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Physiology Unit 1 Study Guide Dr. Walz – Hemostasis Describe the components of blood. Relate the three red blood cell concentration estimates, red blood cell count, hematocrit, and hemoglobin concentration. Components: hematocrit (RBCs), WBCs (mostly neutrophils), and plasma (water with dissolved ions and proteins) Hematocrit: fraction of whole cell volume that consists of RBCs RBC count: absolute # of RBCs/liter Hemoglobin concentration: grams/deciliter Describe hematopoiesis, the process by which blood cells are produced. try to remember your histo Describe the unique characteristics of red blood cells (erythrocytes). histo again – heme, O2, funky disk shape, very compressible, no nucleus Explain how red blood cell surface antigens account for typing of blood by the A B O system and rhesus factor. Based on these antigens, identify blood type of a “universal donor” and a “universal recipient.” antigens are A and B; you make antibodies against what you don’t have – so if you’re Otype, you have antigens against both A and B, so you’re a universal donor; if you’re ABtype, you have antigens against neither, so you’re a universal recipient rhesus factor is another antigen, you’re either positive or negative so strictly speaking, O-negative is the universal donor, AB-positive is the universal recipient Understand the role of normal endothelium in preventing and how endothelial injury regulates coagulation. healthy endothelium prevents coagulation through the following mechanisms: production of NO, PGI2, and ADP dephosphatases, which inhibit platelet activation NO and PGI2 are also vasodilators heparin sulfate and similar proteoglycans activate anti-thrombin III, which inhibits thrombin and activated coagulation factors VII, IX, X, XI, and XII heparin and dermatan sulfate activate heparin cofactor II, which inhibits thrombin thrombomodulin binds thrombin, which then activates protein C to activated protein C (APC), APC inhibits activates factor V and VIII tissue factor pathway inhibitor binds and deactivates VIIa (extrinsic pathway) intact endothelium blocks blood-born coagulation factors from interacting with the ECM, which is prothrombotic injured endothelium promotes coagulation through the following mechanisms: no longer producing anti-coagulation factors no longer shields the blood from ECM – ECM very prothrombotic (see below) releases endothelin, a vasoconstrictor releases von Wilebrand factor, which binds to GPIb-IX-V on platelets (see below) pericytes specifically release tissue factor (TF), which activates factor VII and initiates the extrinsic coagulation cascade (see below) Describe the interactions between endothelium and platelets in regulating these coagulation. after GPIb-IX-V is bound by vWf, platelets undergo the following: “activation”, in which the inactive form of the integrin αIIbβ3 is changed to the activated form activated αIIbβ3 binds fibrinogen and other platelets, forming the primary platelet clot arachidonic acid is converted to TxA2, which promotes the release of dense granules (and is also a vasoconstrictor) dense granules are released, containing: o serotonin – minor vasoconstrictor o ADP – activates platelets through the P2Y1 and P2Y12 receptors ( trigger internal release of Ca2+ αIIbβ3 activation) o Ca2+ -- essential for many coagulation factors (see below) α granules are released, containing vWf, factor V and fibrinogen why is the ECM prothrombotic? ECM is negatively charged, which activates the intrinsic coagulation cascade vWf is strongly bound by the ECM, and vWf activates platelets by binding GPIbIX-V Diagram the enzymes and substrates involved in the formation of fibrin polymers, beginning at prothrombin. Contrast the initiation of thrombin formation by intrinsic and extrinsic pathways. Contrast the mechanisms of anticoagulation of a) heparin, b) EGTA, and c) coumadin. heparin: activates anti-thrombin II and heparin cofactor II, which inhibit serine proteases such as thrombin and factors VII-XII EGTA: strong Ca2+ chelator; Ca2+ is required for the activity of coagulation factors VIIa, IXa, Xa, and thrombin Coumadin: inhibits vitamin K; vitK is a required cofactor for γ-glutamyl carboxylase, which carboxylates the factors that require Ca2+: VII, IX, X, prothrombin, and protein C Describe the mechanisms of fibrinolysis by TPA (tissue plasminogen activator) and urokinase. either tissue-type plasminogen activator (TPA) or urokinase-type plasminogen activator (UPA) converts plasminogen to plasmin, plasmin breaks up fibrin clots into fibrin degradation products. the conversion of plasminogen to plasmin is inhibited by PAI-1 and PAI-2; the action of plasmin is inhibited by anti-plasmin. APC (anticoagulant produced by healthy endothelial cells, see above) inhibits PAIs. Explain the role of the platelet release reaction on clot formation. Distinguish between a thrombus and an embolus. platelet release reaction – platelet activation; already covered above thrombus – stationary blood clot along the wall of a blood vessel embolus – a thrombus or fragment of thrombus that is moving through a blood vessel or has moved and is now blocking a vessel somewhere else Explain why the activation of the clotting cascade does not coagulate all of the blood in the body. localized – healthy endothelium surrounding the break are still producing the anticoagulation factors (especially TPA and ADP-phosphatases). moreover, coagulation factors are at too low a concentration in the blood to promote coagulation unless they are bound on a negatively charged surface (and in the presence of required cofactors such as Ca2+), which only activated platelets (for the intrinsic pathway) or membranebound tissue factor (for the extrinsic pathway) provide. thus coagulation is confined to the area in which the prothrombic factors outweigh the antithrombic factors. ideally, at any rate. The asprin thing (ok this isn’t an official objective, but he talked about it a lot) Asprin inhibits the enzyme COX, which converts arachidonic acid into eicosanoids. Particularly relevant are TxA2, which is prothrombotic and produced by platelets, and