor in the nucleus 2. Binding of the hormone receptor complex to the DNA triggers transcription of a specific gene and the synthesis of a protein that initiates a cellular response ii. Water soluble hormones- utilize a membrane bound receptor 1. Binding of hormone causes a conformational change in the receptor 2. Affects of ligands binding to membrane bound receptors (see figure 4-22): a. Triggers the opening or closing of ion channels OR b. Transfers the signal to a secondary messenger within the cell which triggers a cascade of biochemical events 60 III. Signal Transduction a. Secondary Messenger Pathways i. Signaling pathways amplify the cells response to signals ii. G-protein linked receptor – spans the membrane and is associated with a G protein on the cytoplasmic side (see figure 422c) 1. Ligand binds to the receptor 2. Receptor then activates a G protein iii. G proteins are considered relay proteins that cycle between an inactive and active form b. Types of secondary messenger pathways i. Cyclic AMP Secondary Messenger Pathway (see figure 4-25) 1. G protein activates the enzyme adenylyl cyclase (the effector) 2. Converts ATP to cyclic AMP 3. Activates protein kinase A which phosphorylates other proteins 4. Trigger cellular responses ii. Calcium Secondary Messenger Pathway (see figure 4-26) 1. Binding of extracellular messenger to a G protein linked receptor or a tyrosine kinase receptor 2. Activates phospholipase C which converts PIP2 to DAG and IP3 3. DAG will activate protein kinase C in another signaling pathway 4. IP3 binds to calcium channels triggering the release of calcium from the ER into the cytoplasm 5. Calcium binds to and activates calmodulin which can alter other proteins to bring about a cellular response 61 Cell Communication Post-lecture Practice 1. When a ligand triggers a secondary messenger pathway a cascade of events occurs. Place the following events of the calcium signaling pathway in the proper sequence 1 being the first event and 9 being the last. _____ IP3 binds to an IP3 receptor on the smooth endoplasmic reticulum _____ G-protein is activated _____ the effector phospolipase C is activated _____ ligand binds to G-linked protein receptor _____ calcium is released from the smooth ER and dumped into the cytosol _____ transcription factors are activated _____ cellular response occurs _____calcium activates calmodulin _____ PIP2 is converted into DAG and IP3 2. Categorize the following signaling molecules as local regulators or distant regulators: Chemical signaling through gap junctions Paracrine Neurotransmitters Hormones Neurohormones Cell to cell recognition Autocrine 62 Neurophysiology Study Objectives: 1. Describe the functions of the nervous system. 2. List the types of neuroglia and describe their general functions. 3. Describe the general anatomical structure of a neuron and their function: cell body, dendrites, axon hillock, axon, telodendrites, axon terminals, Schwann cells, and nodes of Ranvier 4. Classify neurons according to function: afferent, efferent, and interneuron 5. Define resting membrane potential and describe its electrochemical basis. 6. Define depolarization, threshold potential, repolarization, and hyperpolarization. 7. Compare ligand gated, voltage gated, and leaky channels. 8. Compare and contrast graded potentials and action potentials 9. Explain how action potentials are generated and propagated along axons. 10. Distinguish between absolute and relative refractory periods 11. Describe the structure and function of a synapse: presynaptic neurons, synaptic cleft, and postsynaptic neurons. 12. Describe the transmission of an impulse across a synapse. 13. Distinguish between how excitatory and inhibitory postsynaptic potentials are generated. 14. Define presynaptic inhibition and presynaptic facilitation. 15. Define temporal summation and spatial summation. 16. Describe how neurotransmitters can be inactivated. 17. Identify factors that influence the speed of a nerve impulse and define salutatory conduction. 18. Categorize neurotransmitters by chemical structure, function, and receptor mechanism. 19. Define types of neural circuits. 63 Neurophysiology Outline I. The Nervous System a. The master controlling and communicating system of the body b. Cells communicate by electrical signals that are rapid and cause immediate responses c. Functions i. Sensory input – monitoring stimuli occurring inside and outside the body ii. Integration – interpretation of sensory input iii. Motor output – response to stimuli by activating effector organs d. Overall Organization i. The two principal cell types of the nervous system are: 1. Neuroglial – cells that surround and support neurons. (descriptions found in figure 5.3 and table 5.1 of your textbook) a. Oligodendrocytes b. Astrocytes c. Ependymal cells d. Microglia e. Schwann cells f. Satellite cells 2. Neurons – excitable cells that transmit electrical signals a. Anatomy of Neurons i. Cell body – contains nucleus and organelles ii. Dendrites – branching extensions 1. Receptive to neurotransmitters from pre synaptic neurons and transmit graded potential towards cell body iii. Axon hillock – where cell body tapers into the axon, site where action potential originate iv. Axon – single process extending from the cell body, transmits action potential away from cell body v. Myelin sheath – formed by schwann cells wrapping around the axon resulting in concentric layers of plasma membrane vi. Nodes of Ranvier – gaps in the myelin sheath vii. Telodendrites – distant branches of the axon viii. Axon terminals – enlarged distal ends containing secretory vesicles filled with neurotransmitters 64 b. Synapses – junctions between neurons (see figure 4-14 and 4-15) i. Function as a control or decision point since they can be excitatory or inhibitory ii. Occurs between axon terminals and a cell body, dendrite, axon hillock, muscle or gland iii. Structure of chemical synapse 1. Presynaptic neuron – transmits impulse towards the synapse, axon terminal with vesicles containing neurotransmitters 2. Synaptic cleft – fluid filled space between pre and post synaptic neuron 3. Postsynaptic neuron - transmits impulse away from synapse, contains receptors for neurotransmitters II. Neurophysiology a. Principles of Electricity i. Electricity = when opposite charges are separated they contain potential energy and when they come together energy is released ii. In cells, the separation of charges by the plasma membrane is referred to as the “membrane potential” iii. Voltage – the measurement of potential energy created by charge separation 1. In neurons voltage is measured in millivolts (1 mV = 1/1000 V) 2. The voltage depends on the quantity of charges and the distance between the charges * More information on the general principles of electricity and the resting membrane potential can be found in Chapter 3 pages 79-86. b. Types of Ion Channels found in Neurons i. Ligand-gated channels – chemically gated, open when neurotransmitters bind. Found on dendrites, cell bodies, and axon hillocks ii. Mechanically gated channels – open in response to physical forces iii. Voltage-gated channels – open or close in response to changes in membrane potential. Found along axon iv. Leaky channels – always open, non-gated, found everywhere 65 c. Membrane Potentials i. Resting Membrane Potential – potential difference across the membrane in a resting neuron (-70mV) 1. Chemical gradient – higher concentration of Na+ in the extracellular fluid and a higher concentration of K+ in the intracellular fluid 2. Electrical gradient – the inside of the membrane is negatively charged and the outside is slightly positive 3. Factors contributing to the resting membrane potential a. Membrane is 50 – 75X more permeable to K+ so K+ ions leak out faster than Na+ leak in b. Intracellular proteins - fixed anions inside the cell c. Sodium-Potassium pump maintains the gradient – 3 Na+ out for every 2 K+ in 4. Stimuli will trigger a disruption in RMP ii. Graded potential – a localized change in membrane potential (see figure 4-2 and 4-3 in your textbook) 1. Short lived and dissipates as it travels 2. Can be stimulated by neurotransmitters binding to ligand gated channels, mechanical stress, or temperature change 3. Examples: receptor potentials, post-synaptic potentials, motor-end plate potentials 4. If the stimulus is excitatory it will cause depolarization of the membrane 5. Magnitude of the stimuli depends on how many Na+ channels open a. This determines the distance that the graded potential will travel b. Magnitude and duration depends on: i. Frequency of stimuli – summation ii. Amplitude of stimuli – strength iii. Depolarization – the membrane potential becomes less negative 1. When neurons are stimulated Na+ channels open and Na+ rushes into the cell down its electrochemical gradient iv. Threshold potential = -55mV the critical level the membrane potential must reach to open voltage-gated Na+ channels on the axon to produce an action potential 1. Strong graded potentials can initiate action potentials if the threshold potential is reached at the trigger zone (axon hillock) 66 v. Action Potential – brief reversal of the membrane potential (see figures 4-4 and 4-7) 1. Propagated away from the cell body down the entire length of the axon without diminishing (all or none) 2. Wave of depolarization followed by repolarization 3. Frequency of axon potentials increases to reflect stronger stimuli vi. Repolarization - the membrane returns to its resting membrane potential 1. Voltage gated Na+ channels close 2. Voltage gated K+ channels fully open and K+ efflux restores the resting membrane potential 3. Membrane potential becomes more negative as K+ rushes out vii. Hyperpolarization - the inside of the membrane becomes more negative than the resting potential 1. Voltage gated K+ channels are sluggish to close 2. K+ permeability lasts longer and membrane potential dips below resting potential viii. Restoring the Resting Membrane Potential: 1. Repolarization restores the electrical gradient 2. Na/K pump restores resting ionic concentrations d. Refractory Period - amount of time required for a neuron to generate another action potential i. Absolute Refractory Period - when another AP cannot be generated (See figure 4-10) 1. From the opening of the Na+ activation gates until the resetting of the activation gates 2. Ensures that each action potential is separate 3. Enforces one-way transmission of nerve impulses ii. Relative Refractory Period (See figure 4-11) 1. The interval following the absolute refractory period 2. Threshold is raised so only exceptionally strong stimuli will trigger another action potential : a. Sodium gates are reset b. Potassium gates are still open c. Hyperpolarization is still occurring 67 e. Factors Influencing Conduction Velocity i. Myelination of axon – increases impulse rate by acting as an insulator preventing charge leakage 1. Saltatory conduction – voltage gated channels are concentrated at the nodes so electrical impulses jump from node to node instead of having to travel down the entire axon (see figure 4-13) ii. Diameter of the axon – the larger the diameter the quicker the impulse travels, less resistance to current flow so adjacent membranes depolarize quicker iii. Alcohol, sedatives, and anesthetics – slow or block nerve impulses by reducing permeability to Na+. iv. Insufficient blood flow – slows impulses, caused by cold or pressure f. Transmission Across the Synapse (see figure 4-15) i. Action potential reaches the axon terminal ii. Voltage-gated Ca2+ channels open and Ca2+ floods into the terminal iii. Synaptic vesicles fuse with the plasma membrane and release neurotransmitters into the synaptic cleft iv. Neurotransmitters diffuse across the synaptic cleft and bind to receptors on chemical gated channels initiating a postsynaptic potential g. Neurotransmitter effects on Postsynaptic Potentials i. Binding of neurotransmitters cause a graded potential (localized change in the membrane) ii. Depending on how the neurotransmitter affects the membrane potential determines if it will excite or inhibit the postsynaptic neuron iii. Types of Postsynaptic Potentials (graded potentials) 1. Excitatory postsynaptic potentials (EPSP) – binding of neurotransmitter opens Na+ channels and causes depolarization (See figure 4-16a) a. Membrane potential becomes less negative and closer to reaching threshold potential therefore closer to firing an action potential 68 2. Inhibitory Postsynaptic Potentials (IPSP) – binding of neurotransmitters cause hyperpolarization of the membrane therefore moving away from threshold and reducing the ability to initiate an action potential (See figure 4-16b) a. Causes K+ or Cl- channels to open b. K+ rushes out or Cl- rushes in, both causing the inside to become more negative iv. Summation - a single EPSP cannot induce an action potential but they can be summed. The axon hillock keeps score of all graded potentials received (See figure 4-17) 1. Temporal summation – a presynaptic neuron increases the frequency of impulses and more neurotransmitters are released in quick succession 2. Spatial summation – postsynaptic neuron is stimulated by multiple presynaptic neurons at the same time 3. IPSPs and EPSPs can also be summed and cancel each other out 4. Modulator Neurons -the effectiveness of the presynaptic input can be affected by another neuron (see neuron B in figure 4-18). Allows for the selective inhibiting/enhancing of a specific presynaptic neuron without affecting the input from other neurons or effecting all targets a. Presynaptic inhibition – the amount of neurotransmitter released from neuron “A” is decreased by neuron “B” b. Presynaptic facilitation – the amount of neurotransmitter released from neuron “A” is enhanced by neuron “B” v. Effects of Neurotransmitters 1. Neurotransmitter receptors mediate changes in membrane potential according to: a. The amount of neurotransmitter released b. The amount of time the neurotransmitter is bound to receptors c. Neurotransmitters will affect the membrane potential as long as they are bound so they must be deactivated 69 vi. Mechanisms for deactivation of neurotransmitters 1. Inactivated by enzymes a. Example: Acetylcholine b. Degraded by the enzyme acetylcholinesterase found in the synaptic cleft i. Ach Acetate + Choline c. Choline is actively transported back into the presynaptic terminal and recycled i. Choline + acetyl CoA Ach 2. Reuptake by presynaptic axon terminals or astrocytes a. Examples: Norepinephrine, dopamine, serotonin b. Taken back up by presynaptic terminal c. Repackaged or broken down by monoamine oxidase (MAO) d. Catechol-O-methytransferase is used by liver and kidney cells to break down NE & E in the circulation 3. Diffuse away from synapse h. Classification of Neurotransmitters by Chemical Structure i. Acetylcholine (ACh) ii. Biogenic amines – catecholamines, serotonin iii. Amino acids – glutamate, glycine, GABA iv. Peptides – endorphins, substance P v. Messengers: ATP and dissolved gases NO i. Classification of Neurotransmitters by Function i. Excitatory neurotransmitters (e.g., glutamate) ii. Inhibitory neurotransmitters (e.g., GABA and glycine) iii. Some neurotransmitters have both excitatory and inhibitory effects 1. Determined by the receptor type of the postsynaptic neuron 2. Example: acetylcholine a. Excitatory at neuromuscular junctions with skeletal muscle (nicotinic receptor) b. Inhibitory in cardiac muscle (muscarinic receptor) j. Classification of Neurotransmitters by Receptor Mechanisms i. Direct: neurotransmitters that open ion channels 1. Promote rapid responses “fast synapses” 2. Examples: ACh and amino acids ii. Indirect: neurotransmitters that act through second messengers 1. Promote long-lasting effects, “slow synapses” 2. Examples: biogenic amines, peptides, and dissolved gases 70 k. Types of Circuits in Neuronal Pools (See figure 4-19) i. Divergent – one incoming fiber stimulates ever increasing number of fibers, often amplifying circuits ii. Convergent – opposite of divergent circuits, resulting in either strong stimulation or inhibition iii. Reverberating – chain of neurons containing collateral synapses with previous neurons in the chain iv. Parallel after-discharge – incoming neurons stimulate several neurons in parallel arrays 71 Neurophysiology Post-lecture Practice 1. Which type of neuroglial cell forms the myelin sheath in the central nervous system? a. astrocytes b. Schwann cells c. oligodendrocytes d. microglial e. ependymal 2. Depolarization: a. Results in a negative charge on the inside of the cell, positive on the outside b. Involves sodium ions flooding into the cell causing the membrane potential to become less negative c. Involves potassium ions flooding out of the cell causing the membrane potential to become more negative d. Triggers hyperpolarization 3. A change in a membrane potential from +30 mV to – 70 mV is an example of: a. Repolarization b. Depolarization c. Hyperpolarization d. Absolute refractory 4. When an action potential arrives at the axon terminals: a. Is weaker than it was when it originated at the axon hillock b. It causes the release of neurotransmitters from synaptic vesicles into the synaptic cleft c. Causes potassium (K+) channels to open d. Turns into a graded potential 5. Explain the events that are involved in the conduction of a nerve impulse. In your answer, include the events involved in the generation of an EPSP graded potential, the propagation of an action potential and how transmission across the synapse occurs. 6. Explain the events that happen during an IPSP and how this decreases the chance of a neuron generating and action potential. 72 Sensory Physiology Study Objectives: 1. Describe the organization of the afferent sensory division. 2. Describe the different types of somatic receptors and the type of stimuli they detect: types of free nerve endings, mechanoreceptors, chemoreceptors 3. Define sensation, perception, adequate stimulus, and law of specific nerve energies. 4. Compare receptor potential and generator potential. 5. Compare and contrast tonic and phasic receptors. 6. Discuss cortical processing of sensory information and perception of stimuli. Coding of sensory stimuli Determining type, location, intensity, and duration of stimuli 7. Distinguish between fast and slow pain pathways. 8. List the chemicals that stimulate the pain pathways. 9. List the two neurotransmitters involved in the pain pathway. 10. Describe the analgesic pathway and the role of endorphins. 73 Sensory Physiology Outline I. Sensory a. Function – specialized cells that monitor internal and external conditions b. Two types of senses: i. General – receptors are distributed throughout the body 1. Afferent impulses are sent to the somatosensory cortex ii. Special – receptors are concentrated in sense organs 1. Afferent impulses are sent to special sense cortexes c. Afferent (sensory) division – carries sensory info from receptors to the CNS i. Somatic afferent fibers – carries impulses from skin, skeletal muscles and joints ii. Visceral afferent fibers – carries impulses from organs within ventral body cavities iii. Special sense afferent fibers – eyes, ears, taste, smell d. Anatomy of Sensory Neurons i. Pseudounipolar neuron 1. Cell body lies in the dorsal root ganglia 2. Action potential is initiated at the peripheral end of the neuron II. Sensory Receptors - found on the peripheral end of sensory neurons. Act as transducers to change an incoming stimulus of one type into an electrical impulse. a. Adequate stimulus - receptors are specific for the type of stimulus it is sensitive to and can transduce b. Receptors can respond to other types of stimuli if strong enough c. “Law of Specific Nerve Energies” – regardless of the type of stimulus the sensation is perceived as what the receptor is specific for d. Sensory Transduction (See figure 6-1) i. A stimulus alters the membrane permeability of the receptor. This leads to the production of a graded receptor potential ii. Receptors that are modified endings of the afferent neuron produce generator potentials iii. Receptors that are separate cells from the afferent neuron produce receptor potentials iv. Release chemicals that open ligand gated channels on the afferent neuron 74 e. Types of Receptors: i. Free nerve endings 1. Nociceptors – activation causes the sensation of pain a. Free nerve endings found in the skin, joints, bones, and blood vessels b. Sensitive to chemicals, tissue damage, and extreme temperatures 2. Themoreceptors – react to changes in temperature a. Free nerve endings in the dermis, hypothalamus, and liver b. You have 3X more cold receptors than warm receptors ii. Mechanoreceptors – stimulated by physical change such as pressure or movement 1. Merkel cells – cells in the stratum basale associated with free nerve endings, detect fine touch 2. Hair root plexus – free nerve endings associated with hair follicles, detect movement of hair 3. Meissner’s corpuscles –detect touch, found in dermal papillae 4. Ruffini corpuscles – sensitive to stretch and distortion, found in the dermis 5. Pacinian corpuscles – deep pressure receptors found in the dermis (See figure 6-5 for an illustration of all the mechanoreceptors described above) 6. Baroreceptors – sensitive to internal pressures. Monitors blood pressure in vessels (carotid sinus and aorta), lungs, bladder, intestines 7. Proprioceptors – monitors position and stretch of muscles, tendons, ligaments, and joint capsules. Helps maintain posture and sense of body position iii. Chemoreceptors – detect chemicals dissolved in solution. Olfactory, taste, osmolarity, pH, CO2, O2 75 III. Organization of the Somatosensory System a. Ascending tracts – a bundle of axons transmitting impulses towards the brain. Usually involves three successive neurons (three levels of processing) (See figure 5-28): i. Receptor level - Primary neuron running from the receptor to the posterior horn of the spinal cord or medullary nuclei ii. Circuit level – Secondary neuron synapses with the first and transmit impulses to the thalamus iii. Perception level – Tertiary neuron running from the thalamus to the primary somatosensory cortex or a special senses cortex. The cerebral cortex is responsible for: 1. Sensation - the awareness of the stimuli 2. Perception – the interpretation of the stimuli b. Each sensory fiber is a “labeled line” - the type, location, strength, and the intensity of the stimuli is encoded in the area of the cortex it travels to and the frequency of the impulse i. Determining type of stimulus or receptor activated 1. Depends on the pathway it takes and the area of the cerebral cortex it travels to 2. The area of the cortex devoted to each region is related to the regions sensitivity (# of receptors) 3. Messing with perception: a. Referred pain (defined in chapter 5 pg 178) - some visceral pathways are shared with somatosensory so the brain perceived it as the more frequently stimulated pathway b. Phantom pain – caused by nerve endings are irritated or remodeling of the cortex ii. Localization of the stimulus 1. Also based on area of cerebral cortex (See figure 5-11b) 2. Accuracy of localization depends on the size of the receptor field. The smaller the receptor field the more accurate. (See figure 6-6) 3. Accuracy also depends on lateral inhibition. Only the most intensely stimulated pathway is excited. Less excited pathways surrounding the stimulated area are inhibited. (See figure 6-7) 76 iii. Intensity of the stimulus 1. Number of receptors stimulated – stronger stimuli usually affect larger areas 2. Frequency of action potentials – stronger stimuli generate larger receptor potential, therefore a greater frequency of action potentials (see figure 6-3) iv. Duration of the stimulus 1. Adaptation – receptors change their sensitivity in the presence of constant stimulus (See figure 6-4) a. Phasic receptors – fast adapting i. Report changes in the environment ii. Burst of firing at the beginning and end of stimulus iii. Examples: temperature, smell, touch b. Tonic receptors – slow adapting or not at all i. Constant firing rate ii. For situations were continuous information about a stimulus is valuable iii. Examples: proprioceptors pain, muscle stretch IV. Pain a. The perception of pain is subjective b. Influenced by past and present experiences c. Unlike other senses pain is coupled with behavioral and emotional responses d. Types of pain pathways i. Fast pain pathways – myelinated 1. Immediate sharp pain 2. Easy to localize ii. Slow pain pathways – unmyelinated 1. Dull aching pain 2. Persists longer and hard to localize e. What stimulates the pain pathways? i. Nociceptors are sensitized to stimuli by chemicals released in damaged tissues 1. Prostaglandins – which are inhibited by aspirin 2. Bradykinins –chemicals activated by enzymes released by damaged tissue 3. Histamine – triggers itching 4. Capsaicin – chemical in chili peppers, stimulates pain and thermoreceptors 77 ii. Primary neuron releases neurotransmitter substance P or glutamate to stimulate ascending pathway. Carried to the thalamus then to the somatosensory cortex for perception. Also sent to the reticular formation which increases level of alertness and the hypothalamus (limbic system) which triggers behavioral and emotional responses to pain (See figure 6-9a) iii. Analgesic Pathway (See figure 6-9b) 1. The CNS has a descending analgesic pathway that can inhibit the pain pathway 2. By presynaptic inhibition, the release of endorphins or enkephalins blocks the release of substance P 3. Endorphins bind to opiate receptors on the axon terminal and block the release of substance P 4. Morphine binds to these opiate receptors to inhibit pain f. Gate control theory (See figure in PowerPoint lecture) 78 Sensory Post-lecture Practice 1. Proprioreceptors monitor: A. limb and muscle position B. taste perception C. arterial blood pressure D. A and C 2. The intensity of a sensory stimulus is coded by _____. A. the amplitude of action potentials B. which receptors are activated C. the frequency of action potentials D. the duration of each action potential E. how rapidly the receptor adapts 3. Primary sensory neurons and secondary sensory neurons would synapse with each other in the: A. Spinal cord B. Brain stem C. Thalamus D. Cerebral cortex E. Either A or B 4. Tonic receptors are: A. fast adapting B. slow adapting C. fire rapidly and then stop firing even in the presence of constant stimulus D. touch receptor E. both A and D 5. The descending analgesic pathway can inhibit the pain pathway by releasing: A. substance P B. glutamate C. prostaglandins D. endorphins E. histamine 79 Central Nervous System Study Objectives: 1. Identify the major brain regions: cerebral hemispheres, diencephalon, brain stem, and cerebellum 2. Describe the structure, function, and location of the three meningeal layers 3. Describe the functions of cerebrospinal fluid 4. Explain the role of the blood brain barrier in protecting the brain 5. List the major lobes and functional areas of the cerebral cortex 6. Define gray and white matter and describe their locations in the CNS 7. Define the types of tracts: projection, association (arcuate), and commissural 8. Explain the general roles of the limbic system 9. Distinguish between short term and long term memories. Describe the factors that affect the transfer of short term to long term memory. 