PGI2, which is antithrombotic and produced by endothelial cells. Asprin inhibits BOTH EQUALLY. However, because platelets are anucleate and cannot make more enzyme, once you’ve inhibited their COX, they’re done making TxA2 for the rest of their (admittedly very short) lives. In contrast, endothelial cells are fully capable of making more COX once the asprin goes away. Therefore, if you take subclinical doses of asprin, you will be inhibiting platelet COX, and thus the production of TxA2, permanently, and inhibiting endothelial COX, and thus the production of PGI2, only briefly. This tips the balance away from coagulation. Key is that you have to take a very small dose of asprin, though, or you’ll just knock everyone’s COX out and accomplish nothing (vascularly speaking). Dr. Yingst – Cell Physiology Necessary Equations • Memorize the simplified version of the Nernst equation, so that you can calculate equilibrium potentials for the common ions. For a valance of +1: [𝑋]𝑖 𝐸𝑥 = −61 mV 𝑙𝑜𝑔 [𝑋]𝑜 For aFor valance a valance of +2: of -2: [𝑋] 𝐸𝑥 = −30.5 mV 𝑙𝑜𝑔 [𝑋] 𝑖 𝑜 For a valance of -1: 𝐸𝑥 = −61 mV 𝑙𝑜𝑔 [𝑋]𝑜 [𝑋]𝑖 = +61 mV 𝑙𝑜𝑔 [𝑋]𝑖 [𝑋]𝑜 • Know how to calculate the driving forces for each of the ions and be able to determine how the driving force on ions is affected by the membrane potential. Ionic current: 𝐼𝑥 = 𝐺𝑥 (𝑉𝑚 − 𝐸𝑥 ) 𝐺𝑥 = conductance for X ≈ 𝑃𝑥 driving force • Know the units for osmotic concentration and how to calculate the contribution a given salt makes to the total osmotic concentration based on its molar concentration. Do not memorize values for φ, because this is a minor correction. 𝜑𝑖𝐶 𝜑 = osmotic coefficient 𝑖 = # of particles formed by dissociation of solute 𝐶 = modal concentration • Know how to predict the direction the membrane potential changes as a function of changes in the permeability to ions, as described by the GHK equation. 𝑉𝑚 = −61 mV log ( 𝑃𝐾 [𝐾 + ]𝑖 + 𝑃𝑁𝑎 [𝑁𝑎+ ]𝑖 + 𝑃𝐶𝑙 [𝐶𝑙 − ]𝑜 ) 𝑃𝐾 [𝐾 + ]𝑜 + 𝑃𝑁𝑎 [𝑁𝑎+ ]𝑜 + 𝑃𝐶𝑙 [𝐶𝑙 − ]𝑖 𝑉𝑚 for most cells ≈ 𝐸𝐾 because 𝑃𝐾 ≫ 𝑃𝑁𝑎 + 𝑃𝐶𝑙 Remember : positive current = flow of POSITIVE ions OUT of the cell negative current = flow of POSITIVE ions INTO the cell flow of negative ions is the other way thus if INa = +60 mV, Na+ is going to flow OUT of the cell; if ICl = +60 mV, Cl- is going to flow INTO the cell More general concepts that are good to know Understand the physiological basis for how the young man became confused after his experience in the sauna, as described in the article in the New York Times. Drank too much pure (hypotonic) water induced hyponatremia, relative increase of water compared to Na+ fall in plasma tonicity movement of water into cells, including brain cells cerebral edema “drunk” presentation (See UpToDate, “General principles of disorders of water balance” and “manifestations of hyponatremia and hypernatremia” for more detail) Know how drinking water containing sodium and glucose promotes rehydration faster than drinking water alone. Ingesting an isotonic solution allows water to stay in the ECF. As glucose is slowly transported into cells, water will follow, thereby rehydrating the ICF as well (without causing edema). See question #5 of the extra homework problems. Understand which transport mechanisms that we studied will be affected by changes in the membrane potential. For anything that involves the movement of ions, the electric gradient is as influential as the chemical gradient. (Vm – Ex = driving force) Know how water is distributed throughout the body. 1/3 ECF, 2/3 ICF ECF further broken down into: 31% interstitial fluid, 7% blood plasma Know the concentrations of the major solutes in the major body fluid compartments. Dude, seriously? Know how the mechanisms by which the major solute gradients are formed across the plasma membrane and across the capillary endothelium. Na+ and K+: Na/K ATPase, aka the “Na/K pump”, 3 Na+ out and 2 K+ in Ca2+: Ca-ATPase, Ca/Na exchange protein (uses the Na+ gradient to shuttle Ca2+ against its gradient -- antiport) glucose: Na/glucose cotransporter (uses the Na+ gradient to shuttle glucose into the cell – symport) Be able to explain how changing the concentration of extracellular potassium will have a significant effect on the resting membrane potential, whereas changing the concentration of extracellular sodium will not. See the GHK equation: 𝑉𝑚 for most cells ≈ 𝐸𝐾 because 𝑃𝐾 ≫ 𝑃𝑁𝑎 + 𝑃𝐶𝑙 Know the physiological consequences of having soluble protein in the plasma, but not in the interstitial fluid. What happens when soluble protein does accumulate in the ISF? Proteins: occupy space solutes are effectively more concentrated – molality (solutes per kg water) is 7% higher than molarity (solutes per L solution) are anionic plasma has more + ions than the ISF Obv. if protein accumulates in the ISF, it will throw off the ion balance (more + ions, fewer – ions than should be) Know how the lipid bilayer functions in terms of forming a barrier to the movement of solutes. What solutes easily cross? Which do not? Cross easily: hydrophobic or small, uncharged polar molecules Require channels: large, uncharged polar molecules and ions Know the difference between net flux and the two unidirectional fluxes. flux: amount of solute which crosses a boundary per unit time (moles/cm2*sec) influx: Jio; efflux: Joi Net flux: efflux minus influx 𝐽𝑛𝑒𝑡 = |𝐽𝑜𝑖 − 𝐽𝑖𝑜 | Know how the unidirectional and net fluxes through the major transport mechanisms are affected by the concentration of the solute on both sides of the membrane and by the value of the membrane potential. Seriously, 𝐼𝑥 = 𝐺𝑥 (𝑉𝑚 − 𝐸𝑥 ) is kind of everything? Understand the functional consequences of having a solute move by diffusion, by a carrier, by a channel, and by active transport. Know in principle how each of these major transporters function and the respective physiological roles each of these plays in cells. Diffusion: free, slow, uncontrollable, unselective, only works if the solute is small and uncharged Channel: fast and moves a large volume of solute; controllable; selectivity varies; usually free used for rapid response! Carrier: slower than a channel; controllable; usually costs something (either ATP or an already established electrochemical gradient); usually highly selective What are the different ways in which carriers are classified? Uncoupled, passive: driven by electrochemical gradient of the moving solute Active: primary: uses ATP secondary (coupled): driven by an already established electrochemical gradient Only active transport can create a concentration gradient!! Know the different mechanisms by which glucose is transported across the plasma membrane by active and passive transport mechanism and the respective physiological roles of each. D-glucose carrier – passive transport; glucose moves down its conc. gradient Na/glucose cotransporter – active transport; Na+ moves down its concentration gradient and takes glucose with it – a concentration gradient for glucose can thus be established outside of the normal “oh we ate all our glucose and now we need more” mechanism Know how cardiac glycosides, such as digitalis, affects the Na,K-ATPase. Bind the E2-P state, preventing it from changing conformation Know the mechanism by which cardiac glycosides cause an increase in the strength of contraction in muscle. This is especially important for strengthening the contraction of the heart. Effectively decrease Na+ gradient by inhibiting the Na/K-ATPase less Ca2+ is transported out of cell by the Ca/Na exchange protein (which relies on the Na+ gradient to move Ca2+) more Ca2+ in muscle cells, more contraction Know what the pump leak model of the plasma membrane is and how this concept is used to link cellular metabolism with the creation and maintance of solute gradients. Metabolic energy is stored in the form of ion gradients, which are then used by other transporters to carry out specific functions e.g., Na/Ca exchange protein moves Ca2+ against its conc. gradient by moving Na+ down its conc. gradient Membrane potential/depolarization/repolarization also an example of the work that can be done by having established gradients! Na+ tends to be super important here Understand osmosis and how it drives the movement of water across plasma membranes. All water equalizes Know the theoretical factors that drive water movement across the plasma membrane and between the plasma and the ISF. across the plasma membrane, only ∆μH2O matters, because pressure is equal across capillary endothelium, both ∆μH2O and ∆μH2O, pressure matter What is the Starling-Landis equation and how does it account for the forces that move fluid between plasma and ISF? Know why differences in hydrostatic pressure do not play a role in determining the driving force for water across the plasma membranes of cells, but does play a role in the direction at which water moves between the plasma and the ISF. osmolality of plasma is slightly higher than the ISF b/c of plasma proteins & associated excess positive ions difference produces the plasma colloid osmotic pressure, πc πc is small (1 mOsm = 19 mmHg) but tips the balance towards osmosis into the plasma Know how to calculate the concentration of water and the difference between osmotic concentration and tonicity and why we need to distinguish between them. concentration of water = 1/osmotic concentration osmotic concentration = 𝜑𝑖𝐶 (see first page) tonicity = relative to 290 mOsm (isotonic) Know how to calculate changes in the osmotic concentration and volumes of the major body fluid compartments as discussed in class. see practice problems Know how the membrane potential of cells is created. Understand how to define “membrane potential,” “equilibrium potential” and “diffusion potential.” Vm created by conc. gradients of ions – primarily K+ membrane potential: difference in charge across a membrane equilibrium potential: value of Vm that exactly balances a concentration difference diffusion potential: potential difference created across a membrane when a charged solute diffuses down its concentration gradient Know the Nernst equation and how to use it to calculate the equilibrium potential of an ion. [𝑋] 𝐸𝑥 = −61 mV 𝑙𝑜𝑔 [𝑋] 𝑖 etc. (see first page) 𝑜 Know how to go about calculating the driving force acting on an ion. Know how to determine if the ion is at equilibrium. If the ion is not at equilibrium, know how to calculate the size of the driving force and how you would determine the direction of the driving force. 𝐼𝑥 = 𝐺𝑥 (𝑉𝑚 − 𝐸𝑥 ) (see first page) if at equilibrium, driving force = zero, so Vm and Ex must be equal POSITIVE CURRENT IS OUT OF CELL, NEGATIVE CURRENT IS INTO CELL (for positive ions) Know the difference between a driving force, a flux, and a current. driving force is a potential, a flux is a movement of solute, and a current is a movement of charge i.e., a flux happens because of a driving force, and because of the flux, current is produced Understand what extracellular solutes play critical roles in controlling cell volume and understand how the permeability of the plasma membrane to these solutes is important in their ability to regulate cell volume. everything is Na+ Know the mechanisms by which cells regulate their volume under normal conditions and be able to describe the contribution of the Na,K-ATPase to the regulation of cell volume. seriously, it’s all Na+ Understand the mechanisms that account for the changes in red cell shape that we discussed in the clinical problem on hereditary spherocytosis. PNa was three times higher than normal, meaning that too much Na+ was getting into the RBCs. because volume control is primarily due to Na+, that meant too much water was also getting into the RBCs, resulting in the spherical shape. What are electrotonic potentials and how are they different than action potentials? What are the physiological roles played by each? Electrotonic, aka graded potentials: decay over distance, decay with time, are proportional to stimulus intensity Action potential: all-or-nothing, independent of size of stimulus, propagate with constant amplitude and shape over distance APs are stimulated by graded potentials that pass a threshold What triggers an action potential in nerves and skeletal muscle? Depolarization that passes a threshold opening of voltage-gated Na+ channels How do voltage-dependent Na channels behave during the initiation of an action potential? enough depolarization opening of the activation gates rapid depolarization (AP) What are the individual steps in the opening and inactivation of Na channels during and action potential and how do these account for the change in sodium conductance at the beginning of an action potential? 