10. Compare and contrast declarative and procedural memory. 11. Define long term potentiation and describe how they modify synapses during memory formation. 12. Describe the function of the reticular formation systems. List factor that activate or inhibit it. 13. Describe the stages of sleep: NREM and REM 14. Define dynamic equilibrium and circadian rhythms. 15. Discuss the cause and effect of desynchronosis. 16. Describe the general structure and main functions of the following regions: medulla oblongata, pons, midbrain, cerebellum, thalamus, and hypothalamus 80 Central Nervous System Outline I. Overall organization of the central nervous system (CNS) a. Central Nervous system – integration and command center i. Brain ii. Spinal cord b. Neural Tissue Organization i. Gray matter – non-myelinated material (cell bodies, dendrites, telodendrites) 1. Nuclei – in the CNS 2. Ganglia – in the PNS ii. White matter – myelinated axons 1. Nerves – bundles of axons in the PNS 2. Tracts – axons in the CNS a. Types Of Tracts - axons running to or from i. Projection – vertical tracts, responsible for the communication between the cerebral cortex and lower CNS ii. Association (arcuate) – connect gyri within the same cerebral hemisphere iii. Commissural – connects gyri between left and right hemispheres c. Protection of CNS i. Bones of the skull and vertebral column ii. Meninges – three CT membranes surrounding the brain 1. Dura Mater – superficial layer, consists of two layers of fibrous CT 2. Arachnoid Mater – loose middle layer 3. Pia Mater – deepest, clings tightly to the brain following every convolution. iii. Cerebrospinal fluid -found in the ventricles and the subarachnoid space around the brain and spinal cord 1. Gives buoyancy to the brain and spinal cord – keeps it from being damaged by its own weight 2. Cushions and protects 3. Transports materials 81 iv. Blood Brain Barrier - capillaries are less permeable due to tight junctions between endothelial cells and between astrocytes 1. Helps maintain a constant environment for the brain 2. Very selective- fat soluble materials, glucose, and select ions and amino acids are allowed to pass, others are not d. Metabolic Requirements of the CNS i. Neurons rely on a constant supply of oxygen and glucose to produce ATP for active transport of ions and neurotransmitters. ii. Oxygen diffuses across the BBB iii. Under normal circumstances glucose is the only energy source for neurons iv. Glucose is transported from the plasma into the interstitial fluid by insulin independent membrane transporters v. Hypoglycemia leads to confusion, unconsciousness and death e. Regions Of CNS (See table 5-2) i. Cerebrum – integration of sensory/motor, higher functions ii. Diencephalon – innate drives and emotions 1. Epithalamus 2. Thalamus 3. Hypothalamus iii. Cerebellum iv. Brainstem –basic functions to maintain life 1. Midbrain 2. Pons 3. Medulla oblongata v. Spinal cord – reflexes II. Cerebrum a. Structure (Anatomy Review) i. Right and Left cerebral hemispheres – divided by longitudinal fissure and connected by the corpus callosum ii. Cerebral cortex is the outer gray matter iii. Inner region is white matter with basal nuclei (gray matter) iv. Lobes of the Cerebrum (see figure 5-9) 1. Frontal 2. Parietal – central sulcus separates frontal and parietal 3. Temporal – outlined by lateral sulcus 4. Occipital 5. Insula – deep to the temporal lobe 82 b. Plasticity of the Brain i. The architecture of the cortex is determined by genetic and developmental processes but it can be modified due to “usedependent competition” for cortical space ii. Formation of new neural pathways and connections between existing neurons iii. Some cortical regions can be remodeled throughout life while other can be for only a limited time c. Functional Areas of the Cortex i. Sensory areas – process afferent impulses, interpret sensations ii. Motor areas – involved in planning and initiating muscular movement iii. Association areas – involve combining information from multiple areas and processing them together, involved in higher functions d. Sensory areas of the cerebral cortex i. Primary somatosensory area – postcentral gyrus in the parietal lobe. Receives impulses involved in touch, pain, pressure, stretch ii. Somatosensory association – integrates sensory input into understanding by analyzing sensory based on past experiences. Lies posteriorly to primary somatosensory iii. Primary visual cortex – receives sensory input from the retina to the occipital lobe. Data only. iv. Visual association area – interprets the raw data and puts it into context. Surrounds the primary. v. Primary auditory – receives sensory input from the vestibulocochlear nerve. Temporal lobe. vi. Auditory association area – lies posterior to primary, interprets sound into context vii. Olfactory cortex –found on medial aspect of temporal lobe. Sensory input from olfactory nerves. Linked limbic system – tied to emotions and memories viii. Gustatory cortex – perception of taste, found in the insula e. Motor areas of the cerebrum i. Primary motor cortex – controls somatic motor neuron output. Lies in the precentral gyrus of the frontal lobe 1. Output is usually controlled by higher motor areas and input from the cerebellum 2. Amount of cortex devoted to each area relates to which regions have the most precise control. 3. Control is contra lateral 83 ii. Premotor cortex – anterior to the primary motor cortex in the frontal lobe. Responsible for coordinating learned motor skills 1. Examples: typing, driving, playing the piano iii. Basal Nuclei (basal ganglia) 1. Adjust the stopping, starting and intensity of movements after receiving input from cerebral cortex and substantia nigra (midbrain) 2. Lesions of nuclei lead to increase motor output leading to increased muscle tone, difficulty initiating movement, and involuntary muscle movement f. Other association areas of the cerebrum i. Prefrontal cortex – involved with intellect, recall, reasoning, judgment, concern for others, personality traits, and management of emotions 1. Develops later in life and is impacted by social environment 2. Linked to emotions (limbic system) ii. Language areas – surrounds lateral sulcus in the left hemisphere only. Receives input from auditory and visual senses. Coordinates with the motor cortex to carry out motor skills involved in speech and writing. (see figure 5-12) 1. Language involves both expression and comprehension 2. Two cortical areas specializing in language are: a. Wernicke’s area – language comprehension and formulation of coherent patterns of speech b. Broca’s area – speech production and word formation, associated with motor cortex g. Cerebral lateralization - distribution of functional areas are not always symmetrical. h. Limbic system – emotional brain, consists of tracts and nuclei of the medial cerebrum, anterior thalamus, and hypothalamus 1. Functions: a. Establishes emotional state and behavioral drive b. Linked to prefrontal cortex, sometimes logic overrides emotion or vice versa c. Long term memory storage and retrieval 84 2. Limbic system structures (see figure 5-16) a. Amygdala – recognizes angry or fearful expressions and assesses danger b. Cingulate gyrus – role in expressing emotion and resolving mental conflicts c. Hippocampus – role in memory along with amygdale 3. Emotions can influence physiological functions ii. Memory - is the storage and retrieval of information 1. The three principles of memory are: a. Storage – occurs in stages and is continually changing (stored in regions that need them) b. Processing – accomplished by the hippocampus and surrounding structures c. Memory traces – chemical or structural changes that encode memory 2. Stages of Memory - short-term memory and long-term memory a. Short-term memory (working memory) i. STM lasts seconds to hours and is limited to 7 or 8 pieces of information ii. Only 5% of sensory input is transferred to STM b. Long-term memory (LTM) has limitless capacity i. Factors that affect transfer of memory from STM to LTM include: 1. Emotional state – we learn best when we are alert, motivated, and aroused 2. Rehearsal – repeating or rehearsing material enhances memory 3. Association – associating new information with old memories in LTM enhances memory 4. Automatic memory – subconscious information stored in LTM 85 3. Two categories of memory a. Fact (declarative) memory: i. Entails learning explicit information (names, dates) ii. Is related to our conscious thoughts and our language ability iii. Is stored with the context in which it was learned b. Skill (procedural) Memory i. Is less conscious than fact memory and involves motor activity (example: riding a bike) ii. It is acquired through practice iii. Skill memories do not retain the context in which they were learned iv. Hard to unlearn v. Stored in the premotor cortex 4. How Memories are Formed a. Long-term potentiation (LTP) - prolonged increase in synaptic strength (See figure 5-18) i. Repetitive stimulation results in modification of synapses that increase the ability of pre-synaptic neurons to stimulate post-synaptic neurons ii. Necessary for memory trace formation b. Aspects of Long-term potentiation i. Synaptic modifications that can occur as a result of LTPs ii. Number and size of presynaptic terminals may increase iii. More neurotransmitter is released by presynaptic neurons iv. Dendritic spines change shape v. Extracellular proteins are deposited at synapses 86 III. Diencephalon (see figure 5-15) a. Thalamus – forms lateral walls of the 3rd ventricle i. Acts as a relay station for all incoming sensory impulses except olfactory ii. Screens sensory impulses and decides if it should be passed onto the cortex and where it should be sent iii. Crude awareness of sensation b. Hypothalamus – slightly anterior and inferior to the thalamus. Important in maintaining body homeostasis i. Functions 1. Autonomic control center – controls ANS centers in the brain stem and spinal cord, BP, HR, digestive tract, respiration rate, pupil size 2. Emotions – heart of limbic system, basic primitive drives such as fear, anger, pleasure 3. Regulates body temperature – thermostat, initiates cooling or heating mechanisms 4. Sleep-wake cycles – acts with pineal gland to set cycles in response to light and dark 5. Food intake – responds to changes in levels of nutrients and hormones. Contains satiety and feeding centers. 6. Water balance and thirst – osmoreceptors that detect concentrations of body fluids, triggers anti-diuretic hormone (ADH) and thirst centers 7. Hormones - produces releasing or inhibiting factors which controls the release of hormones from the anterior pituitary. Produces posterior pituitary hormones, ADH and oxytocin IV. Brain Stem a. Midbrain – superior portion of the brain stem i. Corpora quadrigemina – four protrusions on the dorsal surface, contain sensory nuclei 1. Superior colliculi – visual reflexes 2. Inferior colliculi – auditory reflexes ii. Substantia nigra – axons linked to cerebral basal nuclei, release dopamine, controls motor output. Degeneration of these neurons causes Parkinson’s disease b. Pons – bulging region between midbrain and medulla, anterior to cerebellum i. Pontine nuclei – relay station for tracts between motor cortex and cerebellum ii. Pneumotaxic and apneustic respiratory center – works with medulla to maintain rhythmic breathing 87 c. Medulla Oblongata – base of brain stem, blends inferiorly with the spinal cord i. Pyramids – longitudinal ridges on the ventral surface. Contains motor tracts that cross over (decussation) before they continue down the spinal cord ii. Autonomic Nuclei 1. Cardiovascular center – adjusts force and rate of heart contraction and blood pressure 2. Respiratory center – controls rate and depth of breathing, works with pons for rhythm 3. Vomiting, swallowing, coughing, sneezing, hiccups d. Reticular Formation – loose cluster of neurons extending through the brain stem to the thalamus, hypothalamus, cerebellum and spinal cord. Responsible for the arousal (alertness) of the brain i. Reticular Activation System (RAS) - neurons sending constant impulses to the cortex via the thalamus to keep the cortex conscious and alert. (See figure 5-21) 1. Inhibited by the hypothalamus sleep center, adenosine, alcohol, and tranquilizers 2. Damage suffered by a jolt to the brain stem may result in permanent unconsciousness (coma) V. Types of Sleep a. There are two major types of sleep i. Slow-wave or non-rapid eye movement (NREM) ii. Paradoxical or rapid eye movement (REM) b. One passes through four stages of NREM during the first 30-45 minutes of sleep c. REM sleep occurs after the fourth NREM stage has been achieved d. A typical sleep pattern alternates between REM and NREM sleep e. Characteristics of REM sleep i. Vital signs increase ii. Neuronal activity is high iii. Skeletal muscles (except ocular muscles) are inhibited iv. Most dreaming takes place f. Sleep Patterns i. Alternating cycles of sleep and wakefulness reflect a natural circadian rhythm ii. The suprachiasmatic and preoptic nuclei of the hypothalamus regulate the sleep cycle iii. Adenosine appears to be a sleep inducing chemical that accumulates in the brain 1. Inhibits RAS neurons 2. Caffeine blocks adenosine receptors 88 g. Importance of Sleep i. NREM sleep is presumed to be the restorative stage ii. REM sleep may be a reverse learning process where superfluous information is purged from the brain (one hypothesis) iii. Those deprived of REM sleep become moody and depressed iv. Daily sleep requirements decline with age h. Sleep Disorders i. Narcolepsy – lapsing abruptly into REM sleep from the awake state ii. Insomnia – chronic inability to obtain the amount or quality of sleep needed iii. Sleep apnea – temporary cessation of breathing during sleep VI. Physiological Rhythms (See chapter 18 pgs. 679 - 682) a. Dynamic Equilibrium – variables are continuously fluctuating within their narrow limits i. These fluctuations tend to be in wave patterns called biorhythms ii. If they fluctuate in a cycle every 24 hours they are referred to as circadian rhythms iii. Controlled by the suprachiasmatic nucleus (SCN) in the hypothalamus b. List examples of Circadian Rhythms given in lecture: c. Suprachiasmatic Nucleus (see figure 18-13) i. Secretes clock proteins. ii. Cyclic changes in their concentration throughout the day changes the neural output from the SCN. iii. This neural output produce cyclic changes in effector organs through the day iv. The SCN cycle is a little longer than 24 hours v. Internal clock must be reset daily by external cues in order to stay in sync. 1. Light and dark cycle 2. Melatonin secreted from the pineal gland keeps the SCN in tune with the environment and regulates sleep/wake cycles 89 d. Desynchronosis – internal clock is out of synchronization with the external environment i. Jet lag, work rotations, change in sleep schedule 1. Effects: decreased cognitive function, depression, foggy head, can’t sleep or wake up ii. Seasonal affective disorder: depression during short winter days due to decreased sunlight 1. Can be treated with bright light or melatonin VII. Cerebellum (see figure 5-19) a. Maintains posture, balance, and plays a role in learning and executing skilled motor movements b. Body map – sensory and motor maps of the body so it is aware of what each skeletal muscle is doing c. Functions of the Cerebellum i. Monitors intended movements from the motor cortex and basal nuclei ii. Monitors current movements – receiving input from proprioceptors and the vestibule (equilibrium) iii. Compares intended movements, sensory input, and the actual movement and placement of muscles at that time iv. Sends corrective feedback to the upper motor centers if there is a discrepancy between the intended movement and the actual movement d. Ataxia- disruption of muscle coordination resulting in inaccurate movements i. Caused by damage to the cerebellum through trauma or genetic disease ii. Abnormal walking movements, uncoordinated speech, overshoot objects No Post-Lecture Practice for this lecture 90 Control of Body Movement Study Objectives: 1. Describe descending motor pathways 2. Distinguish between flaccid and spastic paralysis. 3. Define a reflex and list the components of the reflex arc. Distinguish between somatic and autonomic reflexes. Control of Body Movement Outline VIII. Motor Output a. Descending tracts – axons carrying motor commands from the brain to the PNS, majority are anterior and lateral, usually involve two neurons (See figure 5-28b) i. Upper neuron – extends from motor cortex or motor nuclei in the cerebrum to the anterior horn ii. Lower neuron – lie in anterior horn and travel to the effectors in the periphery b. Spinal Cord Trauma: Paralysis– loss of motor function i. Flaccid paralysis – severe damage to the ventral root or anterior horn cells 1. Lower motor neurons are damaged and impulses do not reach muscles 2. There is no voluntary or involuntary control of muscles ii. Spastic paralysis – only upper motor neurons of the primary motor cortex are damaged 1. Spinal neurons remain intact and muscles are stimulated irregularly 2. There is no voluntary control of muscles 3. Exaggerated reflexes 91 I. Reflexes – rapid predictable motor response to a stimulus a. Occur at the spinal cord or brain stem b. May be inborn or learned c. May be somatic or autonomic d. May be monosynaptic or polysynaptic e. Important clinically, exaggerated or absence of reflex responses may indicate neurological problems f. Reflex Activity i. Components of a reflex arc 1. Receptor – detects stimulus 2. Sensory neuron – relays info to CNS 3. Integration – may be monosynaptic or polysynaptic 4. Motor neuron – carries response away from the CNS to the effector 5. Effector – muscle or gland g. Examples of somatic reflexes mediated by the spinal cord i. Stretch reflexes – muscle spindles are stretched and excited, afferent impulse is sent to the spinal cord where it synapses directly with a motor neuron that triggers the muscle to contract (serial). The sensory neuron also synapses with an interneuron that inhibits the motor neurons of antagonist muscles, this is called reciprocal inhibition. ii. Flexor (withdrawal) reflex – initiated by painful stimulus and causes withdrawal of the body part. Examples: touch something hot, abdominal reflex (see figure 5-31) iii. Superficial reflexes – initiated by cutaneous stimulation. Example: plantar reflex h. Autonomic reflexes mediated by the brain or spinal cord No Post-Lecture Practice for this lecture 92 Autonomic Nervous System Study Objectives: 1.Compare the somatic and autonomic nervous systems relative to their effectors, structure, functions, and neurotransmitters. 2. Compare and contrast the roles of the parasympathetic and sympathetic divisions. 3. Describe the origin, location of ganglia, length of pre and postganglionic fibers, and neurotransmitters used for the parasympathetic and sympathetic divisions 4. Describe dual innervation and explain exceptions to dual innervation such as sympathetic tone. 5. Define cholinergic and adrenergic fibers and list the different types and subtypes of cholinergic and adrenergic receptors and their locations 6. Explain the clinical significance of drugs that mimic or inhibit parasympathetic or sympathetic effects. 7. Contrast the localized effects of the parasympathetic system versus the wide spread effects of the sympathetic system 93 I. Efferent (motor) Division –consists of two divisions, somatic and autonomic a. Somatic Nervous System i. Voluntary control ii. Effector = skeletal muscles iii. Muscle fibers must be excited by a motor neuron or they are inactive (On or off) iv. One motor neuron extends from the CNS all the way to the effector muscle b. Autonomic Nervous System i. Involuntary control ii. Effectors = glands, smooth and cardiac muscles iii. Two neuron chain between the CNS and the effector (see figure 7-1) 1. Preganglionic neuron – before the ganglia 2. Postganglionic neuron – after the ganglia iv. Two divisions 1. Sympathetic – fight or flight 2. Parasympathetic – rest and digest II. Anatomy of the Autonomic Nervous system (see figure 7-2 and 7-3 for a summary) a. Anatomy of the Sympathetic System i. Origin sites 1. Thoracolumbar - emerges from thoracic and lumbar regions T1-L2 ii. Length of neurons 1. Short preganglionic 2. Long postganglionic iii. Location of Sympathetic Ganglia - close to vertebral column 1. Paravertebral ganglia – chain running parallel to the vertebral column, extends from C3 to S4 2. Collateral (prevertebral) ganglia – lie anterior to the vertebral column iv. Path of Sympathetic Neurons 1. Cell bodies are located in the lateral gray horns of spinal segments T1 – L2 2. White ramus communicans – pre neuron passes from the spinal nerve to the paravertebral ganglia 3. Gray ramus communicans – post neuron exits the paravertebral ganglia 94 4. Three different routes the preganglion neuron can take once it enters the paravertebral ganglia a. Synapse with post at the same level b. Synapse with post at a different level c. Travel through splanchnic nerve and synapse with post in collateral ganglia 5. The sympathetic nervous system triggers the release of epinephrine from the adrenal medulla a. Some preganglion fibers travel to the adrenal medulla where they synapse with hormone producing cells b. These cells release epinephrine into the blood stream b. Anatomy of the Parasympathetic System i. Origin sites 1. Craniosacral - emerges from brainstem and sacral regions ii. Length of neurons 1. Long preganglionic 2. Short postganglionic iii. Location of Parasympathetic Ganglia - ganglia close to target organ 1. Terminal ganglia – very close to target organ 2. Intramural ganglia – within the walls of the target organ III. Functions of the ANS a. General regulatory functions i. Cardiovascular activities 1. Cardiac output, heart rate, blood pressure and distribution ii. Body fluid chemistry 1. pH, osmolarity, thirst, water content iii. Pulmonary activities 1. Breathing rate, bronchiole diameter, O2 and CO2 content iv. Gastrointestinal activities 1. Motility along digestive tract, mechanical and chemical digestion v. Visceral reflexes 1. Micturation, defecation, sexual reflexes vi. Stress 1. Stimulates various hormones to cope with situation 95 b. Functions of the Sympathetic division – fight or flight i. Enables body to cope rapidly during emergency situations ii. Dominant when excited, frightened, or during exercise 1. Increase heart rate and blood pressure 2. Increase respiratory rate, dilates bronchioles 3. Blood shunted to skeletal muscles, brain, and heart away from digestive organs and skin 4. Dilates pupils 5. Liver releases glucose to meet increased energy needs 6. Increased cellular metabolism 7. Initiates sweating to lower body temperature 8. Increased RBC production and clotting ability 9. Na+ absorption / K+ secretion, decreased urine production c. Functions of the Parasympathetic division – rest and digest i. Dominant in non-stressful situations ii. Conserves energy and directs maintenance activities such as digestion and excretion 1. Blood shunted to visceral organs 2. Constricts pupils 3. Increased digestive glandular secretions and activity 4. Respiratory and lacrimal secretions 5. Blood pressure, heart rate, respiratory rates at low normal levels *See table 7-2 in your textbook and the handout posted on Canvas for additional effects the two divisions of the ANS have on various organs/tissues. d. Dual Innervation - most internal organs are innervated by both autonomic divisions i. Antagonistic control – the divisions counterbalance each other by continuously making adjustments. The ANS either further excites or inhibits the organs. ii. There are exceptions to dual innervation: 1. Most blood vessels, sweat glands, and arrector pili muscles are controlled by sympathetic fibers only 2. Sympathetic Tone: the sympathetic division controls blood pressure and keeps the blood vessels in a continual state of partial constriction a. Increased sympathetic activity constricts blood vessels b. Decreased sympathetic activity dilates blood vessels 96 3. Some sympathetic metabolic effects are not reversed by the parasympathetic division a. Increases the metabolic rate of body cells b. Raises blood glucose levels c. Mobilizes fat as a food source d. Stimulates the reticular activating system (RAS) of the brain, increasing mental alertness IV. ANS Neurotransmitters & Receptors a. Acetylcholine (ACh) and norepinephrine (NE) are the two major neurotransmitters of the ANS i. Neurons that release ACh are cholinergic fibers: 1. All parasympathetic pre and postganglionic neurons 2. All sympathetic preganglionic neurons 3. Sympathetic postganglionic that innervate sweat glands and arrector pili muscles ii. Neurons that release NE are adrenergic fibers: 1. Most sympathetic postganglionic neurons (except sweat glands and arrector pili) b. Types of Receptors - neurotransmitter effects can be excitatory or inhibitory depending upon the receptor type they bind to. Two types of receptors are cholinergic and adrenergic. i. Cholinergic receptors – bind Ach 1. Nicotinic receptors a. Nicotinic receptors are found on: i. Motor end plates (somatic targets) ii. All postganglionic neurons of both sympathetic and parasympathetic divisions iii. The hormone-producing cells of the adrenal medulla iv. The effect of ACh binding to nicotinic receptors is always excitatory 2. Muscarinic a. Muscarinic receptors are found on all effectors stimulated by postganglionic cholinergic fibers: i. Parasympathetic effectors ii. Sweat glands and arrector pili b. The effect of ACh binding to muscarinic receptors can be either inhibitory or excitatory depending on the receptor subtype of the target organ i. Examples – slows cardiac muscle: inhibitory; smooth muscle of digestive: excitatory 97 ii. Adrenergic receptors – binds NE and/or E 1. Alpha Receptors - greater sensitivity to NE a. α 1 – binding of NE is stimulatory. Example: constriction of blood vessels serving the skin and abdominal viscera b. α 2 – binding of NE is inhibitory. Example: inhibits insulin secretion from the pancreas 2. Beta Receptors a. β 1 – found primarily in the heart, binding of NE and E is excitatory. Example: increases cardiac output, release of renin from kidneys to increase BP b. β 2 – binding of E is generally inhibitory. Example: dilates coronary blood vessels and bronchioles in the lungs, relaxes digestive and urinary smooth muscle c. β 3 – found in adipose tissue. Example: stimulates lipolysis *See table 7-3 for a nice summary of which fibers are cholinergic and adrenergic and the receptor types. V. Localized vs. Wide Spread Effects a. Parasympathetic – localized and short lived effect i. Preganglionic synapse with one or a few postganglionic ii. ACH is quickly destroyed b. Sympathetic – longer lasting and body wide mobilization i. Preganglionic synapse with many posts at different levels ii. NE is inactivated slower than ACH iii. NE and E are indirect neurotransmitters, using a second-messenger system iv. Epinephrine is released into the blood and remains there until destroyed by the liver VI. Effects of Drugs on the ANS - drugs are designed to obtain an inhibitory or excitatory effect on a target organ by either blocking or initiating desired effects of neurotransmitters a. Types of drugs: i. Sympathomimetic agents – enhance sympathetic response ii. Sympatholytic agents – decrease sympathetic response iii. Parasympathomimetic agents – enhance parasympathetic response iv. Parasympatholytic agents – decrease parasympathetic response 98 b. Examples of Drugs: i. Atropine – blocks muscarinic receptors therefore blocks parasympathetic effects, increase heart rate and fecal and urinary retention. Would be parasympatholytic. ii. Tricyclic antidepressants – prolong the activity of NE on postsynaptic membranes. Would be sympathomimetic. iii. Over-the-counter drugs for colds, allergies, and nasal congestion – stimulate α-adrenergic receptors. Would be sympathomimetic. iv. Beta-blockers – blocks cardiac B1 receptors, decreases HR and BP. Would be sympatholytic. v. Alpha-blockers - interfere with vasomotor fibers and are used to treat hypertension. Would be sympatholytic. vi. Salbutamol – activates B2 receptors, dilates bronchioles (asthma treatment). Would be sympathomimetic. c. Age and the ANS i. In old age, ANS efficiency decreases, resulting in constipation, dry eyes, and orthostatic hypotension. ii. Orthostatic hypotension is a form of low blood pressure that occurs when sympathetic vasoconstriction centers respond slowly to positional changes. 99 Autonomic Nervous System Post-Lecture Practice 3. Catagorize the following ANS fibers as cholinergic or adrenergic. a. Parasympathetic preganglionic b. Parasympathetic postganglionic c. Sympathetic preganglionic d. Sympathetic postganglionic that innervate arrector pili and sweat glands e. Majority of sympathetic postganglionic 4. Match the following structures with the type of ANS receptors you would find on them. a. Nicotinic receptor b. Muscarinic receptor c. Adrenergic receptor (either alpha or beta) ____ Parasympathetic postganglionic ____ Sympathetic postganglionic ____ Parasympathetic targets ____ Majority of sympathetic targets ____ Arrector pili and sweat glands ____ Skeletal muscle (remember however this is a somatic target not an autonomic target) 5. Autonomic Nervous System a. Randomly pick 6 different tissues off the top of your head and write them down b. Now compare and contrast the effects of the sympathetic and parasympathetic on these different tissues: will the effects be excitatory or inhibitory? c. Give 3 reasons why the sympathetic response has longer lasting effects on the body than the parasympathetic response 100 Muscle Physiology Study Objectives: 1. List the functions of skeletal muscle 2. Describe the four functional properties of muscle tissue 3. Identify and describe the connective tissue sheaths: epimysium, perimysium, and endomysium 4. Describe the microscopic anatomy of muscle fibers. Include the structure and function of the sarcolemma, sarcoplasmic reticulum, terminal cisternae, transverse tubules, myofibrils, sarcomeres, and myofilaments (actin, tropomyosin, troponin, myosin, titin) 5. Describe the structure and function of the neuromuscular junction: axon terminal, synaptic cleft, and motor end plate 6. Describe the events of muscle cell contraction: Steps involved in the transmission of nerve impulses to muscle Excitation-contraction coupling events Steps of the sliding filament theory Explain the role of myosin, actin, sarcoplasmic reticulum (terminal cisternae), transverse tubules, troponin-tropomyosin complex, calcium and ATP in the sliding filament theory 7. Define motor unit, muscle tension, recruitment, isotonic contraction (concentric vs. eccentric), isometric contraction, muscle tone, graded response, and “all or none” response 8. Describe the following factors and how the contribute to muscle tension: frequency of stimulation (wave summation), intensity of stimulation (motor unit summation), treppe, size of muscle, and optimal operating length 9. Describe three ways ATP is generated during muscle activity: direct phosphorylation, aerobic respiration, anaerobic glycolysis 10. Describe muscle fatigue 11. Define oxygen debt and explain why it must be repaid 12. Distinguish between fast glycolytic, fast oxidative, and slow oxidative muscle fibers, explain the characteristics of each 101 13. Compare the effects of aerobic vs. resistance exercise on muscles 14. Compare and contrast skeletal muscle and smooth muscle based on their innervation, structure, and contraction mechanisms. 15. Describe the characteristics of single unit and multi unit smooth muscle. 16. Describe the stress-relaxation response in smooth muscle. Muscle Physiology Outline I. Functions of Skeletal Muscle a. Movement – muscles attach directly or indirectly to bone, pull on bone or tissue when they contract b. Maintain posture / body position – muscles are continuously contracting to make adjustments to maintain posture c. Stabilize joints – tendons crossing joints and muscle tone d. Thermogenesis - generate heat when contracting II. Properties of Muscle Tissue a. Excitable – respond to nerve stimulus b. Contractible – shorten when stimulated c. Extensible – can stretch beyond resting length when relaxed d. Elastic – can recoil/rebound to original resting length after contraction or stretching III. Gross Anatomy of Skeletal Muscle (See figure 8-2) a. Endomysium – surrounds individual muscle fibers b. Perimysium – surrounds bundles of muscle fibers called fascicles c. Epimysium – dense irregular CT, surrounds the entire muscle IV. Microscopic Anatomy of Skeletal Muscle (See figure 8-2, 8-3, 8-4) a. Sarcolemma – plasma membrane surrounding muscle fiber b. Sarcoplasm i. Contains a lot of mitochondria, glycogen, myoglobin, and contractile organelles called myofibrils c. Myofibril i. Long fiber-like organelle that fills the sarcoplasm of the cell ii. Runs parallel to muscle fiber d. Sarcomere i. Aligned end to end along the length of the myofibril ii. Z-line – boundary at the end of each sarcomere 102 iii. Myofilaments - contractile proteins in the sarcomere and arrangement gives muscle its striations 1. Myosin (thick) filaments a. Tail with split head b. Arranged in bundles c. Heads contain: i. ATP binding site ii. ATPase enzyme which splits ATP to provide energy during contraction iii. Actin binding site 2. Actin (thin) filament a. Attached to Z – line and extends towards the center of the sarcomere b. Contains active binding site for myosin heads 3. Regulatory proteins - proteins that regulate the binding of myosin to actin a. Tropomyosin – spirals around actin, blocks active site when muscle is relaxed b. Troponin – contains three binding sites i. Binds to actin ii. Binds to tropomyosin and controls its position on active binding site iii. Contains calcium binding site 4. Titin (elastic) filaments a. Large protein attached to z-line and runs through the center of thick filaments b. Gives muscle elastic property; uncoils when muscle stretches yet stiffens to avoid over extension, and recoil when muscle relaxes e. Sarcoplasmic reticulum (SR) – specialized smooth endoplasmic reticulum. i. Surrounds each myofibril. ii. Terminal cisternae – expanded ends of SR. Stores and releases calcium when muscle fiber is stimulated to contract f. Transverse Tubules (T-tubule) – deep indentations of the sarcolemma into the muscle fiber i. Lies between two terminal cisternae ii. Conducts electrical impulse from the sarcolemma into the muscle fiber iii. Coordinates muscle contraction by triggering calcium release from the terminal cisternae 103 V. Skeletal Muscle Contraction a. In order to contract, a skeletal muscle must: i. Be stimulated by a somatic motor neuron ii. Propagate an electrical current, or action potential, along its sarcolemma iii. Have a rise in intracellular Ca2+ levels, the final trigger for contraction b. Excitation-contraction coupling -linking the electrical signal to the contraction i. The neuromuscular junction is formed from: 1. Axon terminals, which have synaptic vesicles that contain acetylcholine (ACh) 2. Synaptic cleft 3. The motor end plate, which is a specific part of the sarcolemma that contains ACh receptors ii. Excitation-contraction coupling events (See figure 8-11): 1. When a nerve impulse reaches the end of an axon at the neuromuscular junction: a. Voltage-regulated calcium channels open and allow Ca2+ to enter the axon b. Ca2+ inside the axon terminal causes vesicles to fuse with the axon membrane and release ACh into the synaptic cleft by exocytosis c. ACh diffuses across the synaptic cleft to ACh receptors on the motor end plate d. Binding of ACh to its receptors initiates an action potential in the muscle e. ACh bound to ACh receptors is quickly destroyed by acetylcholinesterase 2. Once generated, the action potential: a. Is propagated along the sarcolemma b. Travels down the T tubules c. Triggers Ca2+ release from terminal cisternae 3. Ca2+ binds to troponin and causes: a. A conformational change in troponin b. Tropomyosin rolls off the actin active binding sites allowing them to be exposed for myosin to attach 104 c. Sliding Filament Theory (See figure 8-12): i. Events of contraction: 1. Cross bridge formation – myosin cross bridge attaches to actin filament 2. Working (power) stroke – myosin head pivots and pulls actin filament toward M line 3. Cross bridge detachment – ATP attaches to myosin head and the cross bridge detaches 4. “Cocking” of the myosin head – energy from hydrolysis of ATP cocks the myosin head into the high-energy state ii. Muscle Relaxation 1. When the nerve stimulation ceases: a. Ca2+ is removed and actively transported back into the SR (requires ATP) b. Tropomyosin roles back over the binding sites, and the muscle fiber relaxes d. Tension – force muscle exerts on an object when contracted i. Load or resistance is the opposing force exerted on the muscle ii. Muscle tension must over come the force of the load in order to shorten e. Phases of a Muscle Twitch (See figure 8-13) i. Latent period – first few milliseconds, excitation-contraction coupling ii. Period of contraction – cross bridge cycling, tension increases iii. Period of relaxation – calcium transported back into SR, cross bridge cycling ends, tension decreases f. Graded Muscle Response - individual muscle fiber contraction is an “all or none” response, but whole muscles can vary in tension produced and length of contraction i. Factors Effecting Tension 1. Intensity of stimulus – number of motor units a. Motor unit – a single motor neuron and all the muscle fibers it supplies (See figure 8-18) b. Recruitment – calling additional motor units, therefore stimulating more fibers and increasing muscle tension c. Threshold stimulus – minimal stimulus needed to invoke visible muscle contraction d. Maximal stimulus – all motor units are recruited, strongest contraction produced e. Asychronous recruitment of motor units – alternates motor units 105 2. Frequency of stimulation (See figure 8-20) a. Twitch – single impulse, contraction followed by relaxation b. Wave summation – when impulses are delivered in succession the second twitch will be stronger then the first c. Complete tetanus – rapid stimulation results in sustained smooth contraction without periods of relaxation i. Refractory Period in Skeletal Muscle 1. Contractile response lasts longer, far beyond the refractory period of the action potential 2. This is important in skeletal muscle’s ability to produce tetanus d. Treppe: The Staircase Effect – increased contraction in response to multiple stimuli of the same strength. i. Different than summation because relaxation occurs. ii. Contractions increase because: 1. There is increasing availability of Ca2+ in the sarcoplasm 2. Reduced slack of the elastic series component 3. Muscle enzyme systems become more efficient because heat is increased as muscle contracts 3. Size of Muscle a. Number of muscle fibers per muscle b. Size of individual muscle fibers – fibers produce more myofilaments in response to demands placed on them. Fibers hypertrophy. 4. Optimal operating length – the resting length in which maximum contraction can be generated (70 -130%) a. Occurs when the muscle is slightly stretched and filaments barely overlap (see figure 8-21) 106 g. Types of Contractions i. Isotonic – same tension 1. Muscle tension remains constant during contraction 2. Muscle length changes during contraction, shortens or lengthens 3. Types of isotonic contractions: a. Concentric - muscle shortens and does work i. Examples: pick up pencil, kick soccer ball b. Eccentric – muscle contracts as it lengthens i. Helps counter act gravity or prevent joint injury “muscle braking” ii. Example: squats – quadriceps stretch but are contracted to counter act gravity and control movement ii. Isometric – same length 1. Tension increases but muscle length remains the same 2. Muscle is unable to produce enough force to overcome the load 3. Example: pushing against a stationary wall h. Muscle Tone i. Constant low level of tension in relaxed muscles ii. Maintained by spinal reflexes that activate alternating motor units iii. Keeps muscles firm and ready to respond to stimuli VI. Muscle Metabolism (See figure 8-22) a. Role of ATP - muscles need a constant supply of ATP to carry out contractions i. For cross bridge formation and power stroke ii. For disconnecting of cross bridges iii. For active transport of calcium back into the terminal cisternae iv. For Na-K pump v. Muscles only have enough ATP stored for 4-6 seconds worth of contraction. Therefore ATP must be constantly regenerated. vi. Three pathways that supply additional ATP: 1. Creatine phosphate (direct phosphorylation) 2. Oxidative phosphorylation 3. Glycolysis 107 vii. Creatine phosphate (direct phosphorylation) 1. Creatine phosphate, transfers energy and a phosphate to ADP forming ATP 2. Creatine phosphate + ADP Creatine + ATP 3. Creatine phosphate is stored in the muscle fibers 4. Provides a rapid source of energy for 10 – 15 seconds of contraction viii. Oxidative Phosphorylation - Aerobic Respiration 1. Occurs in the mitochondria 2. Main source when O2 is present 3. Fueled by glycogen stores and glucose and fatty acids delivered by the blood 4. Can provide hours of muscle contraction for prolonged moderate activity 5. Slower because it requires the delivery of oxygen and glucose 6. There is cardiovascular limits to the amount of nutrients that can be delivered to muscle a. CV system cannot keep up with O2 demands b. Blood vessels in the muscle are compressed during maximal contraction c. Oxidative phosporylation may not be able to produce enough ATP quick enough to keep up with the demands ix. Glycolysis – anaerobic 1. Glucose is broken down to pyruvic acid and produces 2ATP 2. In the absence of O2 pyruvic acid is converted to lactic acid 3. Produces minimal amounts of ATP but occurs quickly 4. Provides 30-60 seconds of high level activity b. Muscle Fatigue - decline in muscle tension as a result of previous activity i. Muscles are unable to contract despite being stimulated 1. Results from a deficit of ATP (not a total absence) 2. Anaerobic respiration becomes less efficient as lactic acid accumulates and pH drops in the muscle fiber 3. Muscle fibers lose K+ as the Na-K pump is unable to restore ion balance since it requires ATP ii. Neuromuscular fatigue – caused by a shortage of neurotransmitters at the NMJ 108 c. Oxygen Debt - the amount of extra oxygen the body must take in to restore muscle chemistry back to resting state i. The liver converts lactic acid in the blood to pyruvic acid which can be converted to glucose or enter aerobic respiration now that O2 is available ii. Glycogen stores are replenished in muscles and liver iii. Creatine is re-phosphorylated into creatine phosphate and stored in muscles iv. O2 rebinds to myoglobin d. Types of Muscle Fibers (See table 8-1 and figure 8-23) i. Muscle fibers differ in their methods of metabolism based on: 1. Pathways they use to produce ATP 2. Duration of muscle contraction 3. How quickly their ATPases work 4. Speed (velocity) of contraction ii. Muscle Fiber Types 1. Slow – oxidative (red) a. Slow to contraction but most resistant to fatigue b. Good for endurance and continuous contraction c. Better equipped for oxidative phosphorylation: i. Numerous mitochondria and rich supply of capillaries ii. Small in diameter iii. High myoglobin content d. Slow myosin ATPase activity 2. Fast – oxidative (pink) a. Fast to contraction but resistant to fatigue b. Also equipped for oxidative phosphorylation c. Fast myosin ATPase activity 3. Fast glycolytic fibers (white) a. Fast to contract but fatigue quickly b. Good for power and speed for short durations c. High glycogen reserves and relies mainly on glycolysis d. Fatigue quickly due to lactic acid build up e. Large fibers generate more force but poor nutrient diffusion f. Light in color due to reduced myoglobin g. Fewer capillaries and mitochondria 109 e. Effects of Exercise on Muscle Fibers i. Aerobic Exercise 1. Results in more efficient muscle metabolism and resistance to fatigue 2. Increases capillaries, mitochondria and myoglobin 3. Also increases efficiency of the heart, lungs, body metabolism, and neuromuscular coordination ii. Resistance – weight lifting and isometric contractions 1. Fibers produce more myofilaments and myofibrils causing muscle fibers to hypertrophy 2. Increases glycogen stores 3. Results in increased muscle size and strength VII. Smooth Muscle Tissue a. Structure and Location i. Composed of spindle-shaped fibers ii. Organized into two layers (longitudinal and circular) iii. Found in walls of hollow organs (except the heart) b. Innervation of Smooth Muscle i. Smooth muscle lacks neuromuscular junctions ii. Innervating nerves have bulbous swellings called varicosities that release neurotransmitters iii. Some neurotransmitters are excitatory and some are inhibitory, depending on the receptor c. Structural Characteristics (see figure 8-29) i. SR is less developed than in skeletal muscle and lacks a specific pattern ii. T tubules are absent iii. Thin filaments only contain tropomyosin (NO troponin) iv. Thick and thin filaments are arranged diagonally, causing smooth muscle to contract in a corkscrew manner d. Contraction Mechanism (see figure 8-30 and 8-31) i. Actin and myosin interact according to the sliding filament mechanism ii. Calcium influx from the extracellular space triggers Ca2+ release from the SR iii. The trigger for contractions is a rise in intracellular Ca2+ 110 iv. Role of Calcium Ion 1. Ca2+ binds to calmodulin 2. Activated calmodulin activates the myosin light chain kinase enzyme which transfers phosphate from ATP to myosin cross bridges 3. Phosphorylated cross bridges interact with actin to produce shortening v. Smooth muscle relaxes when intracellular Ca2+ levels drop e. Types of Smooth Muscle i. Single Unit 1. Visceral smooth muscle is autonomous 2. Smooth muscle pacemaker cells display rhythmic, spontaneous variations in membrane potentials known as slow wave potentials. (See figure 8-32) 3. Self-excitable (myogenic) – can produce spontaneous action potentials without external stimulation 4. Cells are electrically coupled to one another via gap junctions and contract rhythmically as a unit 5. Pacemaker smooth muscle cells (Interstitial cells of Cajal) membrane potential oscillates closer and further away from threshold a. If threshold is reached a burst of action potentials is triggered causing rhythmic smooth muscle contractions i. Drive several digestive processes (e.g., peristalsis and segmentation) 6. Hormones, paracrines, mechanical stress, and nerve stimuli determines the starting point of the slow wave potentials. Example: a. Food in the GI tract – closer to threshold b. Empty GI tract – further away from threshold 7. Response to Stretch a. Smooth muscle exhibits a phenomenon called stress-relaxation response in which: i. Smooth muscle responds to stretch only briefly, and then adapts to its new length ii. The new length, however, retains its ability to contract iii. This enables organs such as the stomach and bladder to temporarily store contents 111 ii. Multiunit 1. Multiunit smooth muscles are found: a. In large airways to the lungs, large arteries, arrector pili muscles, attached to hair follicles, and in the internal eye muscles 2. Their characteristics include: a. Rare gap junctions b. Structurally independent muscle fibers c. A rich nerve supply, forms motor units d. Graded contractions in response to neural stimuli 112 Muscle Physiology Post-Lecture Practice 1. View “Neuromuscular Junction” and “Sliding Filament Theory” animations on Canvas or you can go to Google video and type these topics in to find numerous animations depicting these processes. 