1. at rest, activation gates are closed and inactivation gates are open 2. upon sufficient depolarization, activation gates open 3. when Vm becomes positive enough (at peak of AP), inactivation gates close 4. inactivation gates remain closed until cell is repolarized key here is that the inactivation gates close after a short delay, stopping the Na+ influx and letting GK take back over, which repolarizes the cell because the inactivation gates WILL NOT reopen until cell is repolarizes absolute refractory period, during which the cell cannot be stimulated to produce another AP What are some of the consequences of the fact that the opening and closing on individual channels is random? accommodation – when cell is depolarized too slowly, only some voltage-gated Na channels open (and then close) because cell must repolarize for the Na channels to reopen, there are then not enough Na channels available to enable the cell to cross threshold How does the driving force on Na and K change during the course of an action potential? as the cell depolarizes, Vm approaches ENa (when the cell is at V0, driving force is very strong on Na+; as the cell depolarizes, it lessens) as it repolarizes, Vm approaches EK (similarly, when the cell is at V0, driving force on K+ is low, because Vm ≈ EK, but as the cell depolarizes, driving force increases) Which ion channels are involved in producing an action potential? How does the conductance of the membrane to Na and K change during the course of an action potential? How do individual types of channels contribute to these changes? voltage-gated Na+ and K+ channels – v-g Na channels responsible for depolarization; v-g K channels responsible for repolarization types of K+ channels: K+ leak channels – open most of the time; responsible for resting Vm delayed outward rectifying K+ channels – K+ current during AP transient A-type K+ channel – responsible for after-hyperpolarization determines frequency of APs What is accommodation and how does it occur? see above What is the relationship between the strength and duration of a stimulus that can produce an action potential? to cross threshold, a stimulus must be either low strength and long duration, or high strength and short duration Know what the length constant and time constant are, what factors affect their values, and how these constants are used to describe how far and how fast local currents flow. length constant: initial depolarization decreases exponentially with distance 𝑉 = 𝑉0 𝑒 −𝑥 𝜆 𝑟 where 𝜆 = √ 𝑟𝑚 , 𝑟𝑚 = resistance across membrane; 𝑟𝑖 = internal resistance 𝑖 𝑎𝑅 and 𝜆 = √ 2𝑅𝑚, 𝑎 = axon radius; 𝑅𝑚 = resistance across membrane per unit area;𝑅𝑖 = 𝑖 internal resistance per unit area thus λ proportional to √axon radius longer λ = farther a charge in voltage can travel time constant: 1 𝜏 = (𝑟𝑚 ∙ 𝑟𝑖 )2 ∙ 𝐶𝑚 where 𝐶𝑚 = capacitance of membrane shorter τ = faster propagation Know how local currents are involved in the propagation of the action potential. local currents initiate APs by depolarizing to threshold Understand how myelin affects the rate at which action potentials are propagated and what occurs to conduction velocity during multiple sclerosis. myelination: increases membrane resistance (rm) longer λ decreases capacitance (Cm) shorter τ also saltatory conduction multiple sclerosis is an autoimmune disorder wherein myelin in the peripheral nervous system is destroyed eventually, signals cannot be propagated to or from the periphery and paralysis results Be acquainted with the different pathologies that are associated with defects in the membrane properties that we have discussed. ????? Know the basic mechanisms by which signals are transmitter across electrical and chemical synapses. electrical synapses – mediated by gap junctions; ionic current is directly transmitted chemical synapses – mediated by a neurotransmitter; signal inhibits (hyperpolarizes) or excites (depolarizes) membrane of post-synaptic cell Know the basic types of receptors for neurotransmitters and how neurotransmitters can either excite or inhibit the postsynaptic membrane. ionotropic: ion channel is part of receptor rapid response! channel activation either depolarizes or hyperpolarizes post-synaptic membrane metabotropic: G-protein coupled activate α and β subunits, which then go do stuff in the cell response is slow (seconds to minutes) Know what accounts for size and duration of a post-synaptic potential. the post-synaptic potential triggered by a neurotransmitter is a graded potential, i.e. it is proportional to the strength of the stimulus (the amount of neurotransmitter encountered) and the duration of the signal; as with all graded potentials, it decays over time and distance key here is that the neurotransmitter, itself, does not trigger an AP on the postsynaptic cell; instead it triggers a local potential that then triggers the AP in the target cell IFF it is big and/or long enough Know the sequence of events that occur at the neuromuscular junction that results in the subsequent production of an action potential in the associated muscle fibers. 