2. Give a brief description of the events happening in the 4 steps of the sliding filament theory. (use your physiology terminology) 3. Compare and contrast skeletal and smooth muscle by listing at least three physiological distinctions for each type of muscle tissue. (hint: think about how they differ in innervation, structure, and contraction mechanisms) Skeletal Smooth __ 113 Endocrine System Study Objectives: 1. Define endocrine gland, hormones, and target cell/organ 2. Describe the factors affecting target cell activation. 3. Define humoral, neural, and hormonal stimuli. Be able to recognize examples of each. 4. Discuss how the hypothalamus and the pituitary gland are structurally and functionally related. 5. Describe the structural and functional differences between the anterior and posterior pituitary gland. 6. List the major endocrine organs and the hormones they secrete. Then for each hormone, discuss what stimulates its release, the target cells, and its effect on the target cells. (this is where your optional endocrine worksheet may be handy.) 7. Describe the role of the renin-angiotensin-aldosterone pathway in the maintenance of blood pressure and volume. 8. Describe the general stress responses that accompany the General Adaptation Syndrome. What hormones are involved? 9. Compare and contrast the events of the alarm reaction, resistance reactions, and the exhaustion phase of G.A.S. 10. Describe the consequences of long term stress on the physiology of the body. 11. Distinguish between the absorptive state and the postabsorptive state. Which hormones are dominate in each state? 12. Distinguish between insulin dependent and insulin independent glucose transporters. Give examples of where they are found. 13. Distinguish between the causes of type 1 diabetes and type 2 diabetes. 14. Describe the three cardinal signs of diabetes mellitus. What are the common long term complications caused by the disease? 114 Endocrine System Outline I. What is the Endocrine System? a. Composed of glands that secrete hormones b. Responsible for continuous processes such as growth, cell metabolism, & reproduction II. What do Hormones Do? a. Hormones are chemical substances that travel through the blood to a target cell i. Target cells must have specific receptors to which the hormone binds ii. These receptors may be intracellular or located on the plasma membrane iii. They trigger a change in cellular activity b. Target cell activation depends on three factors: i. Blood levels of the hormone ii. Relative number of receptors on the target cell 1. Up-regulation – target cells form more receptors in response to the hormone 2. Down-regulation – target cells lose receptors in response to the hormone iii. The affinity of those receptors for the hormone c. Control of Hormone Release i. Hormones are synthesized and released in response to humoral, neural, and hormonal stimuli: 1. Humoral stimuli - secretion of hormones in response to changing blood levels of ions and nutrients. Examples: a. Concentration of calcium ions in the blood and the release of PTH b. Concentration of blood glucose and the release of insulin 2. Neural stimuli – nerve fibers stimulate hormone release. Example: preganglionic sympathetic fibers stimulate adrenal medulla to release catacholamines 3. Hormonal stimuli – release of hormones in response to hormones produced by other endocrine organs. Example: The anterior pituitary gland secretes hormones that stimulate other endocrine glands 115 IV. Hypothalamus – Pituitary Axis a. Hypothalamus i. Regulatory hormones from the hypothalamus control the release of hormones from the anterior pituitary 1. Releasing hormones stimulate the release of hormones from the anterior pituitary 2. Inhibiting hormones shut off release of hormones from the anterior pituitary ii. Produces oxytocin and antidiuretic hormone that is secreted by the posterior pituitary b. Pituitary gland – two-lobed endocrine gland that secretes nine major hormones i. Posterior lobe - neurohypophysis, made up of neural tissue 1. The posterior lobe is a down growth of hypothalamic neural tissue and has a neural connection with the hypothalamus (see figure18-4) 2. Nuclei of the hypothalamus synthesize oxytocin and antidiuretic hormone (ADH) 3. These hormones are transported to the posterior pituitary where they are stored and released. 4. Posterior pituitary hormones: a. Antidiuretic Hormone (ADH) (a.k.a Vasopressin) i. Function: triggers increased water reabsorption in the kidney tubules ii. Release of ADH is stimulated by: 1. Increase in osmolarity detected by the hypothalamus 2. Decrease in blood pressure and volume b. Oxytocin – causes contractions of uterus smooth muscle during labor ii. Anterior lobe - adenohypophysis, made up of glandular tissue 1. The anterior lobe of the pituitary and the hypothalamus are connected by the hypophyseal portal system (see figure 18-7) 116 2. Anterior pituitary hormones (figure 18-5): a. Tropic hormones – regulates the release of hormones from other endocrine glands i. Thyroid-stimulating hormone (TSH) ii. Adrenocorticotropic hormone (ACTH) iii. Follicle-stimulating hormone (FSH) iv. Luteinizing hormone (LH) v. Growth hormone (GH) b. Additional non-tropic hormones released by the anterior pituitary i. Prolactin (PRL) ii. Melanocyte-stimulating hormone (MSH) c. Growth Hormone (GH) (see figure 18-10) i. Targets most cells, especially bone and skeletal muscle when young ii. Growth promoting actions: 1. stimulates bone and soft tissue growth. 2. increases protein synthesis, cell growth, and cell division. iii. Metabolic actions: 1. mobilizes fat stores and increases fatty acid levels in the blood 2. increases blood glucose a. through glycogenolysis the breakdown of glycogen b. inhibits glucose uptake in skeletal muscle d. Adrenocorticotropic hormone (ACTH) i. Targets the adrenal cortex ii. Stimulates the release of glucocorticoids V. Adrenal glands – paired, pyramid-shaped organs atop the kidneys a. Structurally and functionally, they are two glands in one (see figure 19-7): i. Adrenal medulla – nervous tissue that acts as part of the sympathetic nervous system ii. Adrenal cortex – glandular tissue derived from embryonic mesoderm b. Adrenal Cortex - synthesizes and releases steroid hormones called corticosteroids 117 i. Regions of the adrenal cortex and hormone secreted (see figure 197): 1. Zona reticularis – gonadocorticoids (mainly androgens) 2. Zona fasciculate – glucocorticoids (mainly cortisol) 3. Zona glomerulosa – mineralocorticoids (mainly aldosterone) ii. Hormones released by Adrenal Cortex: 1. Glucocorticoids (Cortisol) - helps the body resist stress by: a. Increasing blood glucose levels b. Cortisol has the following effects : i. Promotes gluconeogenesis - formation of glucose from non-carbohydrates ii. Enhances lipolysis iii. Triggers protein catabolism in skeletal muscle iv. Suppresses the immune system v. See figure 19-9 2. Mineralocorticoids (Aldosterone)– regulate the electrolyte concentrations of extracellular fluids. a. Regulates blood pressure, blood volume, and Na+ and K+ levels in the blood i. Stimulates reabsorption of Na+ by the kidneys ii. Causes secretion of K+ b. Aldosterone secretion is stimulated by: i. Low blood Na+ ii. Rising blood levels of K+ iii. Decreasing blood volume or pressure iv. Stress c. The Four Mechanisms of Aldosterone Secretion: i. Plasma concentration of sodium and potassium – directly influences the zona glomerulosa cells ii. ACTH – causes small increase in aldosterone during stress 118 iii. Renin-angiotensin mechanism – kidneys release renin in response to decreased BP, stimulates aldosterone release. Reninangiotensin-aldosterone pathway: 1. Is triggered when the kidneys release renin 2. Renin converts the plasma protein angiotensinogen into angiotensin I 3. Angiotensin I is converted into angiotensin II by ACE (angiotensin converting enzyme) 4. Angiotensin II: a. Causes systemic arteriole vasoconstriction b. Stimulates the adrenal cortex to release aldosterone 5. Results in increased blood pressure and volume iv. Atrial natriuretic peptide (ANP) – produced by the heart in response to increased pressure, inhibits the release of aldosterone VI. Long term stress a. What is stress? i. Stress = any factor that disrupts our natural balance (homeostasis) ii. Stressor = anything that causes us to adjust 1. Can be emotional, physical, environmental 2. Can be an immediate response to a threat or a response to prolonged exposure to stress iii. Stress stimulates the hypothalamus to initiate a chain of reactions that results in general adaptation syndrome (see figure 19-13) b. General Adaptation Syndrome (G.A.S) i. Definition: “the sum of all non-specific systemic reactions of the body to long continued exposure to stress” (Hans Selye) ii. Phases of G.A.S. 1. Alarm reaction – mobilize resources 2. Resistance reaction – cope with stress 3. Exhaustion – deplete reserves 119 iii. Alarm Reaction 1. Immediate response to stress triggers the sympathetic nervous system “fight or flight” through the hypothalamus 2. Mobilizes the body for immediate physical activity 3. Short-lived iv. Resistance Reaction 1. If stress persists longer than a few hours then the resistance reaction is initiated 2. Prepares the body for long term protection, slow to start but longer lasting 3. The hypothalamus triggers the pituitary gland to secrete hormones that will allow the body to continue to survive the stress until homeostasis is returned 4. Overall goal of resistance reaction is to: a. Maintain blood pressure and volume b. Increase ATP production c. Prevent water loss d. Prevent inflammation from causing tissue damage 5. Maintained by ADH, aldosterone, cortisol, growth hormone, and thyroid hormones v. Exhaustion Phase 1. If the resistance reaction fails to overcome the stress eventually the body reserves are exhausted and the resistance reaction cannot be sustained 2. The adrenal cortex cannot produce aldosterone and cortisol 3. “Link between the breakdown of the hormonal adaptation mechanism and fatal diseases” Hans Selye a. Results in illness or death b. Cancer, heart disease, depression, hypertension, diabetes vi. Prolonged exposure to stress hormones: 1. Depresses cartilage and bone formation 2. Depresses the immune system 3. Promotes changes in the cardiovascular, neural, muscular, and gastrointestinal function (usually due to hypokalemia = potassium deficiency) a. Cardiac arrhythmias b. Muscle wasting c. Fatigue, concentration loss, irritability 120 c. Some Stress is Good! i. We all need a little stress ii. Norepinephrine which is a neurotransmitter released during stress plays a role in: 1. Creating and retrieving memories 2. Improves moods (feel good chemical) VII. Pancreas – controls blood glucose levels a. Anatomy Review (see figure 22-8 19-15) i. Located behind the stomach ii. Has both exocrine and endocrine functions 1. Acinar cells – exocrine cells that produce digestive enzymes that are secreted into the duodenum 2. The endocrine cells are organized into the islets of Langerhans. Contain both: a. Alpha (α) cells that produce glucagon b. Beta (β) cells that produce insulin b. Control of Blood Glucose i. Insulin and glucagon act as antagonistic hormones to control blood glucose levels. Most of the time both of these hormones are found in the blood, it is the ratio of the two that determines which is dominant. (See figure 19-20) 1. Absorptive State – occurs when ingested nutrients are being absorbed into the blood from the digestive tract a. Metabolic fuels are stored during the absorptive state (fed state). b. Circulating glucose is used for energy or is stored as glycogen in the liver and skeletal muscles. c. Excess circulating fatty acids are stored into triglycerides, mainly in adipose tissue. d. Excess amino acids not needed for protein synthesis and excess glucose are converted to fatty acids and stored as triglycerides in adipose tissue. 2. Postabsorptive State – fasting state that occurs between meals a. When blood glucose drops during the postabsorptive state glycogen is broken down into glucose b. Many body cells will burn fatty acids to spare glucose for the brain. To supply the brain, amino acids can be converted to glucose by gluconeogenesis. 121 ii. Insulin - lowers blood glucose, fatty acid, and amino acid levels and promotes their storage. Dominate during the absorptive state. 1. Insulin’s effects: a. Enhances transport of glucose into body cells b. Stimulates glycogenesis in skeletal muscle and liver cells c. Promotes the transport of amino acids into cells for protein synthesis. d. Promotes the transport of fatty acids into adipocytes e. Inhibits metabolic activity that would increase blood glucose levels such as: glycogenolysis, gluconeogenesis, and lipolysis f. (See figure 19-18) 2. Glucose Transporters - plasma membrane carriers that facilitate the passive diffusion of glucose into cells. a. Some are insulin independent – do not require insulin for transporters to be present in the membrane i. Brain, working muscles, liver, digestive mucosa, pancreas B-cells b. Most are insulin dependent – present in the membrane when insulin binds to cell receptors i. The case in most cells especially resting muscle and adipose tissue c. Insulin promotes up regulation of GLUT 4 i. Glucose transporters are contained in intracellular vesicles and are inserted into the plasma membrane when insulin is present. Triggers a 10 – 30X increase in glucose uptake iii. Glucagon – increases blood glucose levels 1. Glucagon secretion increases when the blood concentration of glucose is too low. Dominate during the postabsorptive state. 2. Its major target is the liver, where it promotes: a. Glycogenolysis – the breakdown of glycogen to glucose b. Gluconeogenesis – synthesis of glucose from lactic acid and noncarbohydrates c. Promotes fat metabolism (lipolysis) 122 iv. Summary of hormones controlling blood glucose: 1. Growth hormone, cortisol, epinephrine, and glucagon all increase blood glucose 2. Insulin is the only hormone that decreases blood glucose v. Diabetes Mellitus - inadequate insulin action resulting in hyperglycemia. 1. Type I diabetes mellitus is due to an insulin deficiency a. Cause is usually autoimmune - destruction of Beta cells 2. Type II diabetes mellitus is due to the reduced sensitivity of target cells to the presence of normal or increased insulin a. Cause can be genetic predisposition and/or lifestyle, diet, exercise, ect. 3. The three cardinal signs of DM are: a. Polyuria- increased urine output due to glucosuria and osmotic diuresis. Can lead to dehydration and circulatory and renal failure. b. Polydipsia – excessive thirst c. Polyphagia – excessive hunger and food consumption 4. Consequences of Diabetes (See figure19-19) a. Liver use of fatty acids leads to ketosis. Acidosis develops and can depress brain function. b. Increase in protein degradation can reduce growth and leads to the wasting of skeletal muscles. c. Long-term complications include degenerative disorders of the vascular and nervous systems. VIII. Control of Blood Calcium Levels a. Blood calcium levels affect many physiological events including: i. neural and muscular excitability ii. excitation-coupling in skeletal, cardiac, and smooth muscle iii. cell signaling iv. blood clotting b. Controlled by two hormones calcitonin and parathyroid hormone. i. Parathyroid Glands - tiny glands on the posterior side of the thyroid (see figure 19-22) 1. Secretes parathyroid hormone which increase blood calcium levels 123 2. Effects of parathyroid hormone: a. Stimulates osteoclasts to digest bone matrix b. Enhances the reabsorption of Ca2+ and the secretion of phosphate by the kidneys c. Stimulates calcitriol synthesis (vitamin D) by the kidneys which increases absorption of Ca2+ by intestinal mucosal cells (see figure 19-27) 3. Rising Ca2+ in the blood inhibits PTH release ii. Thyroid gland 1. Secretes the hormone calcitonin which lowers blood calcium levels a. Produced by the parafollicular, or C cells in the thyroid gland b. Antagonist to parathyroid hormone (PTH) 2. Calcitonin targets the skeleton and kidneys, where it: a. Inhibits osteoclast activity thus the release of calcium from the bone matrix b. Increase renal Ca2+ excretion iii. Calcium disorders 1. Hypocalcemia - deficient PTH secretion a. Nervous system becomes hyperexcitable b. Causes muscle tetany c. Caused by autoimmune disease 2. Hypercalcemia - excess PTH secretion a. This reduces the excitability of muscle and nervous tissue b. Other effects are the thinning of bones and the development of kidney stones. c. May be caused by a tumor IX. Additional Endocrine Glands and the Hormones they secrete a. Thymus i. Thymosin – matures T-cells b. Ovaries i. Estrogen – female characteristics ii. Progesterone- works with estrogen to maintain uterine cycle c. Testes i. Testosterone– male characteristics 124 d. Adipocytes i. Leptin – decreases food intake by acting as a satiety factor e. Stomach i. Ghrenlin – increases hunger **Optional - read more about leptin and ghrenlin in chapter 17 pgs 638 – 641 and see figure 17-2 if you are interested in factors influencing food intake. Endocrine Post Lecture Assignment: Complete the Endocrine Worksheet posted on Canvas. This worksheet is not for points but it will be a good study resource when it comes to learning the functions of all the hormones we discussed. It focuses you on the endocrine gland, the hormones it releases, the target of the hormones and their effect. 125 Blood Study Objectives: 1. List the functions of blood 2. Describe the composition of whole blood 3. Describe the structure and function of the cell types making up the formed elements of blood: erythrocytes, types of leukocytes, platelets 4. Define erythropoiesis and describe where erythrocyte production and destruction take place. 5. Define hematopoiesis and where does it occur? 6. Define hemostasis. Describe the processes of vascular spasm and platelet-plug formation. 7. Describe the stages involved in the coagulation process (intrinsic and extrinsic clotting pathways). 8. Name the factors that promote and inhibit blood clotting. 9. Define and know possible causes for the following disorders: anemia, polycythemia, leukocytosis, thromboembolism, thrombocytopenia, and hemophilia 126 Blood Outline I. Functions of Blood a. Transport i. Oxygen and nutrients to the cells ii. Waste away from cells iii. Hormones b. Regulation i. Maintain body temperature by absorbing and distributing heat c. Protection i. WBC fight infection ii. Blood clotting prevents blood loss II. Composition of Blood (see figures 11-1 & table 11-1) a. Plasma – 90% water along with dissolved compounds i. Proteins – albumin, antibodies, clotting proteins. Proteins help maintain osmotic pressure. 1. Albumin – 60% of plasma proteins a. Transports substances such as bilirubin and bile salts 2. Globulins a. α , β – transports hormones, cholesterol, and iron; angiotensinogen and clotting factors b. Gamma globulins – antibodies 3. Fibrinogen a. Precursor for the clotting protein fibrin ii. Electrolytes – sodium, potassium, calcium, magnesium, chloride, bicarbonate b. Formed elements – erythrocytes, leukocytes, platelets i. Erythrocytes (red blood cells) 1. Biconcave shape 2. Contains no nucleus or organelles 3. Enzymes in cytoplasm: a. Glycolytic enzymes to carry out glycolysis b. Carbonic anhydrase – converts CO2 to HCO34. Last ~120 days and are then destroyed by the spleen or liver 5. Function – to transport oxygen and to a lesser extent carbon dioxide 6. Contains hemoglobin – protein that binds and carries oxygen (see figure 11-2) a. Made of 4 globin polypeptides and 4 heme groups 127 7. Erythropoiesis – production of new erythrocytes (~3 million per second) a. Occurs in the red bone marrow b. Rate of production is controlled by erythropoietin produced by the kidneys in response to blood oxygen levels (see figure 11-4) 8. Anemia - decrease in oxygen carrying ability of the blood. Causes: a. Decreased number of RBC (low hematocrit) b. Deficient or abnormal hemoglobin c. Deficiency in iron or vitamin B12 d. Kidney disease, decrease in EPO e. Blood loss f. Malaria g. Sickle-cell anemia 9. Polycythemia – increased numbers of erythrocytes / hematocrit a. Causes: cancer, high altitudes, lung and heart disease, dehydration ii. Leukocytes – white blood cells 1. Functions a. Protect against infection and initiates inflammation b. Destroy cancerous cells c. Tissue repair 2. Types of Leukocytes (see figure 11-8) a. Granulocytes – granule containing cells with lobed nuclei i. Neutrophils (60 – 70%) 1. Phagocytes 2. First on the scene of infection and triggers inflammation ii. Eosinophils (1-4%) 1. Associated with allergies and parasite infections iii. Basophils (< 1%) 1. Contain and release histamine b. Agranulocytes – without granules i. Monocytes (2 - 6%) 1. Travel into the tissue and mature into macrophages 128 ii. Lymphocytes (25 – 33%) 1. Specific immune defenses 2. B cells & T cells 3. Hemopoiesis - all blood cells arise from a common stem cell found in the red bone marrow (see figure 11-9). iii. Thrombocytes – platelets 1. Irregular shaped cell fragments from megakaryocytes (see figure 11-10) 2. Play a role in blood clotting 3. Hemostasis –prevents the loss of blood when blood vessels are damaged a. 3 phases:vascular spasm, platelet plug formation, coagulation b. Platelet plug formation (see figure 11-11) i. Broken or damaged blood vessels cause platelets to become sticky and cling to the site ii. Release chemicals that attract other platelets (ADP) iii. Release chemicals that cause vasoconstriction: serotonin, epinephrine, thromboxane A2 iv. Normal endothelial cells release prostacyclin and NO to inhibit platelet aggregation c. Vascular spasms i. Blood vessels constrict to diminish blood flow and loss d. Coagulation -formation of a network of fibers that seals the blood vessel. Involves a clotting cascade. i. Clotting cascade (see figure 11-14): 1. Involves 12 clotting factors 2. Requires the presence of Ca2+ and platelet factor 3 (PF3) produced by aggregating platelets 3. Summary of events:An initial inactive clotting factor, found in the plasma, is activated by exposed collagen. This activates the next factor and so on….. Until thrombin converts fibrinogen into fibrin 129 a. Intrinsic Pathway - initiated when Hageman factor is activated by exposed collagen b. Extrinsic Pathway - Factor X is activated by thromboplastin released by damaged tissues ii. Role of Thrombin (see figure 11-13) 1. Converts fibrinogen to fibrin 2. Activates stabilizing factor (XIII) 3. Enhances conversion of more thrombin from prothrombin 4. Enhances platelet aggregation iii. Clot retraction - platelets trapped in the clot contract and squeeze serum out iv. Vessel repair - platelets attract fibroblasts that repair blood vessel v. Clot dissolution - thrombin and tissue plasminogen activator (tPA) converts plasminogen into plasmin which breaks down fibrin (see figure 11-15) vi. Clotting disorders 1. Thromboembolism – clots forming in intact vessels 2. Imbalance in clotting – anticlotting mechanisms 3. Slow moving blood 4. Release of thromboplastin from damaged tissue 5. Hemophilia – deficiency in one of the clotting factors (usually VIII), excessive bleeding 6. Thrombocytopenia – deficiency in platelets 7. Impaired liver 8. Lack of vitamin K No Post-Lecture Practice for this lecture 130 Cardiac Physiology Study Objectives: 1. Describe the location of the heart in the body 2. Identify the major anatomical areas of the heart: chambers, valves, and greater vessels 3. Trace the path of blood flow through the heart 4. Describe the intrinsic conduction system and explain the electrical pathway through the heart. Explain the initiation and conduction of impulses through the intrinsic conduction system. 5. Describe the conduction of impulses through the contractile myocardial cell and the events leading to cardiac muscle contraction. 6. Describe the phases of the cardiac cycle and explain the following as they relate to the cardiac cycle: Atrial and ventricular systole and diastole Operation of the heart valves and heart sounds Pressure changes associated with blood flow through the heart P, QRS, T deflections of a normal ECG 7. Define cardiac output and describe the factors that affect it: Factors influencing heart rate Factors influencing stroke volume: intrinsic and extrinsic 8. Contrast the effects of sympathetic and parasympathetic stimulation of the heart. 9.Define: systole, diastole, inotropic, chronotropic, electrocardiogram, bradycardia, tachycardia, arrhythmia, fibrillation 131 Cardiac Physiology Outline I. The Cardiovascular System a. Cardiovascular system is composed of: i. The heart and blood vessels ii. Functions in transportation of blood: 1. delivers oxygen and nutrients to tissues 2. removes carbon dioxide and waste products from tissues b. Gross Anatomy of the Heart (review anatomy on figure 9-4) c. Microscopic Anatomy of Heart Muscle i. Cardiac muscle is striated, short, fat, branched, and interconnected ii. Intercalated discs anchor cardiac cells together and allow free passage of ions through gap junction d. Cardiac Tissue i. Myocardial cells: 1. 99% of the heart is made of contractile cardiac muscle cells 2. Generates the force of contraction produced by the heart ii. Autorhythmic cells: 1. 1% of cells that are self-excitable 2. Generate action potentials spontaneously without neural stimuli e. Intrinsic Conduction System i. Autorhythmic cells composed the intrinsic conduction system of the heart ii. Coordinates the rhythmic excitation and contraction of the cardiac muscle to ensure efficient pumping iii. The action potential generated by autorhythmic cells travel through the conduction system and to surrounding myocardial tissue by gap junction iv. Sequence of Excitation (see figure 9-8) 1. Sinoatrial (SA) node –pacemaker, generates impulse (70 times/minute) 2. Atrioventricular (AV) node (40-60 times/minute), delays the impulse about 0.1 second 3. Impulse passes from atria to ventricles via the atrioventricular bundle (bundle of His) 4. AV bundle splits into two pathways in the interventricular septum (bundle branches) 5. Bundle branches carry the impulse toward the apex of the heart (35 times/minute) 6. Purkinje fibers carry the impulse from the heart apex to the ventricular walls (30 times/minute) 132 v. Ectopic focus – abnormal overly excitable area begins to depolarizes faster than the SA node (see figure 9-9) 1. Can lead to a premature heartbeat (extrasystole) and/or accelerated heart rate 2. Can be caused by heart disease, anxiety, lack of sleep, to much caffeine, nicotine vi. What gives autorhythmic cells the unique ability to spontaneously generate action potentials? (see figure 9-7) 1. They have an unstable membrane potentials called pacemaker potentials 2. Their membrane gradually depolarizes and drifts towards threshold due to slow Na+ entry 3. When threshold is reached they fire an action potential 4. Calcium influx (rather than sodium) causes the depolarization phase of the action potential 5. Repolarization is cause by K+ efflux vii. Electrocardiography (see figures 9-13 & 9-14) 1. EKG – tracing of the electrical currents created by the intrinsic conduction system. Test to screen for a variety of cardiac abnormalities a. P wave – atrial depolarization b. QRS complex – ventricles depolarization c. T wave – ventricles repolarization 2. Cardiac Abnormalities (see figure 9-15) a. Bradycardia - <60 BPM b. Tachycardia - >100 BPM c. Arrhythmias – uncoordinated atrial and ventricular contractions i. Damaged SA node – pace set by AV node ~ 50 BPM ii. Heart block – damage to the AV node, ventricles contract at ~30 BPM d. Fibrillation – irregular chaotic twitching of the myocardium II. Cardiac Muscle Contraction a. Contraction of cardiac muscle cells: i. Must be stimulated by autorhythmic cells to contract ii. Have a long absolute refractory period (see figure 9-12) 1. Prevents summation and tetany 2. Ensures filling of the chambers 133 b. Action potentials in Cardiac Muscle Cells (see figure 9-10) i. Contractile myocardial cells have a stable resting membrane potential ii. Depolarization wave travels through the gap junctions and opens fast voltage gated Na+ channels in the contractile cell iii. Triggers an action potential iv. Na+ channels close and slow Ca2+ channels and K + channels open causing the plateau phase v. Plateau phase – Ca2+ influx from the ECF prolongs the action potential and prevents rapid repolarization vi. Ca2+ close and K+ channels remain open causing repolarization due to K+ efflux c. Contraction of Cardiac Muscle (see figure9-11) i. Cardiac muscle contraction is similar to skeletal muscle contraction ii. The action potential traveling down the T-tubules triggers the influx of Ca2+ from the ECF iii. The Ca2+ influx induces the release of additional Ca2+ from the SR iv. Ca2+ binds to troponin allowing sliding of the myofilaments d. Metabolism of Cardiac Muscle i. Relies almost exclusively on aerobic respiration ii. Constant and adequate blood supply is critical iii. Adaptive to multiple fuel sources: glucose, fatty acids, lactic acid) III. Cardiac Physiology a. Cardiac Cycle i. Contraction of the myocardium must occur in a coordinated rhythm to ensure proper pumping of blood ii. Atrial excitation and contraction must be completed before ventricular contraction occurs iii. Cardiac cycle refers to all events associated with one complete heart beat 1. Systole – contraction of heart muscle 2. Diastole – relaxation of heart muscle iv. Phases of the Cardiac Cycle (see figure 9-16) 1. Mid-to-late diastole – ventricular filling a. Blood passively flows into ventricles from atria b. Atria contract (atrial systole) c. AV valves open, SL valves closed 134 2. Ventricular systole a. Atrial diastole b. Rising ventricular pressure results in closing of AV valves c. Isovolumetric contraction phase d. Ventricular ejection phase opens semilunar valves 3. Early diastole - isovolumetric relaxation a. Ventricles relax b. Backflow of blood in aorta and pulmonary trunk closes semilunar valves c. Atria re-filling d. Atria pressure increases, AV valves open and cycle repeats v. Heart Sounds - (lub-dup) are associated with closing of heart valves 1. First sound occurs as AV valves close and signifies beginning of systole 2. Second sound occurs when SL valves close at the beginning of ventricular diastole b. Cardiac Output (CO) - the amount of blood pumped by each ventricle in one minute i. CO = (heart rate [HR]) x (stroke volume [SV]) 1. HR is the number of heart beats per minute 2. SV is the amount of blood pumped out by a ventricle with each beat ii. Cardiac Output: Example 1. CO (ml/min) = HR (75 beats/min) x SV (70 ml/beat) CO = 5250 ml/min (5.25 L/min) iii. Cardiac reserve is the difference between resting and maximal CO c. Regulation of Heart Rate (see table 9-3 & figure 9-20) i. Heart rate is modulated by the autonomic nervous system 1. Parasympathetic activity –slows HR down via Ach a. Increases K+ permeability, hyperpolarization 2. Sympathetic activity–increases HR via NE/E a. Increases Na+, and Ca2+ channels, speeds up depolarization ii. Chronotropic agents – affect heart rate 1. Positive chronotropic factors increase heart rate 135 2. Negative chronotropic factors decrease heart rate iii. Other factors that affect HR 1. Hormones - Epinephrine and Thyroxine increase HR 2. Ions a. Elevated K+ and Na+ – decrease HR 3. Physical factors 4. Age – decreases HR 5. Exercise – increases HR 6. Temperature – increases HR d. Regulation of Stroke Volume i. Stroke volume = end diastolic volume (EDV) minus end systolic volume (ESV) 1. EDV = amount of blood collected in a ventricle during diastole 2. ESV = amount of blood remaining in a ventricle after contraction ii. Factors Affecting Stroke Volume (see figure 9-21 through 9-25) 1. Internal Factors: a. Preload – amount ventricles are stretched by contained blood, dependent on EDV i. Frank-Starling’s Law: increased stretch = increased contraction strength ii. Affected by volume of venous return and ventricular filling time iii. Factors that would increase preload: 1. Exercise 2. Slower heart beat iv. Factors that would decrease preload 1. Blood loss 2. Rapid heart beat b. After load – back pressure exerted by blood in the large arteries leaving the heart i. Increase in after load decreases stroke volume ii. Atherosclerosis, arteriosclerosis, hypertension, loss of elasticity of blood vessels 136 2. Extrinsic Factors: a. Contractility – cardiac cell contractile force due to factors independent of stretch and EDV i. Inotropic agents – effect contractility 1. Positive inotropic increases contractility 2. Negative inotropic decreases contractility ii. Increase in contractility comes from: 1. Increased sympathetic stimuli 2. Hormones – thyroxine, epinephrine a. Sympathetic stimulation releases norepinephrine and initiates a cyclic AMP second-messenger system (see figure 14-30 pg. 503) 3. Increased ECF Ca2+ and some drugs like digitalis iii. Agents/factors that decrease contractility include: 1. Acidosis 2. Increased extracellular Na+ and K+ 3. Calcium channel blockers *See figure 9-25 for a summary of controlling cardiac output by adjusting heart rate and stroke volume. 137 Cardiac Physiology Post-Lecture Practice 1. Compare and contrast skeletal, smooth, and cardiac muscle by listing three distinctions for each type of muscle tissue. (hint: think about how they differ in innervation, structure, and contraction mechanisms and then pick two for each) Skeletal Smooth Cardiac 2. Describe / contrast the changes in membrane potential for a cardiac autorhythmic cell verses a contractile myocardial cell by labeling what happens in each phase. Use graphs from your textbook as a reference. 138 3. Fill out this chart below. Determine if the following factors would increase, decrease, or have no effect on heart rate, stroke volume, and cardiac output. Factor Affect on Heart Rate Affect on Stroke Volume Affect on Cardiac Output Increased Sympathetic Stimulation Increased Parasympathetic Stimulation Increased Venous Return Slow Heart Rate Extremely Fast Heart Rate Exercise Sudden Drop in Blood Pressure Rising Blood Pressure Sudden Drop in Blood Volume Excess Calcium Chart was adapted from InterActive Physiology CD, ©2006 Pearson Education. 139 Blood Pressure Study Objectives: 1. Compare and contrast the structure and function of arteries, arterioles, capillaries, venules, and veins. 2. Discuss the factors that affect blood flow and how they relate to blood pressure: a. Blood flow = pressure gradient / resistance. b. Discuss the factors that affect resistance: viscosity, length, elasticity, and peripheral resistance 3. Define blood pressure. Explain the clinical significance of systolic, diastolic, and pulse pressures. 4. Describe, in detail, the major factors which affect mean arterial blood pressure. a. Relate the importance of cardiac output, blood volume, and peripheral resistance, to blood pressure. b. Distinguish between intrinsic and extrinsic controls of arteriole diameter. c. Describe the effects of epinephrine, ADH, angiotensin II, histamine, and kinins on blood pressure. 5. Describe the role of the baroreceptor reflex in regulating blood pressure. 6. Define ultrafiltration and reabsorption and describe the process of net filtration in the capillaries. 7. Explain how the return of lymph through lymph vessels maintains blood volume and pressure. 8. Describe the factors that play a role in venous return. 140 Blood Pressure Outline I. Types of Blood Vessels a. Capilaries Venules Veins Heart Arteries Arterioles b. Review histology of blood vessels II. Blood Flow a. Flow rate – volume of blood per unit time. Flow rate = Pressure gradient / Resistance. Depends on: i. Pressure gradient – difference in pressure between the beginning and ending of a vessel (see figure 10-2) ii. Vascular resistance – hindrance or opposition to blood flow through a vessel 1. As resistance increases flow rate decreases 2. Factors affecting resistance: a. Viscosity – friction between molecules increases resistance (# of circulating RBC) b. Length – increased surface area increases resistance (remains constant in body) c. Elasticity d. Peripheral resistance – friction between the blood and the vessel wall (see figure 10-3) i. Radius the main determinant of resistance 1. Increased surface area exposed to blood increases resistance 2. Flow is faster in larger vessels than smaller III. Arteries a. Elastic arteries – offer little resistance due to their large diameter and elastic properties i. Function – maintain constant flow of blood through capillaries despite ventricular systole and diastole ii. Arteries distend during systole iii. Recoils pushing blood forward during diastole (see figure 10-6) IV. Blood Pressure - force exerted by the blood on the vessel wall (see figures 10-7 through 10-9) a. Systolic pressure – maximum pressure during ventricular systole b. Diastolic pressure – minimum pressure following ventricular diastole and blood moving forward into arterioles c. Pulse pressure – difference between the two 141 d. Mean arterial pressure – average pressure in the vessel throughout the cardiac cycle i. MAP = DP + 1/3 (pulse pressure) ii. MAP = cardiac output (CO) x total peripheral resistance (TPR) 1. CO = stroke volume x HR 2. TPR = radius and viscosity e. Arterioles – small radii, have more resistance i. Can adjust diameter to: 1. Vary distribution of blood to organs 2. Regulate arteriole pressure ii. Arteriole smooth muscle always displays a state of vascular tone (partial constriction). Maintained by: 1. Myogenic activity of smooth muscle cells 2. Sympathetic fibers iii. Factors influencing the level of smooth muscle contraction / arteriole radius (see figure10-10): 1. Intrinsic (local) controls – determines distribution of cardiac output a. Chemical i. Increased metabolic activity triggers vasodilation 1. Decreased O2 2. Increased CO2 3. Increased adenosine 4. Increased NO ii. Histamine and prostaglandins – vasodilation b. Physical influences i. Temperature 1. Heat – vasodilation 2. Cold – vasoconstriction ii. Myogenic response to stretch 1. Increased perfusion – increases stretch triggers vasoconstriction 2. Decreased perfusion – decreased stretch triggers vasodilation 2. Extrinsic controls – regulates systemic blood pressure a. Sympathetic Nervous System i. Maintains overall MAP for the system but local regulation can over ride it for tissues that need increased blood flow 142 b. Hormones i. ADH (a.k.a vasopressin) – vasoconstriction ii. Angiotensin II –vasoconstriction iii. NE / Epinephrine 1. α receptors – vasoconstriction 2. Β receptors – vasodilation (skeletal and coronary blood vessels) iv. Atrial Natriuretic Peptide – vasodilation **See figure 10-14 for a nice summary of how these intrinsic and extrinsic factors affect total peripheral resistance. f. Blood pressure regulation i. Short term regulation – adjustments occur within seconds. Involves the Baroreceptor Reflex: 1. Baroreceptors monitor MAP and initiate reflex responses to maintain BP homeostasis a. Receptors - found in the carotid sinus and aortic arch b. Sent to cardiovascular control center in the medulla c. Response – adjusts parasympathetic/ sympathetic activity (see figures 10-35 through 10-38) ii. Long term regulation – minutes to days. Involves adjusting blood volume. 1. Hormones a. Renin – angiotensin II – aldosterone pathway b. ADH V. Capillaries a. Site for exchange of materials between the blood and the tissues b. Precapillary sphincters control the flow of blood through the capillary beds (see figure 10-19) i. Smooth muscle that respond to local controls (see figure 10-20) c. Factors that influence diffusion in capillary beds i. Minimal diffusion distance ii. Maximized surface area for exchange (600m2) iii. Maximized time for exchange (slow velocity of flow) d. Exchange of solutes across capillary wall (see figure 10-18) i. Fat soluble solutes pass through endothelial cells ii. Small water soluble solutes pass through pores iii. Plasma proteins are too large to pass iv. Protein hormones cross by vesicular transport 143 e. Movement of fluid across the capillary wall occurs because of differences in hydrostatic and osmotic pressures (see figure 10-22) i. Plasma hydrostatic pressure – exerted on the vessel wall due to pushing of blood ii. Plasma osmotic pressure – created by movement of water as it is pulled down its concentration gradient iii. Net Filtration Pressure - determines if there is a net gain or net loss of fluid from the blood 1. Takes into account all hydrostatic and osmotic forces on the capillary 2. Bulk flow – movement of fluid across the capillary walls. Involves (see figure 10-23): a. Ultrafiltration – movement out of the capillary into the interstitial fluid, occurs at the arteriole end b. Reabsorption – movement into the capillary from the interstitial fluid, occurs at the venule end VI. Lymphatic Vessels (see figure 10-24 &10-25) a. More fluid is filtered into the ECF that reabsorbed b. This extra fluid is picked up by lymph capillaries i. Fluid leaks into lymph capillaries when interstitial pressure is high and one-way flap-like valves prevent lymph from leaking back out ii. Fluid is returned back to the blood by the lymph system iii. Pump-less one way system -lymph moves towards the heart iv. Flow is accomplished by: 1. Valves 2. Milking action of skeletal muscle 3. Contraction of smooth muscle in vessel walls 4. Pressure changes in the thorax VII. Veins - carry blood back to heart a. Large diameter, little resistance, low pressure b. At rest contains more than 60% of the total blood volume (see figure 1027) c. Factors affecting venous return (see figure10-28): i. Pressure gradient ii. One-way valves iii. Skeletal muscle contraction iv. Respiratory pump v. Cardiac suction vi. Sympathetic activity **see figure 10-34 for a nice summary of the numerous factors that influence MAP 144 VIII. Cardiovascular Disease (see figures 9-29 through 9-31 & table 9-4) a. Cardiovascular disease accounts for over half of all deaths in the United States i. Myocardial infarction - heart attack ii. Atherosclerosis – hardening of the arteries iii. Arteriostenosis – narrowing of the arteries b. Treatments for Cardiovascular Disease i. Life style changes and drugs ii. Angioplasty – use balloon or laser to remove the blockage from the artery 1. Or insert a stent to keep artery open iii. Coronary bypass surgery – use another blood vessel from another part of the body as a bridge to get around the blockage Blood Pressure Post Lecture Assignment: On Canvas I have posted a Blood Pressure Concept Map. It contains numerous terms that all relate to mean arterial pressure. You can print these terms, cut them out, and then arrange them in various ways to show relationships between them and how they affect mean arterial blood pressure. If you don’t want to spend the time cutting them up you could just write your own flow chart using these terms and making relationships. For example which factors would increase BP, which factors decrease BP, etc. 145 Body Defenses / Immunology Study Objectives: 1. List the organs in the lymphatic system and describe their functions. 2. Distinguish between innate and acquired (adaptive) immunity. 3. List the non-specific defenses of the body. a. Describe the characteristics, chemicals and cells involved in the inflammatory response. b. List the body’s antimicrobial proteins i. Explain the roles of interferon and the complement system c. Explain how the release of pyrogens help protect the body against invading bacteria 4. Compare and contrast the origins, maturation process, and general functions of B and T lymphocytes. 5. Define the following: immunity, antigens, and antibodies 6. Describe the process of (humoral) antibody mediated immunity a. Describe the process of clonal selection of a B cells b. Describe the role of plasma cells and memory cells c. Explain the functions of antibodies d. Compare and contrast active and passive immunity 7. Describe the events of cell-mediated immunity a. Describe the role of antigen presenting cells, T helper cells and cytotoxic T cells in the cell-mediated response b. Describe the function of perforins and granzymes released by cytotoxic T cells 8. Distinguish between primary and secondary immune responses 9. Describe and give examples of the following immunological disorders: immediate and delayed hypersensitivities, immunodeficiencies, and autoimmune diseases. 146 Body Defenses / Immunology Outline I. Lymphoid Organs a. Lymphoid tissues and organs –provide defense against disease by: i. Function: 1. Housing and facilitating the maturation of lymphocytes 2. Cleansing the lymph of pathogens ii. Organs/tissues (see figure 12-1): 1. Lymph nodes 2. Tonsils 3. MALTs (mucus associated lymph tissue) 4. Spleen 5. Thymus 6. Bone marrow II. Body Defenses a. Body defense mechanisms are aimed at eliminating abnormal cells or any foreign materials that are not self i. Invading pathogens (viruses, bacteria, ect.) ii. Removal of worn out cells, damaged tissue iii. Identification and destruction of abnormal or cancerous cells iv. Rejection of foreign tissue v. Inappropriate responses can lead to allergies or autoimmune diseases b. The body has two defense systems – that differ in timing and specificity yet are interactive and interdependent i. Innate immunity ii. Adaptive or Acquired immunity III. Innate (nonspecific) system responds quickly and consists of: a. First line of defense – physical barriers; intact skin and mucosa prevent entry of microorganisms b. Second line of defense – antimicrobial proteins, phagocytes, and other cells i. Inhibit spread of invaders throughout the body ii. Inflammation is its hallmark and most important mechanism c. Engulfing and Destroying Pathogens i. Neutrophil and macrophage destruction of bacteria ii. Phagocytosis: 1. Engulfs foreign material into a vacuole 2. Enzymes from lysosomes digest the material 147 d. Inflammation - the inflammatory response is triggered whenever body tissues are injured (see figure 12-2) i. Purpose: 1. Prevents the spread of damaging agents to nearby tissues 2. Disposes of cell debris and pathogens 3. Sets the stage for repair processes ii. The four cardinal signs of acute inflammation (see figure 12-3) 1. Redness 2. Heat 3. Swelling 4. Pain iii. Inflammation is mediated by phagocytes 1. Toll-like receptors (TLRs) present on phagocytes recognize and bind to foreign microbes and microbes that have been marked by an opsonin (complement proteins or antibodies) (see figure 12-4). 