1. AP travels to presynaptic terminal 2. depolarization opens Ca2+ channels Ca2+ flows into cell 3. ACh released by exocytosis 4. ACh binds receptor on postsynaptic terminal 5. receptor opens nicotinic ACh receptor – this receptor is not selective: both Na+ and K+ can flow through it, but the driving force for Na+ is much much higher than for K+ 6. end plate potential IF SUFFICIENT action potential 7. ACh degraded to choline and acetate by AChE 8. choline taken back up by presynaptic terminal Know the mechanism by which an action potential in the presynaptic membrane causes the release of neurotransmitter into the synaptic cleft. depolarization opening of voltage-gated Ca2+ channels influx of Ca2+ stimulation of exocytosis Know the mechanism by which acetylcholine is synthesized and degraded at the neuromuscular junction. acetyl CoA + choline by choline acetyltransferase within axon terminal (note: not made in cell body and transported to axon terminal – that’s too slow) degraded to choline and acetate by AChE; choline is recycled What is a miniature end-plate potential and how is it related to the concept of the quantal release of neurotransmitter? a neurotransmitter (e.g. ACh) is released in “packets” corresponding to the vesicles it is packaged in in the presynaptic terminal one packet is one quantum of neurotransmitter each packet produces a miniature end-plate potential it is the sum of MEPPs that is relevant as to whether the local potential reaches threshold What is a major symptom of Myasthenia gravis? How is this disease treated? patients have antibodies to the ACh receptor unable to sustain prolonged contraction of skeletal muscle treated with anticholinesterases What is Lambert-Eaton syndrome? patients have antibodies to voltage-gated Ca2+ channels in presynaptic terminals decreased release of neurotransmitter weakened skeletal muscle and diminished stretch reflex Facilitation and post-tetanic potentiation are short term events that occur at the postsynaptic membrane. What are they and how do they both occur? facilitation an increase in the size of the EPP produced in the post-synaptic cell per AP in the presynaptic cell occurs when pre-synaptic cell is stimulated in quick succession occurs DURING this rapid signal received from the presynaptic cell may be due to accumulation in intracellular Ca2+ in presynaptic cell release of more neurotransmitter per AP post-tetanic potentiation: a similar increase in the size of the EPP produced in the post-synaptic cell due to rapid APs from presynaptic cell occurs AFTER serious of rapid signals from presynaptic cell – a subsequent signal from the presynaptic cell within a window will produce a larger EPP maybe same mechanism, who knows What are the space and time constants and what do they measure? you already asked that What is the relationship between conduction velocity of an action potential and the diameter of an excitable cell? velocity of conduction of an AP increases with diameter b/c: 𝑎𝑅 increases length constant: 𝜆 = √ 2𝑅𝑚 decreases cytoplasmic resistance (ri) increases λ and decreases τ 𝑖 What is membrane capacitance and how does it affect the rate at which the membrane potential can change? capacitance (C) is a measure of how much charge (Q) is stored per volt (E) between surfaces that can store charge, i.e. 𝐶 = 𝑄⁄𝐸 the capacitance of the membrane determines how much charge must move in order for Vm to change when current begins to flow, the time course is determined by the time it takes the charge to redistribute on the capacitor with an initial difference in voltage of V0, the charge stored on a capacitor is: 𝑄 = 𝐶𝑚 ∙ 𝑉𝑚 when a channel first opens, the initial voltage change is: −𝑡 𝑉 = 𝑉0 𝑒 ⁄𝑅𝐶 and τ = time required for V0 to fall to 37% of its initial value (t = RC) Dr. Cala – Muscle Physiology 3 types of skeletal muscle skeletal cardiac smooth How does skeletal muscle produce movement of the skeleton? concentric contraction of the agonist (and any synergists) eccentric contraction of the antagonist What is the difference between anatomical and physiological cross-section? anatomical: orthogonal to the length of muscle physiological: orthogonal to muscle fibers pennate muscles have greater physiological cross-section this allows for greater muscle mass in the same area = more force Muscle tension tension is orthogonal to contractile force not exerted on tendon, simply squeezes the muscle! Wall stress tension thickness of muscle How does hypertrophy reduce wall stress? hypertrophy – increase in number of sarcomeres thickens muscle The sarcomere thin filaments: actin, tropomyosin, troponin-T, -I, -C thick filaments: myosin (heavy and light chains) tintin: provides resting tension and acts as a spring actinin & nebulin: stability, passive resistance, active recoil force morphological relationship of sarcoplasmic reticulum to the contractile machinery What is a muscle cell twitch? contraction and relaxation of a single muscle cell in response to depolarization How is a twitch produced? (excitation-contraction coupling) 1. AP depolarization of T-tubules 2. depolarization change in dihydropyridine receptor (DHPR) opening of ryanodine receptor (RyR) in SR Ca2+ release from SR 3. Ca2+ binds to troponin-C cross-bridge cycling contraction 4. SERCA pumps Ca2+ back into SR Ca2+ release from troponin-C relaxation How does the Ca2+ release differ in the 3 muscle types? How do L-type Ca2+ channels differ between muscle types? skeletal: voltage-induced Ca2+ release cardiac: Ca2+-induced Ca2+ release smooth: not really dependent on RyR-activated Ca2+ release The actinomyosin ATPase cycle 1. myosin is bound to actin (rigor). ATP binds release of myosin from actin 2. ATP hydrolysed to ADP+Pi, which remains attached to myosin 3. myosin + ADP+Pi reattaches to actin 4. ADP+Pi is released myosin returns to rigor state Which molecular change produces the actual power in muscle contraction? the dissociation of ADP from myosin Active vs. passive force active force is produced by the cross-bridge cycling proportional to # of cross-bridges formed is maximal at optimal sarcomere length (maximum overlap between thick and thin filaments passive force is the force exerted by the “rubber band-like” proteins (tintin, nebulin) to return the sarcomere to its resting position does not require ATP or Ca2+! see the cardiac lectures for more detail – this is preload!!! What is the relationship between force and velocity? velocity of muscle contraction slows exponentially with increased load maximum load + maximal tetanic tension velocity = 0 load = 0 maximum velocity How do the properties of force and velocity reflect the structure of myofilaments? force # cross-bridges What are the major types of muscle fiber changes? hypertrophy – increase in sarcomeres (myofibrils) hyperplasia – increase in fibers atrophy – decrease in fibers How do slow APs and non-striated contractile proteins lead to the uniqueness of smooth muscle? slow waves are important in rhythmic contractility of smooth muscle; similar to cardiac slow APs in that they are regulated by pacemaker cells (interstitial cells of Cajal in the intestines) and prevent tetanus myofibrils of smooth muscles are tangled up in intermediate filaments the entire cell contracts when the myofibrils contract (instead of shortening along one axis like striated muscle cells) dense bodies connect smooth muscle cells so when one contracts, its neighbors are pulled along with it What is the role of myosin light chain phosphorylation in SM force generation and the latch state? myosin light chain cannot interact with actin unless phosphorylated light chains remain attached (cell contracted) unless de-phosphorylated!!!! (latch state) NO acts on dephosphatase to relax smooth muscle (remember that PS innervation triggers the release of NO rather than acting on the muscle cell itself) What proteins are affected by the genetic disorders malignant hyperthermia, CPVT, and muscular dystrophy, and how do their dysfunctions cause disease? malignant hyperthermia cause: RyR1 point mutation chronic SERCA activation symptoms: increased body temperature, smooth muscle rigidity, lactic acidosis treatment: dantrolene (inhibits RyR) CPVT cause: RyR2 point mutation inappropriate triggered release of Ca2+ symptoms: PVCs and fatal arrhythmias treatment: flecanide muscular dystrophy cause: mutations in dystrophin (protein that couples myofibrils to cell membrane so that contraction in the myofibril produces contraction of the cell) necrosis What is a motor unit? collection of muscle fibers innervated by a single motor neuron all fibers of a motor unit are of the same type How does the size of a motor unit vary among skeletal muscles? Why does it matter? small motor units: precise control, faster reactions, more expensive large motor units: coarse control, slower reactions, less expensive What are the three most common ways to classify motor units? rate of twitch – fast or slow fatigability both dependent on myosin heavy chain isoform metabolism – aerobic or anaerobic What are the types of motor units, and how do they differ? I – slow twitch, non-fatigable (aerobic) IIa – fast twitch, non-fatigable (anaerobic) IIb – fast twitch, fatigable (anaerobic) Why does increasing the frequency of alpha motor neuron frequency increase force? frequency summation – Ca2+ is being released faster than SERCA can pump it out cell remains contracted (this is tetanus) How can skeletal muscle fibers increase the level of force generation by recruitment of additional fibers? increase in voluntary force more motor units activated recruited by the size principle – in increasing size, i.e. type I, then type IIa, then type IIb How can both frequency summation and fiber recruitment occur in exercising muscle? we probably recruit more fibers before we increase the frequency of stimulation. probably. Peripheral vs. central muscle fatigue central – CNS fatigue (decreased neural stimulation) – maybe through inhibitory afferents? peripheral – in muscle cells of motor units Ca2+ transients are reduced somehow Anerobic vs. aerobic metabolism, and relative roles for ATP production anaerobic: phosphocreatine creatine + PO3- and glucose lactic acid 12X faster than aerobic, but must get rid of byproducts 3X as much phosphocreatine stored as ATP, payback is 4X faster aerobic: glucose, fatty acids + O2 CO2 + H2O glycogen is most important, restoration requires ingesting glucose What is oxygen debt? buildup of anaerobic byproducts while aerobic metabolism is ramping up What are the subcellular events that lead to the release of Ach from the neuromuscular junction? see cell physiology notes, above How does Ach activate contraction? see cell physiology notes, above How do common drugs prevent neuromuscular signal transmission? D-tubocurare – competes with ACh anti-AChE – prevents degradation of ACh succinylcholine – receptor agonist Clostridium toxins – inhibits release of synaptic vesicles (the difference in the paralysis produced by C. botulinum and C. tetanus is due to which nerves they act on) What are the afferent nerves of proprioception, and how do they sense the contractile state of the muscle? Golgi tendon organs – sense tension, located in series on tendons muscle spindles – sense stretch, located in parallel with extrafusal, receive both afferent and efferent innervation What are gamma motoneurons? efferent γ-motoneurons regulate the gain of stretch reflex by adjusting level of tension in the intrafusal muscle fibers α-motoneurons innervate extrafusal muscle fibers (“normal” muscle cells) Dr. Laisley – Cardiac Physiology Ion currents and when they occur in fast and slow cardiac APs Depolarization vs hyperpolarization JFC that’s like three lectures Fast AP: Phase 4 (resting Vm): Vm ≈ -90 mV due to K+ not quite EK (-94 mV) b/c of Na+ leak net driving force for K+ still outward (+4 mV) [] gradients maintained by Na/K ATPase Phase 0 (rapid depolarization): due to fast opening of Na+ channels (1-2 ms) rapidly altering Vm of a neighboring cell to -65 mV causes depolarization b/c gap junctions GNa decreases towards end of phase b/c of channel inactivation absolute refractory period !!! the SLOW RECOVERY of the inactivation gates are key to preventing tetanus in cardiac muscle Phase 1 (early repolarization): returns Vm to +10 mV (plateau voltage) due to: o inactivation of fast Na+ channels o slowing of inwards Ca2+ current o voltage-dependent transient outward K+ current (Ito1) Phase 2 (plateau): balance between inward and outward currents maintains cell in depolarized (+10 mV) state for a few 100 ms o this determines strength and duration of contraction primary current is slow inward Ca2+ current Ca2+ channels: o L-type: primary channels long-lasting activated @ -20 mV (last part of phase 0) slowly inactivate during phase 2 o T-type: transient open @ -70 mV balancing outward current: IK1 delayed rectifier currents (smaller than IK1): IKr and IKs atrial myocytes have very rapid IKur Phase 3 (repolarization): progressive decay of inward Ca2+ current increase in outward K+ (IK1) Na/K balance restored by Na/K pump