2. Activated TLRs triggers the phagocyte to: a. Engulf and destroy the pathogen b. And/or release chemicals that promote inflammation (cytokines) c. Inflammatory chemicals are released into the extracellular fluid by injured tissue, phagocytes, lymphocytes, and mast cells 3. Inflammatory chemicals: a. kinins, histamine, prostaglandin, complement, and cytokines, bacterial toxins b. Cause local blood vessels to dilate, resulting in hyperemia (heat and redness) c. Capillaries become “leaky” (edema and pain) d. Attract other WBCs to the area 4. Additional neutrophils are released from the bone marrow in response to leukocytosis-inducing factors released by injured cells 5. Mobilization of WBC – leukocytes emigrate from the blood into the tissues a. Margination – neutrophils cling to the walls of capillaries in the injured area b. Diapedesis – neutrophils squeeze through capillary walls c. Chemotaxis – inflammatory chemicals attract neutrophils to the injury site and they begin phagocytosis 148 e. Other Secreted Chemicals i. Pyrogens – secreted by macrophages 1. Cause hypothalamus to elevate the body’s set temperature (fever) 2. Moderate fever can be beneficial, as it causes: a. The liver and spleen to sequester iron and zinc (needed by microorganisms to grow and divide) b. Increase rate of chemical reactions which speeds up tissue repair ii. Antimicrobial Proteins 1. Enhance the innate defenses by: a. Attacking microorganisms directly b. Hindering microorganisms’ ability to reproduce 2. The most important antimicrobial proteins are: a. Interferon (see figure 12-5) i. Released by virus infected cells and binds to receptors on neighboring healthy cells ii. Interferon protects these neighbors by activating genes for PKR (an antiviral protein) iii. PKR nonspecifically blocks viral reproduction in the cell if it becomes infected iv. Also slows division of tumor cells v. Enhances natural killer cells 1. Lyse and kill cancer cells and virusinfected cells on first exposure to them 2. Immediate and nonspecific response 3. Immunosurveillance b. Complement proteins i. 25 or so proteins that circulate in the blood in an inactive form ii. Forms membrane attacking complex that punch holes in foreign cell’s membrane and causes the cell to lyse (see figure 12-6b) iii. Also acts as opsonins and chemotaxins iv. Activated by: 1. Exposure to carbohydrate chains on the surface of micro-organisms 2. Exposure to antibodies produced by the acquired immune response against the micro-organism 149 IV. Acquired or Adaptive (specific) defense system a. Third line of defense – mounts attack against particular foreign substances i. Takes longer to react than the innate system ii. Targets invaders that the body has previously been exposed to iii. Involves lymphocytes iv. Works in conjunction with the innate system b. Characteristics of Acquired Immunity i. The acquired immune system is: 1. antigen-specific - requires the production of specific lymphocytes and antibodies against a specific antigen 2. systemic - not restricted to the initial infection site 3. has memory -second encounter causes a more rapid and vigorous response ii. Antigens - any substance capable of provoking an immune response. Antigens include foreign protein, nucleic acid, some lipids, and large polysaccharides iii. It has two separate but overlapping branches: 1. Humoral, or antibody-mediated immunity 2. Cellular, or cell-mediated immunity iv. Lymphocytes - originate from stem cells in the red bone marrow 1. Each lymphocyte is equipped with: a. a unique receptor that binds a specific antigen b. and a MHC receptor that distinguishes self 2. Immunocompetent – cells display a unique type of receptor that responds to a distinct antigen (based on genetic variance) a. Become immunocompetent before they encounter antigens they may later attack b. Are exported to secondary lymphoid tissue where encounters with antigens occur c. Mature into fully functional antigen-activated cells upon binding with their recognized antigen 3. B lymphocytes become immunocompetent in the bone marrow a. Responsible for antibody-mediated immunity b. Defend against extracellular pathogens by producing antibodies 150 4. T lymphocytes become immunocompetent in the thymus a. Responsible for cell-mediated immunity b. Defend against intracellular pathogens and cancer c. Maturation of T Cells i. T cells mature in the thymus under negative and positive selection pressures ii. Negative selection – eliminates T cells that are strongly anti-self iii. Positive selection – selects T cells with a weak response to self-antigens, which thus become both immunocompetent and selftolerant c. Antibody-Mediated Response i. Triggered when B-cells with specific receptors bind to a specific antigen ii. The binding event activates the lymphocyte to multiply (clonal selection) (see figure 12-12) 1. Most B cells become plasma cells that produce antibodies to destroy antigens 2. Some B cells become long-lived memory cells that will remain in the body to respond to the antigen if exposed again iii. Antibodies (immunoglobulins) – proteins that travel in the plasma and combine with a specific antigen. 1. Function: mark the antigens for destruction by specific or nonspecific mechanisms 2. Structure: Y shaped molecules with variable region on the tips of each arm that binds a specific antigen (12-10) 3. Antibodies inactivate antigens in a number of ways (see figure 12-11): a. Complement fixation – bind and lyse cell, inflammation b. Opsonization – mark antigen for phagocytosis c. Neutralization – block harmful effects of toxins d. Agglutination – clumping of foreign cells e. Precipitation – clumping of antigens f. Attract natural killer cells d. Cell Mediated Response i. T cells can only recognize and bind antigens that are presented to them by antigen presenting cells (APC). APCs are macrophages that engulf pathogens and then present pieces of the antigen to lymphocytes. (See figure 12-18 and 12-20) 151 ii. Antigens must be presented by APC to a THelper cell which triggers the cell to release cytokines that stimulate division of various cells: 1. Enhances proliferation of B-cells 2. and Cytotoxic T-cells which specialize in killing cancer and virus infected cells iii. Mechanisms of Cytotoxic T cell (see figure12-14) 1. Cytotoxic T cells bind to virus infected and cancerous cells and destroy them by releasing: a. Perforins that punch holes in the target cells membrane (see figure 12-15) b. Granzymes that cause the cell to undergo apoptosis **Table 12-3 summarizes the immune’s response to extracellular bacteria and table 12- 2 summarizes the immune response to intracellular pathogens such as viruses. These figures do a nice job of distinguishing between the antibody and cell mediated responses while also showing the overlap that occurs between the innate and acquired defense when an immune response is initiated. V. Immunological Memory a. Immunity – ability to defend against specific invaders b. Immune Responses (see figure 12-13) i. Primary immune response – cellular differentiation and proliferation, which occurs on the first exposure to a specific antigen 1. Lag period: 3 to 6 days after antigen challenge 2. Peak levels of plasma antibody are achieved in 10 days 3. Antibody levels then decline ii. Secondary immune response – re-exposure to the same antigen 1. Sensitized memory cells respond within hours 2. Antibody levels peak in 2 to 3 days at much higher levels than in the primary response 3. Antibodies bind with greater affinity, and their levels in the blood can remain high for weeks to months c. Mechanisms for acquiring immunity i. Active Immunity - B cells encounter antigens and produce antibodies against them 1. Naturally acquired – response to a bacterial or viral infection 2. Artificially acquired – response to a vaccine of dead or attenuated pathogens a. Vaccines – spare us the symptoms of disease, and their weakened antigens provide antigenic determinants that build our immunity 152 ii. Passive Immunity -differs from active immunity in that: 1. B cells are not challenged by antigens 2. Immunological memory does not occur 3. Protection ends when antigens naturally degrade in the body 4. Naturally acquired – from the mother to her fetus via the placenta or IgA antibodies in breast milk 5. Artificially acquired – from the injection of serum that contains the immunoglobulins VI. Immune Disorders a. Hypersensitivity - abnormal, vigorous immune responses (overzealous immune system) (Table 12-5) i. Immediate hypersensitivity – occurs within seconds to 20 minutes 1. Allergies and Asthma (see figure 12-24) a. Plasma cells produce IgE antibodies which attach to mast cells b. Mast cells release histamine – which causes inflammation and itching c. Also releases a leukotriene called slow reactive substance – causes smooth muscle contraction in air ways d. Treated with anti-histamines and newer drugs that block leukotrienes such as Singular 2. Anaphylactic Shock - systemic allergic response that is life-threatening a. Allergen directly enters blood b. Systemic histamine and SRS releases may result in: i. Constriction of bronchioles ii. Sudden vasodilation and fluid loss from the bloodstream iii. Hypotensive shock and death c. Treated with epinephrine ii. Delayed hypersensitivity - symptoms appear after 1-3 days 1. Inflammation caused by cytotoxic T-cells release of lymphokines 2. Treated with corticosteroids 153 b. Immunodeficiency - production or function of immune cells is lacking or abnormal i. Severe combined immunodeficiency disease (SCID) 1. Deficiency of B and T-cells ii. Acquired Immune Deficiency Syndrome (AIDS) 1. HIV destroys THelper cells c. Autoimmune diseases - the immune system does not distinguish between self and non-self i. The body produces antibodies and cytotoxic T-cells that attack its own tissues ii. Possible causes: 1. Inefficient lymphocyte programming 2. Appearance of new self-antigens 3. Antibodies produced against foreign antigens react with self-antigens (streptococcus and rheumatic fever) 154 Body Defenses Post-Lecture Practice 1.Which of the following is NOT considered a lymphoid organ/tissue? a. Liver b. Spleen c. Tonsils d. Peyer’s patches in the intestinal mucosa e. Thymus 2. All of the following are part of the innate immune system EXCEPT: a. production of complement proteins b. inflammation c. production of antibodies d. phagocytosis by neutrophils 3. Which type of lymphocyte would physically destroy cells infected by an intracellular pathogen? a. B-cell b. Plasma cell c. T-helper cell d. Cytotoxic T cell 4. Which cell type produces antibodies? a. plasma cells b. T-helper cells c. memory cells d. macrophages e. all of the above 5.Where do T-lymphocytes mature? a. Thymus b. Spleen c. Lymph nodes d. Bone marrow e. Tonsils 155 Respiratory Physiology Study Objectives: 1. List the functions of the respiratory system 2. Identify the organs of the respiratory system and a general function of each. 3. Describe the structure and function of the mucus membrane (ciliated pseudostratified with goblet cells), the respiratory membrane, and the pleural sac. 4. Describe the mechanism of pulmonary ventilation. a. Describe the changes in pressure, volume and events involved in inspiration and expiration. b. Describe the factors that affect ventilation: lung compliance, elasticity, surface tension, and resistance 5. Compare the volumes and capacities of air exchanged during ventilation. 6. Distinguish between obstructive and restrictive pulmonary disorders 7. Explain how the following gas principles apply to respiration: Dalton’s Law, Boyle’s Law, and Henry’s Law. 8. Explain how blood transports both oxygen and carbon dioxide. 9. Describe the factors that affect the binding of oxygen to hemoglobin thus affecting the loading and unloading mechanisms. 10. Explain the differences between “external” and “internal” respiration. 11. Explain the roles of the medulla and pons in the regulation of respiration. 12. Describe the factors that affect respiratory center activity: chemical factors (CO2, O2, pH), reflexes, hypothalamic controls (emotions), and cortical controls (voluntary) 13. Compare and contrast the roles of peripheral and central chemoreceptors in the regulation of respiration. 156 Respiratory Outline I. Functions of the Respiratory System a. Gas exchange – between the external environment and the blood b. Filters, humidifies, and warms inspired air c. Production of sound d. Smell e. Maintains pH homeostasis II. Anatomy Review a. Structures (see figure 13-2) i. Nose ii. Pharynx iii. Larynx iv. Trachea v. Bronchi vi. Bronchioles vii. Alveolar ducts viii. Alveoli ix. Respiratory Membrane 1. Site of gas exchange between the alveoli and the blood 2. Formed by the alveolar wall and the capillary wall x. Pleural membrane (serous membranes) (see figure 13-5) 1. Pleural Sac – double walled membrane surrounding the lungs 2. Visceral pleura - covers the lung surface 3. Parietal pleura - lines the walls of the thoracic cavity 4. Pleural fluid fills the area between layers to allow gliding and resist separation III. Respiratory Pressures (see figure 13-6 & 13-7) a. Respiratory pressures are described relative to atmospheric pressure @ sea level: i. Patm = 760 mm Hg ii. Negative pressure: -1mm Hg = 759 mm Hg iii. Positive pressure: + 1 mm Hg = 761 mm Hg iv. 0 mm Hg = 760 mm Hg b. Intrapulmonary pressure (a.k.a alveolar pressure) – pressure within the alveoli c. Intrapleural pressure – pressure within the pleural cavity 157 d. Transpulmonary pressure – difference between the intrapulmonary and intrapleural pressures i. Intrapleural pressure is always less than intrapulmonary pressure ( -4 mmHg ) ii. Keeps the airways open e. Pneumothorax – occurs when intrapleural pressure equals atmospheric pressure, causes lungs to collapse (see figure 13-3) IV. Respiration Events a. Events in Respiration i. Pulmonary ventilation ii. External respiration iii. Gas transport iv. Internal respiration b. Pulmonary ventilation – moving air in and out of the lungs i. Mechanical process that depends on volume changes in the thoracic cavity 1. Caused by the contraction/relaxation of intercostal muscles and the diaphragm 2. ∆ Volume → ∆ Pressure → flow of gases a. Boyle’s law – the relationship between the pressure and volume of gases P1V1 = P2V2 i. P = pressure of a gas in mm Hg ii. V = volume of a gas in cubic millimeters iii. See figure 13-9 ii. Phases of Ventilation 1. Intrapulmonary pressure and intrapleural pressure fluctuate with the phases of breathing 2. Two phases (see figure 13-11): a. Inspiration – flow of air into lung. i. Intrapulmonary P decreases as thoracic cavity expands (volume increases); air moves into lungs from the higher pressure to lower pressure b. Expiration – air leaving lung. i. Intrapulmonary P increases as lungs recoil (volume decreases); air moves out of lungs from the higher pressure to the lower pressure 158 iii. Factors Affecting Ventilation 1. Lung Compliance - the ease with which the lungs can be expanded a. Reduced by factors that produce resistance to distension of the lung tissue and surrounding thoracic cage i. Pulmonary edema, fibrosis, surface tension of the alveoli 2. Elasticity – how readily the lungs recoil after stretching a. Elastic CT and surface tension of the alveoli 3. Surface tension -the attraction of liquid molecules to one another in the alveolus (see figure 13-5) a. The liquid coating is always acting to reduce the alveoli to the smallest possible size b. Surfactant, a detergent-like complex, reduces surface tension and helps keep the alveoli from collapsing 4. Airway Resistance a. Friction is the major source of resistance to airflow i. The relationship between flow (F), pressure (P), and resistance (R) is: F = Pressure gradient / Resistant ii. Affected by: 1. Autonomic Nervous System – controls diameter of bronchioles (see table 13-1) a. Sympathetic – bronchodilation decreases resistance b. Parasympathetic – bronchoconstriction increases resistance 2. Chronic Obstructive Pulmonary Diseases: asthma, bronchitis, emphysema (see figure 13-14) c. Testing Respiratory Function i. Respiratory capacities are measured with a spirometer ii. Spirometer – an instrument consisting of a hollow bell inverted over water, used to evaluate respiratory function 159 iii. Spirometry can distinguish between: 1. Obstructive pulmonary disease – increased airway resistance 2. Restrictive disorders – reduction in lung compliance and capacity from structural or functional lung changes iv. Respiratory Volumes (see figure 13-16) 1. Tidal volume (TV) – air that moves into and out of the lungs during normal breathing (~ 500 ml) 2. Inspiratory reserve volume (IRV) – air that can be inspired forcibly beyond the tidal volume (2100–3200 ml) 3. Expiratory reserve volume (ERV) – air that can be evacuated from the lungs after a tidal expiration (1000– 1200 ml) 4. Residual volume (RV) – air left in the lungs after strenuous expiration (1200 ml) 5. Dead space volume - air that remains in conducting zone and never reaches alveoli ~150 ml 6. Functional volume - air that actually reaches the respiratory zone ~350 ml v. Respiratory Capacities – two or more volumes added together 1. Inspiratory capacity (IC) – total amount of air that can be inspired after a tidal expiration (IRV + TV) 2. Expiratory capacity (EC) - total amount of air that can be expired after a tidal inspiration (ERV + TV) 3. Functional residual capacity (FRC) – amount of air remaining in the lungs after a tidal expiration (RV + ERV) 4. Vital capacity (VC) – the total amount of exchangeable air (TV + IRV + ERV) 5. Total lung capacity (TLC) – sum of all lung volumes (approximately 6000 ml) 6. Forced vital capacity (FVC) – gas forcibly expelled after taking a deep breath a. Forced expiratory volume (FEV) – the amount of gas expelled during specific time intervals of the FVC vi. Total ventilation – total amount of gas flow into or out of the respiratory tract in one minute 1. (respiratory rate X tidal volume) vii. Restrictive vs. Obstructive diseases 1. Obstructive disease - increases in RV, decrease in ERV 2. Restrictive disease -reduction in VC, TLC, and IRV 3. See figure 13-17 160 d. External Respiration – gas exchange between pulmonary blood and alveoli across the respiratory membrane i. Oxygen movement from the alveoli into the blood ii. Carbon dioxide movement out of the blood into the alveoli iii. Factors influencing external respiration: 1. Partial pressure gradients and gas solubility a. Dalton’s Law – partial pressure gradients. i. Total pressure exerted by a mixture of gases is the sum of the pressures exerted independently by each gas in the mixture. ii. The partial pressure of each gas is directly proportional to its percentage in the mixture (see figure 13-21) b. Oxygen movement into the blood from the alveoli i. The alveoli have a higher PO2 than the blood ii. Oxygen moves by diffusion towards the area of lower partial pressure c. Carbon dioxide movement out of the blood to the alveoli i. Blood returning from tissues has a higher PCO2 than the air in the alveoli ii. See figure 13-22 d. Henry’s Law – gas solubility i. Gas will dissolve into liquid in proportion to its partial pressure. ii. The amount of gas that will dissolve in a liquid also depends upon its solubility iii. Various gases in air have different solubilities: 1. Carbon dioxide is the most soluble; 20X more soluble than oxygen 2. Nitrogen is practically insoluble in plasma iv. Hemoglobin acts as a “storage depot” for O2 by removing it from the plasma as soon as it is dissolved. (See figure 13-25) 1. This keeps the plasma’s PO2 low and prolongs the partial pressure gradient between the plasma and the alveoli 2. Leads to a large net transfer of O2 161 2. Matching of alveolar ventilation and pulmonary blood perfusion a. Ventilation and perfusion are matched for efficient gas exchange i. Ventilation – the amount of gas reaching the alveoli ii. Perfusion – the blood flow reaching the alveoli b. Changes in PCO2 and PO2 in the alveoli cause local changes: i. When alveolar CO2 is high and O2 is low: Bronchioles will dilate and arterioles constrict ii. When alveolar CO2 is low and O2 is high: Bronchioles will constrict and arterioles will dilate iii. See figure 13-19 3. Structural characteristics of the respiratory membrane: a. Are only 0.5 to 1 µm thick, allowing for efficient gas exchange b. Have a total surface area (in males) of about 60 m2 (40 times that of one’s skin) c. Thickening causes gas exchange to be inadequate: inflammation, edema, mucus, fibrosis d. Decrease in surface area with emphysema, when walls of adjacent alveoli breakdown (see figure 1323) * See table 13-5 for a summary of some of the factors influencing external respiration. e. Gas Transport in the Blood i. Oxygen transport in the blood 1. 98% of oxygen is transported attached to hemoglobin (oxyhemoglobin [HbO2]) 2. A small amount is carried dissolved in the plasma (~2%) 3. Each Hb molecule binds four oxygen atoms in a rapid and reversible process 4. Hemoglobin Saturation/Dissociation Curve (See figure 13-24) a. The % hemoglobin saturation depends on the PO2 of the blood i. In the alveoli – 98% saturation ii. In the tissues - ~75% saturation iii. In an exercising muscle the PO2 equals ~ 20 mmHg 162 b. Factors Affecting Saturation of Hemoglobin (See figure 13-26) i. Increases in the following factors decreases hemoglobin’s affinity for oxygen: 1. Temperature 2. H+ (acidity) 3. PCO2 4. 2,3-biphosphoglycerate (BPG) ii. These factors modify the structure of hemoglobin and alter its affinity for oxygen and enhances oxygen unloading from Hb iii. These parameters are higher in systemic capillaries supplying tissues, where oxygen unloading is the goal ii. Carbon dioxide is transport in the blood 1. CO2 is transported in three forms: a. Dissolved in plasma – 7% b. Bound to hemoglobin – 23% is carried in RBCs as carbaminohemoglobin, at a different binding site than oxygen c. Most is carried as bicarbonate ions in plasma – 70% is transported as bicarbonate (HCO3–) i. Carbon dioxide diffuses into RBCs and combines with water to form carbonic acid (H2CO3), which quickly dissociates into hydrogen ions and bicarbonate ions 2. Exchange of Carbon Dioxide (See figure 13-27) a. At the tissues: i. Bicarbonate quickly diffuses from RBCs into the plasma ii. The chloride shift – to counterbalance the outrush of negative bicarbonate ions from the RBCs, chloride ions (Cl–) move from the plasma into the erythrocytes b. At the lungs: i. Bicarbonate ions move into the RBCs and bind with hydrogen ions to form carbonic acid ii. Carbonic acid is then split by carbonic anhydrase to release carbon dioxide and water iii. Carbon dioxide then diffuses from the blood into the alveoli 163 f. Internal Respiration - exchange of gases between blood and body cells i. Oxygen diffuses from blood into tissue ii. Carbon dioxide diffuses out of tissue into blood V. Control of Respiration a. Medullary centers (see figure 13-29): i. The dorsal respiratory group (DRG), or inspiratory center: 1. Appears to be the pacesetting respiratory center 2. Excites the inspiratory muscles and sets eupnea (12-15 breaths/minute) 3. Becomes dormant during expiration ii. The ventral respiratory group (VRG) is involved in forced expiration b. Pons centers – pneumotaxic and apneustic areas i. Influence and modify activity of the medullary centers ii. Smoothes out inspiration and expiration transitions c. Depth and Rate of Breathing i. Cortical controls are direct signals from the cerebral motor cortex that bypass medullary controls (conscious control) 1. Examples: voluntary breath holding, taking a deep breath ii. Hypothalamic controls act through the limbic system to modify rate and depth of respiration 1. Example: breath holding that occurs in anger, hyperventilation from anxiety iii. Three chemical factors affecting ventilation: 1. Carbon dioxide levels- main regulatory chemical for respiration a. ↑ CO2 = ↓ blood pH b. Increased CO2 increases respiration. A rise in PCO2 levels (hypercapnia) increases ventilation. c. Changes in CO2 act on central chemoreceptors in the medulla oblongata (See figure 13-31)) i. Carbon dioxide in the blood diffuses into the cerebrospinal fluid where it is hydrated ii. Resulting carbonic acid dissociates, releasing hydrogen ions (decreases pH) d. Hyperventilation – increased depth and rate of breathing that: i. Quickly flushes carbon dioxide from the blood ii. Occurs in response to hypercapnia 164 e. Hypoventilation – slow and shallow breathing due to abnormally low PCO2 levels i. Apnea (breathing cessation) may occur until PCO2 levels rise f. See figure 13-28 Hyperventilation vs. hypoventilation 2. Oxygen levels a. Peripheral chemoreceptors in the aorta and carotid artery detect oxygen concentration changes b. Substantial drops in arterial PO2 (to 60 mm Hg) are needed before oxygen levels become a major stimulus for increased ventilation c. Information is sent to the medulla oblongata via the vagus nerve d. If carbon dioxide is not removed (e.g., as in emphysema and chronic bronchitis), chemoreceptors become unresponsive to PCO2 chemical stimuli i. In such cases, PO2 levels become the principal respiratory stimulus (hypoxic drive) 3. Arterial pH levels a. Changes in arterial pH can modify respiratory rate even if carbon dioxide and oxygen levels are normal b. Increased ventilation in response to falling pH is mediated by peripheral chemoreceptors in the aorta and carotid body (see figure 13-30) c. Acidosis may reflect: i. Carbon dioxide retention ii. Accumulation of lactic acid iii. Excess fatty acid metabolism in patients with diabetes mellitus d. Respiratory system controls will attempt to raise the pH by increasing respiratory rate and depth *See table 13-8 for a summary of chemical factors effect on peripheral and central chemoreceptors. iv. Other Reflexes 1. Pulmonary irritant reflexes – irritants promote reflexive constriction of air passages 165 2. Inflation reflex (Hering-Breuer) – stretch receptors in the lungs are stimulated by lung inflation a. Upon inflation, inhibitory signals are sent to the medullary inspiration center to end inhalation and allow expiration d. Respiratory Adjustments to High Altitude i. Quick movement to high altitude (above 8000 ft) can cause symptoms of acute mountain sickness – headache, shortness of breath, nausea, and dizziness 1. A more severe illness is high-altitude pulmonary edema caused by high pulmonary arterial pressure from constriction of pulmonary arteries in response to low PO2 2. High-altitude cerebral edema – increased cerebral blood flow and permeability of cerebral endothelium when expose to hypoxia ii. Acclimatization to the hypoxia – respiratory and hematopoietic adjustments to altitude include: 1. Increased ventilation – 2-3 L/min higher than at sea level 2. Chemoreceptors become more responsive to PCO2 3. Substantial decline in PO2 stimulates peripheral chemoreceptors 4. Kidneys accelerate production of erythropoietin (slower response ~4 days) 166 Respiratory Post-Lecture Assignment 1. List four factors that affect ventilation: 2. List at least four factors that affect external respiration: 3. During inspiration the thoracic cavity volume ________ causing a ________in intrapulmonary pressure. a. increases; decrease b. decreases; increase c. increase; increase d. decrease; decrease 4. All of the following factors directly affect ventilation EXCEPT: a. Lung compliance b. Elasticity c. Surface tension d. Air flow resistance e. Perfusion 5. The volume of air moving into and out of the lungs during a normal breath is the: a. tidal volume b. vital capacity c. residual volume d. inspiratory reserve volume e. inspiratory capacity 167 6. Most carbon dioxide is transported through the blood as_________. a. Bicarbonate b. Carbaminohemoglobin c. Carbon monoxide d. Carbonic acid e. Oxyhemoglobin 7. In a healthy individual the main stimulus to breath is: a. decreasing carbon dioxide levels b. decreasing oxygen levels c. increasing carbon dioxide levels d. increasing oxygen levels e. alkaline pH 168 Digestive Physiology Study Objectives: 1. Identify the organs of the alimentary canal and accessory organs. 2. Describe the overall functions of the digestive system. 3. Be able to recognize examples of mechanical and chemical digestion. 4. List the factors that regulate digestive tract activity: autonomous smooth muscle, mechanical and chemical receptors, hormones, intrinsic nerves, and extrinsic nerves 5. Describe the structure and general activities of each digestive system organ. 6. Describe the composition and the function of saliva in digestion. 7. Describe the composition and function of bile in digestion. 8. Describe the four phases of gastric motility: filling, mixing, storing, and emptying 9. Describe the function of the parasympathetic nervous system and the following hormones in the digestive processes: gastrin, secretin, and cholecystokinin 10. List the major digestive enzymes, which digestive or accessory organ produces it, the substrate it works on and products produced: amylase, pepsin, trypsin, chymotrypsin, carboxypetidase, lipase, brush border enzymes 11. Describe the mechanisms of absorption of vitamins, electrolytes, sugars, aminoacids, and lipids in the small intestines. 169 Digestive Outline I. Anatomy of the Digestive System a. Organs of the Alimentary Canal i. Mouth ii. Pharynx iii. Esophagus iv. Stomach v. Small Intestines vi. Large Intestines b. Accessory organs – assist with digestion i. Salivary glands ii. Teeth iii. Pancreas iv. Liver v. Gallbladder c. Histology of the Alimentary Canal (see figure 16-2) i. Mucosa – innermost layer lining the lumen, mucus membrane epithelium ii. Submucosa – areolar CT layer iii. Muscularis externa – inner circular and outer longitudinal layer of smooth muscle iv. Serosa – outermost layer lining the external surface II. Functions of the Digestive System a. Ingestion – taking food in b. Propulsion – movement of food along the digestive tract i. Peristalsis 1. Involuntary waves of contraction and relaxation of muscles in the organ walls 2. Propel digestive material forward through the digestive tract ii. Segmentation 1. Contractions that churn and break apart digestive material c. Digestion – breaking down food into smaller molecules i. Mechanical – changing physical structure ii. Chemical – changing chemical structure d. Absorption – transport of nutrients from the lumen of the gastrointestinal tract to the blood e. Defecation – elimination of indigestible substances from the body 170 III. Regulation of Digestive Tract Activity a. Regulation of digestion involves: i. Autonomous smooth muscle ii. Mechanical and chemical stimuli – stretch receptors, osmolarity, and presence of substrate in the lumen iii. Gastrointestinal hormones iv. Extrinsic nerves control by CNS centers v. Intrinsic nerves control by local centers (Enteric Nervous System) vi. See figure 16-3 b. Autonomous Smooth Muscle i. Visceral smooth muscle is autonomous ii. Smooth muscle pacemaker cells display rhythmic, spontaneous variations in membrane potentials (slow wave potential) (review this topic in chapter 8, figure 8-32) iii. Hormones, mechanical stress, and nerve stimuli determines the starting point of the slow wave potentials c. Nervous Control of the GI Tract i. Long reflexes 1. Stimulus may be within or outside the GI tract 2. Involves integration in CNS (usually in the medulla) and output sent via autonomic nerves to GI tract 3. Extrinsic control a. Can alter muscle and gland activity b. Can alter levels of hormone secretions c. Modify intrinsic activity d. Coordinate different parts of the GI tract i. Example: chewing food causes increased gastric secretions in stomach (feed forward mechanism) ii. Short reflexes 1. Involves the enteric nervous system - myenteric and submucous plexus within the digestive tract wall 2. Intrinsic control - entire reflex arc is carried out within the GI tract (responds to local stimuli) a. Coordinates local activity, can work independently of the CNS or it can be influenced by extrinsic nerves because it is linked to long autonomic reflex arcs d. Gastrointestional hormones i. Gastrointestinal peptides can act as digestive hormones and paracrine signals 171 ii. Released into the blood or ECF by cells of the digestive tract iii. Can act on digestive organs and accessory organs to excite or inhibit motility or secretions iv. Can also act on the brain to trigger hunger or satiety IV. Digestive Activities a. Mouth i. Chewing begins mechanical digestion by breaking food into smaller pieces and mixing food with saliva ii. Compacts food into a bolus iii. The salivary enzyme amylase begins the chemical digestion of carbohydrates 1. Polysaccharides Maltose iv. Saliva 1. Secreted from serous and mucous cells in the salivary glands 2. Composition of saliva a. 97-99.5% water b. Digestive enzyme – salivary amylase c. Mucus – moistens food and holds bolus together d. Lysozyme and IgA – antibacterial action 3. Control of Salivation a. Salivary secretion is enhanced by two reflexes: i. Simple reflex - ingested food stimulates chemoreceptors and pressoreceptors that trigger the salivary center in the medulla ii. Acquired reflex - the thought of food, cortex triggers the salivary center in the medulla iii. See figure 16-4 b. ANS control i. Parasympathetic – larger volume of saliva, watery and rich with amylase ii. Sympathetic – smaller volume, more mucus, results in dry mouth b. Deglutition (Swallowing) see figure 16-5 i. Involves the coordinated activity of the tongue, soft palate, pharynx, and esophagus 1. Buccal phase (a.k.a. oropharyngeal)– bolus is forced into the oropharynx (voluntary) 2. Pharyngeal-esophageal phase – controlled by the medulla and lower pons (involuntary) ii. Peristalsis moves food through the pharynx and the esophagus 172 c. Stomach i. Food enters stomach from the esophagus through the gastroesophageal sphincter ii. Functions of the stomach: 1. Mixes and stores food until it can be emptied into the small intestines 2. Degrades the bolus both physically and chemically a. Food is mixed with gastric juices to produce chyme (mechanical) b. Enzymatically digests proteins with the enzyme pepsin (chemical) 3. Secretes intrinsic factor required for absorption of vitamin B12 iii. Four phases of gastric motility 1. Gastric filing 2. Storage 3. Mixing 4. Emptying iv. Gastric filling 1. Stomach relaxes as it fills, rugae flatten out 2. Stomach dilates in response to gastric filling (1L) v. Gastric storage 1. Peristaltic contractions are weak in the body of the stomach, so little mixing occurs vi. Gastric mixing 1. Takes place in the muscular antrum 2. Occurs as chyme is propelled forward against the closed pyloric sphincter by peristaltic contractions 3. Gastric Secretions a. Types of secretions (See table 16-3) i. Exocrine 1. Mucous cells – produce mucus to protect stomach wall from harsh acids 2. Parietal cells – produce HCL and intrinsic factor 3. Chief cells – produce pepsinogen, an inactive form of the protein digesting enzyme pepsin 173 a. Chemical digestion of proteins begins in the stomach b. Pepsinogen is converted into pepsin by HCl c. Pepsin breaks down proteins into peptide fragments d. Proteins Peptides ii. Endocrine 1. G cells – produce the hormone gastrin which stimulates gastric acid secretion iii. Paracrine 1. ECL cells – secrete histamine, stimulates secretion from parietal cells 2. D cells – secrete somatostatin, inhibits secretions from parietal, ECL cells, and G cells b. Regulation of Gastric Secretion i. Neural and hormonal mechanisms regulate the release of gastric juices ii. Excitatory and inhibitory events occur in three phases: 1. Cephalic phase – prior to food entry a. Excitatory events include: i. Sight or thought of food ii. Stimulation of taste, smell, pressure receptors; chewing iii. Vagal stimulation releases ACh – stimulates parietal, G cells, and ECL cells b. Inhibitory events include: i. Loss of appetite or depression ii. Decrease in stimulation of the parasympathetic division 174 2. Gastric phase: once food enters the stomach a. Excitatory events include: i. Stomach distension activation of stretch receptors (neural activation) ii. Activation of chemoreceptors by peptides, caffeine, and alkaline pH iii. Triggers release of gastrin into the blood b. Inhibitory events include: i. An acidic pH lower than 2 - triggers release of somatostatin 3. Intestinal phase: as partially digested food enters the duodenum a. Mostly inhibitory b. Inhibitory phase – distension of duodenum, presence of fatty, acidic, or hypertonic chyme in the duodenum c. Initiates local reflexes and vagal nuclei i. Closes the pyloric sphincter d. Release of hormones that inhibit gastric secretion i. Cholecystokinin and Secretin – decrease gastric secretions and slows gastric motility ii. Gastric inhibitory peptides (GIP) (a.k.a glucose-dependent insulinotropic peptide)– inhibits gastric acid secretion, also promotes insulin release from pancreas * Tables 16-4 and 16-5 summarize factors that stimulate and inhibit gastric secretions. 175 vii. Gastric emptying 1. A strong enough peristaltic wave can push a small amount of chyme through the pyloric sphincter before it closes tightly 2. The rate of gastric emptying is controlled by both gastric and duodenal factors a. Gastric factors that increase gastric emptying i. Amount of chyme in the stomach – the stomach empties at a rate that is proportional to the volume of chyme ii. Distention – triggers smooth muscle and intrinsic plexuses iii. Fluidity of chyme iv. Signaling by the vagus nerve (extrinsic control) v. The hormone gastrin b. The duodenum controls gastric emptying by reducing peristaltic activity in the stomach until it is ready to accommodate more chyme c. Duodenal factors that decrease gastric emptying i. Fatty chyme – digested and absorbed slower than other nutrients in the duodenum ii. Acidity – chyme must be completely neutralized iii. Hypertonicity – need time for absorption of nutrients to catch up with digestion iv. Distention – needs to cope with volume before receiving more 3. Gastric emptying is regulated by: a. The neural enterogastric reflex -when the duodenum fills stretch receptors are stimulated and the pyloric sphincter closes b. Hormonal mechanisms: i. Cholecystokinin and secretin – released by duodenal endocrine cells into the blood; will inhibit gastric motility d. Small Intestines i. Extends from the pyloric sphincter to the ileocecal valve ii. Main function is chemical digestion and absorption of nutrients 176 iii. Three regions: 1. Duodenum – first part a. Chemical digestion, absorption 2. Jejunum – middle a. Absorption 3. Ileum – last part, joins the large intestines iv. Surface area for absorption is increased by villi and microvilli v. Substances must pass through an epithelial cells and then diffuse through the interstitial fluid in the underlying CT into a capillary or lacteal vi. Chyme enters the duodenum where it is mixed with bile from the liver and digestive enzymes from the pancreas 1. Liver a. Functions of the Liver i. Produces bile to aid in the digestion of fats ii. Stores excess nutrients and releases them when needed iii. Detoxifies drugs and metabolites iv. Produces plasma proteins b. Production of Bile by the Liver i. Hepatocytes produce bile and secrete it into bile ducts that empty into the common hepatic duct. ii. The sphincter of Oddi at the base of the common bile duct prevents bile from entering the duodenum between meals iii. Bile will back up into the gallbladder where it is concentrated and stored iv. Function of Bile 1. Bile is secreted into the duodenum to emulsify fats (see figure 16-16) 2. Bile increases the surface area for lipase to work on fats v. Bile is composed of: 1. Aqueous alkaline solution 2. Bile salts a. Nonpolar portion – cholesterol based steroid b. polar portion 3. Cholesterol 4. Lecithin – a phospholipid 5. Bilirubin – byproduct of RBC destruction 177 c. Regulation of Bile Release i. Acidic, fatty chyme causes the duodenum to release: 1. Cholecystokinin (CCK) and secretin into the bloodstream a. Secretin transported in blood stimulate the liver to produce bile b. Cholecystokinin causes the gallbladder to contract and the sphincters to relax ii. Vagal stimulation causes weak contractions of the gallbladder d. Recycling of Bile Salts (see figure 16-15) i. Most bile salts are reabsorbed back into the blood in the ileum are returned by the hepatic portal system ii. About 5% of bile escapes in feces 2. Pancreas a. Secretes pancreatic juices into the duodenum that break down all categories of food i. Acini cells secrete digestive enzymes ii. Duct cells secrete NaHCO3– which neutralizes acidic chyme b. Regulation of Pancreatic Secretion i. When chyme enters the duodenum CCK and secretin enter the bloodstream. Upon reaching the pancreas: 1. CCK induces the secretion of enzyme-rich pancreatic juice 2. Secretin causes secretion of bicarbonate-rich pancreatic juice 3. See figure 16-12 ii. Vagal stimulation also causes release of pancreatic juice c. Pancreatic Enzymes i. Proteolytic enzymes are released in an inactive form and are activated in the duodenum 178 1. Each breaks different peptide bonds resulting in short peptides and amino acids 2. Proteolytic enzymes: a. Enterokinase Trypsinogen Trypsin b. Trypsin i. Chymotrypsinogen Chymotrypsin ii. Procarboxypeptidase Carboxypeptidase ii. Amylase – hydrolyzes polysaccharides into disaccharides iii. Nucleases – hydrolyzes nucleic acids into nucleotides iv. Lipase – hydrolyzes triglycerides into monoglycerides and fatty acids v. Brush Border Enzymes - final chemical digestion is carried out by brush border enzymes found in the plasma membrane of the small intestine’s mucosal cells 1. Sucrase, Maltase, Lactase Disaccharides Monosaccharides 2. Aminopeptidase Peptides amino acids *Table 16-6 in your textbook summarizes the digestive enzymes discussed above vii. Absorption in the Small Intestines 1. Most electrolytes, nutrients and vitamins are completely absorbed 2. Vitamins a. Fat soluble vitamins such as A, D, E, and K are absorbed along with lipids b. Water soluble vitamins such as C and B are passively absorbed with water c. Vitamin B12 is combined with intrinsic factor and absorbed by receptor mediated endocytosis in the ileum 179 3. Minerals a. Ca2+ and iron are absorbed on an as needed basis mostly by active transport i. Ca2+ absorption: 1. Depends on blood levels of ionic calcium 2. Is regulated by vitamin D and parathyroid hormone (PTH) ii. Iron (see figure 16-26) 1. Absorbed iron is stored in the epithelial cells as ferritin until needed 2. If blood iron levels are low it is released into the blood 3. Carried in the blood by transferrin to the bone marrow to be used for RBC production 4. Nutrient Absorption a. Electrolytes i. Cl-, H20, glucose, and amino acids absorption depends on active transport of Na+ into the interstitial fluid ii. Active transport of Na+ creates a concentration gradient iii. Water follows the osmotic gradient and anions passively follow the electrical gradient established by sodium b. Absorption of sugars and amino acids are facilitated diffusion via cotransport with Na+. (See figures 16-23 & 16-24) 1. Na+ re-entry through a cotransporter can drive solutes against the concentration gradient 2. Driven by secondary active transport 3. Enter the capillary bed in the villi 4. Transported to the liver via the hepatic portal vein c. Absorption of lipids (See figure 16-25) i. When micelles get close to the absorptive surface lipids are released and diffuse into intestinal cells where they are: 180 1. Synthesized into triglycerides in the SER 2. Combine with proteins to form chylomicrons in the golgi apparatus 3. Released by exocytosis 4. Enter lacteals and are transported to systemic circulation via lymph viii. Motility in the Small Intestine 1. Segmentation is the most common motion of the small intestine a. It is initiated by intrinsic pacemaker cells (Cajal cells) b. Mixes chyme with digestive juices and exposes it to the absorptive surface of the small intestines c. Moves contents steadily toward the ileocecal valve d. Factors enhancing the intensity of segmentation contractions: i. Distention ii. Gastrin iii. Extrinsic nerve 2. After nutrients have been absorbed: a. A series of peristaltic waves called the migrating motility complex begins with each wave starting distal to the previous b. Sweeps remnants of the previous meal, bacteria, mucosal cells, and debris into the large intestine c. Regulated by the hormone motilin which is released during the postabsorptive state by mucosa endocrine cells 3. Ileum empties into the cecum through the ileocecal valve a. The gastroileal reflex – ileocecal sphincter relaxes and allows chyme to pass into the large intestine i. Triggered by food entering stomach ii. Gastrin and increased motility of the small intestines e. Large Intestines i. Frames the small intestines ii. Extends from the ileocecal valve to the anus 181 iii. Functions: 1. Absorb remaining water, electrolytes, vitamin K 2. Eliminated indigestible food from the body iv. Motility of the Large Intestines 1. Segmentation in the large intestines occurs less frequently (3 to 4 times a day) 2. Gastrocolic reflex – contraction of the ascending and transverse colon results in mass movement of content forward into the rectum a. Triggered by gastrin and extrinsic nerves when food enters the stomach 3. Defecation Reflex a. Distention of the rectum triggers stretch receptors causing the internal sphincter to relax (involuntary) b. When the external sphincter is voluntarily relaxed defecation occurs 182 Digestive Post-Lecture Practice Complete the following practice questions: 1. Regulation of digestive activities involve: a. Autonomous smooth muscle b. Gastrointestinal hormones c. Extrinsic nerves d. Enteric nervous system e. All of the above 2. Bile is produced by the: a. Liver b. Gallbladder c. Pancreas d. Duodenum e. Gastric glands 3. The sight or smell of food will trigger the _______phase of gastric secretions. a. Gastric b. Intestinal c. Cephalic d. Active e. Inhibitory 4. Which of the following digestive enzymes is CORRECTLY matched with its substrate? a. Lipase- carbohydrates b. Maltase – sucrose c. Amylase – nucleic acids d. Trypsin – peptides e. Pepsin – lipids 5. Parietal cells in the gastric pits produce: a. HCl b. Gastrin c. Pepsinogen d. Bile e. Sodium bicarbonate 6. Parasympathetic innervation of the digestive tract occurs primarily through the vagus nerve. a. True b. False 183 7. Chemical digestion of carbohydrates begins in the: a. Mouth b. Esophagus c. Stomach d. Small intestineså e. Large intestines 8. Chemical digestion of proteins begins with: a. Chewing b. Amylase in the mouth c. Pepsin in the stomach d. Trypsin in the duodenum e. Lipase in the duodenum 9. Which of the following is NOT produced in the stomach? a. HCL acid b. Cholecystokinin c. Gastrin d. Mucus e. Pepsinogen 10. Which of the following conditions would decrease the rate of gastric emptying? a. Chyme high in fat in the doudenum b. Large volume of chyme in the stomach c. Vagal stimulation of the stomach d. Gastrin secretion 11. Pancreatic enzymes for digestion are secreted into the: a. Duodenum b. Mouth c. Large intestines d. Gallbladder e. Stomach 12. The absorption of all of the following nutrients rely on the active transport of sodium in the small intestines EXCEPT: a. Chloride b. Glucose c. Amino acids d. Water e. Iron 184 Renal Physiology Study Objectives: 1. List the functions of the kidneys. 2. Describe the anatomy of the kidneys. 3. Describe the structure and function of the nephron. 4. Describe the structure and function of the juxtaglomerular apparatus. 5. Define glomerular filtration, tubular reabsorption, and tubular secretion. 6. Define the forces (pressures) involved in glomerular filtration. 7. Describe the mechanisms that function in the autoregulation of the glomerular filtration rate (GFR): myogenic and tubuloglomerular feedback mechanism 8. Describe the extrinsic controls regulating the glomerular filtration rate: sympathetic nervous system and renin-angiotensin-aldosterone pathway 9. Discuss the tubular reabsorption of sodium, glucose, water, and amino acids. 10. List the substances that are normally reabsorbed in the nephron and those that are not. 11. Compare the role of aldosterone and atrial natriuretic peptide in sodium and water balance. 12. Compare obligatory and facultative reabsorption of water. 13. Describe the role of ADH in water retention 14. Describe the role of aldosterone in K+ secretion. 15. Describe the processes in the renal regulation of pH balance by explaining how the kidneys regulate hydrogen and bicarbonate ion concentrations in the blood. 16. Describe the mechanism responsible for establishing the medullary osmotic gradient. 17. Contrast the mechanisms in formation of dilute urine verses concentrated urine. 18. Explain the physiology of the micturition reflex. 185 Renal Physiology I. Functions of the Urinary System a. Kidneys – eliminate unwanted plasma constituents through the urine while conserving materials of value to the body i. Excrete nitrogenous waste – urea, uric acid, creatinine ii. Regulate blood volumes – by regulating H2O balance and release of erythropoietin iii. Regulates blood pressure – releases renin which triggers vasoconstriction and aldosterone secretion iv. Regulates chemical composition of the blood – regulating ions and osmolarity v. Stabilizes pH – balances acids and bases vi. Converting Vitamin D into its active form b. Ureters, bladder, and urethra – transport and store urine II. Anatomy of the Kidney (see figure 14-1 through 14-3) a. Regions i. Cortex – outer region ii. Medulla – deep to the cortex iii. Renal pelvis – flat funnel shaped cavity b. Microscopic Anatomy i. Nephron – structural and functional unit of the kidneys 1. Composed of vascular and tubular components 2. Responsible for the filtration of blood and urine formation 3. Tubular Component a. Bowman’s capsule – cup surrounding the glomerulus, collects filtrate b. Proximal convoluted tubule – extends from the Bowman’s capsule c. Loop of Henle – hairpin loop d. Distal convoluted tubule – leads away from the ascending loop of Henle to the collecting duct e. Collecting duct – receives filtrate from DCT of numerous nephrons 4. Vascular Component a. Afferent arterioles – supply glomerulus b. Glomerulus – capillary knot c. Efferent arterioles – drains the glomerulus d. Peritubular capillaries – surround tubular portions of the nephron in the cortex e. Vasa recta – surround tubular portions of the nephron in the medulla 186 5. Types of Nephron a. Cortical nephron – majority of the nephron is within the cortex with a short loop of Henle b. Juxtamedullary nephron – glomeruli is deep in the cortex and have a long loop of Henle that extends deep into the medulla ii. Juxtaglomerular Apparatus (JGA) (see figure 14-11) 1. Region between the beginning of the DCT and the afferent arteriole 2. Contains cells that regulate the rate of filtration and blood pressure a. Macula densa – in the DCT, contain osmoreceptors that monitor solute concentration and flow rate of filtrate b. Granular cells (JG) – smooth muscle cells in the afferent arteriole, act as mechanoreceptors to monitor BP, synthesize and secrete renin III. Renal Processes a. The four basic processes of the nephrons are: i. glomerular filtration ii. tubular reabsorption iii. tubular secretion iv. excretion b. Glomerular filtration i. Plasma is filtered from the glomerulus into the Bowman’s capsule. ii. Solutes and fluid are forced through the filtration membrane by hydrostatic pressure iii. Blood cells and plasma proteins normally do not enter the filtrate iv. The glomerulus is more efficient at filtration than other capillary beds because: 1. Its filtration membrane is significantly more permeable to solutes and water due to capillary pores 2. Glomerular blood pressure is higher due to a larger afferent arteriole than efferent arteriole 3. It has a higher net filtration pressure v. Glomerular Filtration Rate (GFR) - the total amount of filtrate formed per minute by the kidneys. 