intracellular Ca2+ reduced by Na/Ca exchanger & sarcolenmal Ca2+ ATPase Slow AP: o Phase 4 (resting Vm): slow diastolic depolarization o due to LACK OF IK1!! mediated by: o pacemaker current, If o Ca2+ current, ICa o outward K+ current, IK If: o non-specific cation channel becomes activated during repolarization of previous AP @ -50 mV autoexcitation!! Phase 0 (depolarization): caused by inward Ca2+ flow o channels become activated @ 55 mV (end of phase 4) no phase 1 in slow response fibers; phase 2 cannot be distinguished from phase 3 Phase 3 (repolarization): mediated by outward K+ current IK Ligand-gated Ion Currents IKACh: activated by ACh shortens AP in atrial myocytes hyperpolarizes Vm in SA and AV nodes IKATP inhibited by normal ATP levels activated with decrease in the ATP/ADP ratio shortens AP in atrial and ventricular myocytes The basic cardiac conduction system and where fast vs slow APs are located SA node atria, AV node DELAY!! bundle of His left and right ventricles fast APs: atrial and ventricular myocytes, Purkinje fibers slow APs: SA and AV nodal cells Regulation of cardiac conduction by the autonomic nervous system SS stimulation: activation of β-adrenergic receptors stimulation of all three currents BUT greater stimulation of If and ICa more rapid depolarization, increases repolarization time more rapid and shorter APs in the SA node increased heart rate PS stimulation: ACh activates ligand-gated IK(ACh) channel decreased Vm (hyperpolarization) increased threshold slower depolarization ACh also decreases If and ICa slower depolarization resting heart rate is primarily controlled by PS Components of the ECG and “relative interval durations” Component What it is P wave Atrial depolarization PR interval Depolarization propagated through AV node AV bundle branches QRS complex Depolarization of ventricular myocardium Q: depolarization of interventricular septum R: primary depolarization of left ventricle ST segment All regions of ventricles depolarized – plateau phase !! ST elevation or depression occurs during myocardial ischemia!! T wave Repolarization of ventricles QT interval Ventricular AP duration Normal duration 80-100 ms 120-200 ms <120 ms <400 ms Basic rules of how ECG waves on the ECG are generated – positive vs negative a positive deflection indicates an approaching wave of depolarization a negative deflection indicates a receding wave of depolarization !! remember that depolarization moves downward and to the left The location of and polarity of all 12 leads aVR – right arm +, left arm and leg – (thus waves are inverted compared to other leads) aVL – left arm +, right arm and left leg – aVF – left leg +, right and left arm – V1 and V2 – primarily right ventricle (but usually obscured by larger left ventricle depolarization) large S waves because LV depolarization moves away V5 and V6 – primarily left ventricle large R waves because LV depolarization moves towards How to estimate/calculate MEA; left vs right axis deviation two best signals to use: lead with the greatest net positive amplitude of R is most parallel lead with the smallest difference between R and S is most orthogonal vectors usually between -30° and +110° Basics of ECG interpretation: Heart rate (HR) – R to R Rhythm Axis Chamber hypertrophy Left ventricle hypertrophy Large increase in QRS amplitude T wave inverted and asymmetric Left axis deviation Split P waves Right ventricle hypertrophy Tall R waves in RV leads Deep S waves in LV leads T wave inverted and asymmetric Right axis deviation P wave amplitude increased in right chest leads Myocardial ischemia/infarction mostly observable through changes in the S and T waves ST segment is full depolarization T wave is repolarization inhomogeneities in AP propagation affect S & T subendocardial ischemia – increased QT interval and/or T amplitude subepicardial ischemia – T wave inversion severe subendocardial ischemia – ST depression severe subepicardial ischemia – ST elevation Basics of cardiac EC coupling and effects of sympathetic stimulation EC coupling same as for skeletal muscle; see Dr. Cala’s muscle section SS stimulation of β-adrenergic receptors does the following: 1. increase Ca2+ flux across SR by phosphorylating Ca2+ channels 2. increase SR Ca-ATPase activity 3. decrease Ca2+ sensitivity of myofilaments shorter and stronger contractions The 3 factors that affect cardiac function and how they differ preload force within cardiac muscle at rest o this is PASSIVE FORCE remember that? force developed by contracting cardiac muscle depends on preload prior to onset of contraction – Starling’s Law of the Heart, see below for more detail INDEPENDENT OF ATP AND [Ca2+]!!!!! afterload weight a muscle senses and must work against o in a normal heart, this is equal to the aortic pressure as afterload increases: o rate of shortening decreases o extent of shortening decrease o onset of shortening increases o time to maximal shortening is UNCHANGED contractility biochemical potential of muscle to perform work that is independent of preload and afterload e.g., SS stimulation bringing in more Ca2+ The Frank Starling mechanism increased stretch during diastole increased force of contraction during systole i.e., more blood in, more blood out PASSIVE TENSION independent of ATP and Ca2+ Where the 4 cardiac valves are located and how they regulate the different phases of the cardiac cycle S1 vs S2; systolic vs diastolic murmurs S1: closure of tricuspid and mitral valves onset of systole peak of R wave S2: closure of pulmonic and aortic valves end of systole end of T wave systolic murmurs occur between S1 and S2 diastolic murmurs occur after S2 The basics of the Wiggers diagrams are you seriously fucking kidding me this diagram is the worst The components of ventricular function: Component Units Equation Cardiac output L/min heart rate (bpm) x stroke volume (mL/beat) Stroke volume mL/beat end diastolic volume (EDV) – end systolic volume (ESV) EDV − ESV SV Ejection fraction = EDV EDV Stroke work ergs stroke volume (mL) x mean aortic pressure (dynes/cm2) The 4 factors that determine stroke volume heart rate ventricular compliance preload or EDV (venous return) afterload