125mL/min or 180L/day! 1. Factors governing filtration rate at the capillary bed are: a. Net filtration pressure b. Total surface area available for filtration c. Filtration membrane permeability 187 2. Forces Involved in Glomerular Filtration (see table 14-1) a. The glomerular capillary pressure (55 mm Hg) is the result of the blood pressure pushing on the inside of the capillary wall b. The plasma-colloid osmotic pressure (30 mm Hg) is due to the retention of plasma proteins in the blood of the glomerulus. i. The concentration of water is higher in the capsule, because proteins are absent there. Water tends to return to the glomerulus by osmosis c. There is also a hydrostatic pressure (15 mm Hg) tending to move fluid from the Bowman’s capsule into the glomerulus d. From the previous examples: The net pressure = glomerular blood pressure - (plasma-colloid osmotic pressure + Bowman’s capsule hydrostatic pressure) i. 55 - (30 +15) = 10 ii. The net filtration pressure is 10 mm Hg by this example. vi. Regulation of Glomerular Filtration Rate 1. Uncontrolled shifts in the GFR can lead to fluid and electrolyte imbalances a. If the GFR is too high: i. Needed substances cannot be reabsorbed quickly enough and are lost in the urine b. If the GFR is too low: i. Everything is reabsorbed, including wastes that are normally disposed of 2. Changes in GFR primarily result from changes in glomerular capillary blood pressure. 3. Three mechanisms controlling the GFR: a. Renal autoregulation (intrinsic control) b. Sympathetic NS (extrinsic control) c. Hormonal mechanisms (the RAA system) 4. Intrinsic Controls a. Autoregulation - regulates the GFR by factors within the kidneys. i. Under normal conditions, it prevents inappropriate changes in the GFR 188 ii. Autoregulation entails two types of control: 1. Myogenic – responds to changes in pressure in the renal blood vessels. (see figure 14-9) a. Controlled by arteriole smooth muscle cells i. If the arterial pressure increases, the afferent arterioles constrict to lower GFR. ii. If the arterial pressure decreases the afferent arterioles dilate to increase GFR. iii. Tubuloglomerular feedback mechanism senses changes in flow rate in the nephron’s tubular component (see figure 19-10) 1. Involves the cells of the JGA 2. Macula densa cells – detect change in flow-rate and osmolarity a. Increase in flow rate – releases vasoactive chemicals that cause vasoconstriction of afferent arteriole b. Decrease in flow rate – inhibits release of vasoactive chemicals causing vasodilation of afferent arteriole 5. Extrinsic Controls a. Sympathetic Nervous System i. When the sympathetic nervous system is at rest or low levels autoregulation mechanisms prevail and afferent arteriole is dilated ii. However, the sympathetic nervous system can override the autoregulatory mechanisms to carry out long term adjustments for blood pressure if blood volume drops (see figure 14-12) 189 iii. If arterial blood pressure severely drops, the baroreceptor reflex triggers vasoconstriction of systemic arterioles 1. The afferent arterioles constrict by sympathetic innervation. Less blood flows through the glomeruli, lowering the blood pressure in these capillaries. 2. The decrease in the GFR reduces urine volume. 3. This helps to conserve plasma volume, increasing blood pressure. iv. The sympathetic nervous system also stimulates the renin-angiotensin-aldosterone mechanism b. Renin-angiotensin-aldosterone pathway (see figure 14-16) i. Renin release is triggered by the following: 1. Reduced stretch of the granular JG cells 2. Stimulation of the JG cells by activated macula densa cells 3. Direct stimulation of the JG cells via β1-adrenergic receptors by renal nerves ii. Is triggered when the JG cells release renin 1. Renin acts on angiotensinogen to produce angiotensin I 2. Angiotensin I is converted to angiotensin II 3. Angiotensin II: a. Causes systemic arteriole vasoconstriction b. Stimulates the adrenal cortex to release aldosterone 4. As a result, both systemic blood pressure and blood volume increase c. Tubular Reabsorption - is the selective transfer of substances needed by the body from the filtrate back into the peritubular capillaries i. Reabsorption rates are high: 124 of 125 ml of filtered fluid per minute, 99% for water, 100% for glucose, and 99.5% for Na+ 190 1. By transepithelial transport a reabsorbed substance must cross the tubule wall, enter the interstitial fluid, and pass through the wall of the peritubular capillaries, entering the blood. 2. Epithelial cells of the nephron tubule have a luminal membrane and a basolateral membrane (see figure 14-14) ii. Sodium Reabsorption (see figure 14-15) 1. Sodium reabsorption is mostly driven by active transport a. Na+ enters the tubule cells at the luminal membrane by diffusion b. Then it is actively transported out of the tubules by a Na+-K+ pump at the basolateral membrane 2. 67% of sodium reabsorption occurs in the proximal tubule at a constant rate 3. The reabsorption of sodium in the loop of Henle plays a role in the production of varying concentrations and volumes of the urine 4. In the distal tubule, reabsorption of sodium is variable and depends on aldosterone. More or less is reabsorbed, depending on the needs of the body. a. Aldosterone increases Na+ absorption in the DCT and collecting ducts by promoting the insertion of: i. Additional Na+ channels in the luminal membrane ii. Additional Na-K+ pumps into the basolateral membranes b. About 8% of the filtered Na+ is dependent on aldosterone for reabsorption. If aldosterone is absent it is lost in the urine 5. Atrial Natriuretic Peptide Activity (see figure 14-17) a. ANP inhibits Na+ reabsorption which: i. Decreases blood volume ii. Lowers blood pressure b. ANP lowers blood volume and pressure by: i. Acting directly on collecting ducts to inhibit Na+ reabsorption ii. Inhibits RAA pathway iii. Dilates afferent arteriole triggering an increase in GFR which reducing water and sodium reabsorption 191 iii. Reabsorption of water, glucose, amino acids, and anions - linked to the active reabsorption of Na+ 1. Active pumping of Na+ drives reabsorption of: a. Water by osmosis, aided by water-filled pores called aquaporins b. Anions following by diffusion c. Glucose and amino acids by secondary active transport 2. Reabsorption of Water a. The accumulation of sodium in the lateral spaces produces an osmotic gradient and hydrostatic pressure that pushes the water into the peritubular capillaries. (see figure 14-19) b. 80% of water reabsorption is obligatory in the proximal tubule and loop of Henle. Occurs by osmosis, no control. c. 20% of water reabsorption is facultative in the distal tubule and collecting duct. Based on the secretion of ADH (vasopressin), depends on body’s needs, i. ADH works on tubule cells through a cyclic AMP mechanism ii. Promotes the insertion of aquaporins on the luminal membrane thus increasing water reabsorption (see figure 14-26 & 14-27) iii. Produces concentrated urine 3. Reabsorption of glucose and amino acids are reabsorbed by secondary active transport and cotransported with sodium on the luminal membrane 4. Oppositely-charged chloride ions follow sodium iv. Nonreabsorbed Substances 1. A transport maximum (Tm): a. Reflects the number of carriers in the renal tubules available b. Exists for nearly every substance that is actively reabsorbed c. When the carriers are saturated, excess of that substance is excreted 192 2. Substances are not reabsorbed if they: a. Lack carriers b. Are not lipid soluble c. Are too large to pass through membrane pores d. Urea, creatinine, uric acid and other nitrogen containing wastes are excreted d. Tubular secretion - a selective process by which substances from the peritubular capillaries enter the lumen of the nephron tubule. i. Provides a mechanism to speed up the elimination of substances from the blood ii. Tubular secretion is important for: 1. Disposing of substances not already in the filtrate 2. Eliminating undesirable substances such as urea and uric acid 3. Ridding the body of excess potassium ions 4. Controlling blood pH iii. Tubular Secretion of K+ 1. K+ is almost completely reabsorbed in the proximal tubule 2. Aldosterone stimulates the tubular cells to secrete potassium if plasma levels are elevated 3. K+ secretion occurs in the distal tubule 4. As the basolateral pump transports sodium into the lateral spaces, it pumps potassium into the tubular cells where it diffuses into the lumen for elimination. (see figure 14-21) iv. Acid-Base Balance 1. Concentration of hydrogen ions is regulated sequentially by: a. Chemical buffer systems – act within seconds b. The respiratory center in the brain stem – acts within 1-3 minutes c. Renal mechanisms – require hours to days to effect pH changes 2. Renal Mechanisms of Acid-Base Balance a. The most important renal mechanisms for regulating acid-base balance are: i. Conserving (reabsorbing) or generating new bicarbonate ions ii. Excreting bicarbonate ions iii. Losing a bicarbonate ion is the same as gaining a hydrogen ion; reabsorbing a bicarbonate ion is the same as losing a hydrogen ion 193 b. Reabsorption of Bicarbonate (see figure 15-9) i. Secreted hydrogen ions form carbonic acid with filtered bicarbonate ii. Carbonic acid dissociates to release carbon dioxide and water iii. Carbon dioxide then diffuses into tubule cells, triggering further hydrogen ion secretion and bicarbonate reabsorption iv. Thus, bicarbonate disappears from filtrate at the same rate it is reabsorbed c. Generating New Bicarbonate Ions (see figure 151) i. Dietary hydrogen ions must be counteracted by generating new bicarbonate ii. Two mechanisms generate new bicarbonate ions: 1. Both involve renal excretion of acid via secretion and excretion of hydrogen ions or ammonium ions (NH4+) 2. The excreted hydrogen ions must bind to buffers in the urine (phosphate buffer system) iii. In response to acidosis: 1. Hydrogen Ion Excretion a. Kidneys generate bicarbonate ions and add them to the blood b. An equal amount of hydrogen ions are added to the urine c. H+ binds with buffers in the filtrate (monohydrogen phosphate) 2. Ammonium Ion Excretion a. This method uses ammonium ions produced by the metabolism of glutamine in PCT cells b. Each glutamine metabolized produces two ammonium ions and two new bicarbonate ions 194 c. Bicarbonate moves to the blood and ammonium ions are excreted in urine d. Bicarbonate Ion Secretion (see figure 15-10) i. When the body is in alkalosis, type B cells: 1. Exhibit bicarbonate ion secretion 2. Reclaim hydrogen ions and acidify the blood IV. Varying Urine Concentration a. Kidneys excrete varying concentrations and volumes of urine depending on the body’s needs i. Can produce urine ranging from 0.3ml/min at 1200 mosm/L to 25 ml/min at 100 mosm/L b. This variation in reabsorption is made possible by a large, vertical osmotic gradient in the interstitial fluid of the medulla from 300 to 1200 mosm/liter. (see figure 14-24) i. This increase follows the juxtamedullary nephron’s loop of Henle deeper and deeper into the medulla. ii. The gradient is established by means of the countercurrent system c. Countercurrent – the movement in opposite directions of filtrate through the ascending and descending limbs of the loop of Henle. Also applies to the flow of blood through the vasa recta. i. Countercurrent multiplier – refers to the ability to increase the osmolarity of the interstitial fluid (see figure 14-25) 1. Due to the properties in the two limbs of the loop: a. The descending loop of Henle: i. Is relatively impermeable to solutes ii. Is permeable to water b. The ascending loop of Henle: i. Is permeable to solutes ii. Is impermeable to water 2. The ascending limb actively transports NaCl out of the tubular lumen into the surrounding interstitial fluid. It is impermeable to water. Therefore, water does not follow the salt by osmosis. 3. The ascending limb produces an interstitial fluid that becomes hypertonic to the descending limb. This attracts the water by osmosis for reabsorption. 195 ii. Countercurrent exchanger - The hairpin structure of the vasa recta allows the blood of the vasa recta to equilibrate with the interstitial fluid (see figure 14-28) 1. Prevents the dissipation of the medullary osmotic gradient 2. Blood is isotonic when it enters and when it leaves the medulla d. Formation of Concentrated Urine i. ADH is the signal to produce concentrated urine 1. Allowing the distal and collecting ducts to become permeable to water (see figure 14-27) 2. In the presence of ADH, 99% of the water in filtrate is reabsorbed e. Diuretics – large volume of dilute urine i. Osmotic diuretics include: 1. High glucose levels – carries water out with the glucose 2. Alcohol – inhibits the release of ADH 3. Caffeine and most diuretic drugs – inhibit sodium ion reabsorption 4. Lasix and Diuril – inhibit Na+-associated symporters V. Transport and Storage of Urine a. Urine Excretion – elimination of what remains in the tubular lumen. The unwanted filtrate material. i. Urine is transported from the kidney to the bladder by the ureters. Due to gravity or peristaltic waves. ii. The bladder temporarily stores urine 1. Micturition Reflex (see figure 14-29) - act of emptying the bladder a. The filling of the bladder activates stretch receptors which trigger reflex contractions of the bladder and relaxation of the internal sphincter b. Urine is forced past the internal sphincter c. Must voluntary relax external sphincter to void the bladder of urine *No post-lecture practice for this lecture. 196 Reproductive Physiology Study Objectives: 1. List the functions of the reproductive system. 2. List the bipotential tissues and what they will become in males or females during embryonic development. 3. Describe the role of the SRY gene in embryonic development in males. 4. Describe the role of testosterone, DHT, and anti-mullerian hormone in the embryonic development in males. Also know which cells secrete these hormones. 5. Describe how the lack of the SRY gene leads to the embryonic development of females. 6. Briefly describe the events that occur during meiosis in respect to number of nuclear divisions and number of chromosomes present in the daughter cells. What types of cells undergo meiosis? What is the final result of meiosis? 7. Define: gametes, sister chromatids, homologous chromosomes, tetrads, autosomal chromosomes vs. sex chromosomes. 8. Define: spermatogonia and oogonia, primary gametes and secondary gametes. 9. Define spermatogenesis and discuss the role of GnRH, FSH, LH, testosterone, and inhibin in spermatogenesis. (Know who secretes each hormone, their target cell, and their effect.) 10. Define oogenesis and discuss the role of GnRH, FSH, LH, estrogen, and inhibin in oogenesis. (Know who secretes each hormone, their target cell, and their effect.) 11. Describe the function of the corpus luteum and progesterone in maintenance of the endometrial lining. 12. Explain the effects of fertilization and hCG on the corpus luteum. 13. Describe the roles of FSH, LH, estrogen and progesterone in the female reproductive cycle. a. Describe the three stages of the ovarian cycle: follicular, ovulation, luteal phase b. Describe the three stages of the uterine cycle: menstrual, proliferation, secretory 197 Reproductive Physiology Outline I. Functions of the Reproductive System a. Secretion of sex hormones – influence growth and development of organs and tissues b. Production of gametes – sperm and ova i. Male gonads testes sperm ii. Female gonads ovaries eggs c. Produce offspring i. Male – deliver sperm to the female reproductive tract ii. Female – provide an environment for fetus development II. The human life cycle a. Sexual reproduction in humans involves: i. Meiosis: 1. Stem cells within the gonads are diploid 2(n) = 46 Contain two sets of chromosomes 2. Gametes are haploid (n) = 23 having only one set of chromosomes ii. Fertilization 1. Is the fusion of sperm and egg 2. Creates a zygote (2n), or fertilized egg that will develop into a new organism III. Sex Determination a. Inheritance of X and Y chromosomes i. XX = female ii. XY = male b. Bipotential stage: during the first 6 weeks of fetal development the internal reproductive organs have the potential to develop into male or female structures i. Bipotential tissues: 1. Gonads a. Testis or ovary 2. Wolffian duct - remains in males 3. Mullerian duct – remains in females 198 c. Embryonic Development: Males i. Role of SRY gene in male development – gene found on the Y chromosome 1. Produces the SRY protein that causes the gonad medulla to differentiate into the testes a. Sertoli cells – secrete anti-Mullerian hormone, cause the Mullerian duct to degrade b. Leydig cells – secrete testosterone and dihydrotestosterone (DHT) leading to the development of the Wolffian duct and external male genitalia d. Embryonic Development: Females i. Females do not have the Y chromosome so they lack the SRY gene to produce SRY proteins ii. Gonadal cortex becomes the ovaries iii. Wolffian ducts degenerates in absence of testosterone iv. Mullerian ducts become 1. Superior portion of vagina 2. Uterus 3. Fallopian tubes v. In the absence of testosterone and DHT the external genitalia develops as females IV. Meiosis (information can be found in supplemental chapter 11pgs 219-228 in back of textbook) a. Chromosome Review i. Humans have 23 pairs of chromosomes ii. Each somatic cell has two sets of chromosomes (one maternal, one paternal) and is said to be diploid (2n) iii. Each pair of homologous chromosomes carry equivalent genes which determine particular traits iv. There are alternative forms of each gene which are called alleles v. Gametes only have 23 chromosomes and are said to be haploid (n) b. Purpose of Meiosis i. Meiosis is a type of cell division that produces gametes (sperm and ova) from stem cells in the reproductive tissue 1. Reduces the original number of chromosomes in half in preparation for fusing with another gamete 2. Recombination (scrambling) of parents’ genomes to create a unique set of chromosomes in each gamete 199 c. Stages of Meiosis i. Overview 1. In meiosis there is two rounds of division which results in 4 haploid cells See figure 11-2 a. 1st round separates duplicated homologous chromosomes b. 2nd round separates sister chromatids ii. Interphase 1. Occurs prior to Prophase I of meiosis 2. G1 phase 3. S-phase homologous chromosomes replicate into sisters 4. G2 phase – checkpoint iii. Meiosis I –first division 1. Prophase I a. Duplicated homologous chromosomes pair up (tetrads) b. Crossing over occurs: homologous chromosome exchange equivalent segments c. Occurs between non-sister chromatids i. How are non-sister chromatids different from sister chromatids? 2. Metaphase I a. Homologous chromosomes line up in pairs along the central plane in tetrads b. Independent assortment: which side each chromosome lines up on is independently of the other pairs 3. Anaphase I a. Homologous chromosomes are separated and move to opposite poles 4. Telophase I and Cytokinesis a. Results in two haploid cells with 23 duplicated chromosomes iv. Meiosis II 1. Prophase II 2. Metaphase II a. Sister chromatids (duplicated chromosomes) line up along midline 3. Anaphase II a. Sister chromatids separate and are pulled towards opposite poles 4. Telophase II and Cytokinesis a. Results in 4 haploid gametes 200 d. Three factors contributing to genetic recombination i. Crossing over during prophase and metaphase I (see figure 11.6) 1. Additional mixing of alleles produces further variation in offspring ii. Independent assortment of chromosomes in Metaphase I & II 1. Total # of chromosome combinations = 2n 2. Humans 223 = 8 million combinations iii. Random fertilization - egg is fertilized randomly by one sperm 1. 8 million x 8 million = 64 TRILLION possibilities (not considering crossing over) V. Gametogenesis – production of gametes (see figure 20-15) a. Begins in utero and resumes during puberty i. Mitotic divisions in embryonic gonads increases number of spermatogonia or oogonia ii. DNA replication (S-phase) primary gametes with 46 duplicated chromosome iii. Meiosis I secondary gametes with 23 duplicated chromosomes iv. Meiosis II egg (ova) or spermatid with 23 chromosomes b. Spermatogenesis -production of sperm cells (see figure 20-8) i. Begins at puberty and continues throughout life ii. Occurs in the seminiferous tubules iii. Regulation of Spermatogenesis 1. GnRH LH Leydig cells testosterone sex characteristics 2. GnRH FSH Sertoli cells spermatocyte maturation 3. Inhibin triggers negative feedback loop for FSH secretion 4. Testosterone triggers negative feedback loop through the kiss1 neurons for LH and GnRH secretion 5. See figure 20-10 c. Oogenesis – production of ova i. The total supply of primary follicles are present at birth ii. Ability to release eggs begins at puberty iii. Refer to figure 20-14 for detail on when the first and second meiotic division occur 201 VI. Menstrual Cycle in Females a. Ovarian cycle –changes that occur in the ovaries, divided into three phases (see figures 20-16 – 20-19): i. Follicular phase – follicular growth in ovary 1. Low levels of FSH and LH, increased sensitivity to FSH 2. Granulosa cells producing increasing amounts of estrogen through positive feedback. 3. Moderate levels of estrogen selectively inhibits FSH and LH secretion. 4. High levels of estrogen late in the follicular stage stimulates the production of GnRH thus triggering increased production in FSH and the LH surge. ii. Ovulation – ova released from ovary, triggered by surge in LH iii. Luteal phase – corpus luteum produces hormones to prepare for pregnancy 1. Estrogen and progesterone being produced 2. High levels of progesterone during the luteal phase inhibits LH and FSH production. 3. Corpus luteum – remnants of the ovulated follicle, produces increasing amounts of progesterone and some estrogen for about two weeks after ovulation a. If fertilization does not occur –it degenerates into scar tissue and drop in hormones triggers menstruation b. If fertilization occurs – the oocyte secretes human chorionic gonadotropin (hCG) which causes the corpus luteum to persist so the menstrual cycle will not be initiated b. Uterine cycle – changes in the endometrial lining of the uterus, also divided into three phases: i. Menses- shedding of the lining 1. Triggered by drop in progesterone and estrogen ii. Proliferation phase – endometrial lining adds new layers 1. Stimulated by increasing estrogen levels iii. Secretory phase – increased blood flow to endometrium, increased glandular secretions 1. Stimulated primarily by increased progesterone c. Summary of Hormonal Control of the Menstrual Cycle – see figure 20-18 202 Reproductive Post-lecture Practice Draw and label the events occurring in the stages of meiosis for a cell that is 2n = 4 and give a brief description for each event. Include the phases of meiosis I and meiosis II. Other things you should include somewhere in your drawing is the labeling of chromatin, homologous chromosomes, sister chromatids, daughter chromosomes. For an additional challenge show crossing over and independent assortment of chromosomes. 203 204 Name:_________________ Lab Section:_________________ REPRODUCTION HOMEWORK Instructions: Use your textbook or other reference sources to answer the questions below. All answers must be in your own words! This assignment will be worth up to 11 points and is due by midnight after your last lecture exam. No late work will be accepted. 1. Briefly summarize how the cortical reaction that occurs during fertilization prevents polyspermy. (1 pt) 2. When the developing embryo reaches the uterus and capable of implanting it is called a ______________________(a hollow ball of cells). (1/2 pt) 3. What is the function of the following membranes? (1 pt) a. Chorion (chorionic tissue) b. Amnion 4. Through what process does nutrients, gases, and waste move across the placenta? (1/2 pt) 5. At about what week does the placenta take over progesterone production from the corpus luteum? (1/2 pt) 6. What hormone produced by the placenta is responsible for altering the mother’s glucose and fatty acid metabolism? (1/2 pt) a. How does this hormone specifically affect the mother’s glucose levels and fatty acid metabolism? (1 pt) 205 7. Between what weeks does normal parturition (labor and delivery) occur? (1/2 pt) 8. In the days leading up to parturition estrogen levels soar. List three ways high estrogen levels prepare the uterus and cervix for labor and delivery. (1.5 pts) 9. In your own words, write a brief summary of the positive feedback loop responsible for parturition. (2 pt) 10. During lactation, the primary hormone responsible for milk production/secretion is __________________and the ejection of milk from the mammary glands is stimulated by the hormone ________________. (1 pt) 11. The absence of the hormone ___________________leads to symptoms in postmenopausal women. List two or three symptoms below (1pt): 206