or arterial blood pressure How the law of LaPlace applies to the heart 𝜎 = 𝑃 ∙ 𝑅⁄𝑊 where σ = wall stress, P = pressure, R = radius of curvature of the wall, and W = wall thickness 𝜎∙𝑊 𝑃= 𝑅 when R increases (such as when heart dilates), more stress is needed to produce a given pressure How to interpret PV loops – load effects vs contractility IVVR – isovolumic ventricular relaxation IVVC – isovolumic ventricular contraction as preload increases, capacity of LV to generate P increases stroke volume increases as afterload increases, stroke volume decreases but this increases end-diastolic volume (preload) so stroke volume increases again increased contractility increased SV & SW w/constant load increased rate of ejection of blood from ventricle You need to know the 4 types of murmurs – focus on aortic insufficiency vs stenosis Murmur Sound Cause & Effect aortic stenosis LVP during ejection >> aortic P due to narrowing of aorta SV due to afterload LV hypertrophy aortic insufficiency blood leaks back into LV after ejection EDV EDP preload SV blood flow between LA and LV LAP & LA hypertrophy LV filling EDV & EDP SV blood leaks across MV during ejection LAV & LAP LV filling EDV & EDP SV mitral stenosis mitral insufficiency for reference, normal sound graph is: What you are not responsible for on the exam You do not need to memorize specific numbers You do not need to know the specific locations and differences in IKr vs IKs You will not need to discriminate between similar types of arrhythmias, but you need to know where to look on the ECG for these arrhythmias You do not need to know the exact location of specific valve auscultation sites You do not need to memorize the 3 waves or peaks from the jugular vein pulse You do not need to know anything after the mitral insufficiency slide/page in the notes Dr. O’Leary – Cardiovascular Physiology Describe the relationship between pressure, flow and resistance. 𝑃1 − 𝑃2 = flow × resistance where P1 = aortic pressure, P2 = central venous pressure, resistance = total peripheral resistance (TPR) 8𝜂𝑙 if resistance, 𝑅 = 𝜋𝑟4 , where η = viscosity, l = length, and r = radius then flow = (𝑃1−𝑃2)(𝜋𝑟 4 ) 8𝜂𝑙 the radius r becomes the most important factor for determining resistance (and hence flow) arterioles are most important for establishing TPR b/c of ++ smooth muscle in walls also flow = velocity x cross-sectional area, just to confuse things Compare and contrast the anatomy of blood vessels at the different levels of the vascular tree. remember your anatomy Compare and contrast the changes in pressure, velocity, area, and blood volume at different levels of the vascular tree. pressure: from aorta to IVC biggest across arterioles (b/c resistance) velocity: from aorta to capillaries, on venous side dependent on cross-sectional area o cross-sectional area – area of all blood vessels at any level % total blood volume dependent on pressure and compliance arteries have high pressure and low compliance, veins have low pressure and high compliance o 70% of TBV is in venous system Understand the concept of compliance. Δ𝑉 Δ𝑃 i.e., how much volume changes due to a change in pressure 𝐶= Discuss the effects of posture on transmural and perfusion pressures. transmural pressure – pressure across the walls of blood vessels perfusion pressure -- ∆P across tissue (arterial P – venous P) upright posture: p = height of column x density of fluid x gravity hydrostatic pressure dependent on distance above and below heart Mean Arterial Pressure (MAP) ≈ diastolic pressure + 1/3 pulse pressure Understand the concepts of local control including: reactive hyperemia – in blood flow after a period of no flow active hyperemia – when metabolic rate , blood flow actively metabolizing tissue produces vasodilators (H+, K+, lactate, etc.) metabolism = vasodilation no flow = constituent vasodilators not carried away when flow resumes, local concentrations of vasodilators autoregulation – ability of tissue to maintain constant blood flow despite changes in perfusion pressure range over which autoregulation is effective is the autoregulatory range (duh) hypothesis 1: metabolic -- P causes in blod flow, which local concentration of vasodilators vasoconstriction hypothesis 2: myogenic – when smooth muscle is stretched, it contractions when P, recoil by smooth muscle walls vasoconstriction mechanical (tissue pressure) effects – compression of blood vessels, e.g. in endocardium during systole because perfusion is ∆P across tissue, if P ≈ across tissue, ∆P ≈ 0 Understand the concepts of remote control, effect of activation of alpha, beta, V1, and AII receptors. neural – control by autonomics (primarily SS) norepinephrine (NE) release causes vasoconstriction except in some skin & muscle vessels – vasodilation PS in genitals, heart, brain – ACh vasodilation (via NO) circulating factors: vasopression vasoconstriction o via pituitary renin/angiotensin vasoconstriction o via kidney (renin) and lungs (angiotensin I angiotensin II) norepinephrine & epinephrine (via adrenal medulla) o blood vessels with β-2 receptors vasodilation o [] or blood vessels without β-2 receptors and with α receptors vasoconstriction o cardiac β-1 receptors HR and contractility Understand the concepts of basal tone and resting tone. basal tone – vascular smooth muscle tone when all remote and local factors are removed but….not physiologically possible, as basal levels of SS activity, etc., so: resting tone is somewhat higher than basal tone (varies by tissue) Differentiate between active and passive vasoconstriction/vasodilation. active vasoconstriction is mediated when this relaxes (to basal tone), it is passive vasodilation active vasodilation is mediated when this is removed (to basal tone), it is passive vasoconstriction Describe the forces controlling fluid movement across the capillary. πt – oncotic pressure in tissue interstitium – pulls fluid out of capillary πc – oncotic pressure in capillary – pulls fluid into capillary Pt – hydrostatic pressure within tissue – pushes fluid out of capillary Pc – hydrostatic pressure within capillary – pushes fluid into capillary net force for filtration = (𝑃𝑐 + 𝜋𝑡 ) − (𝑃𝑡 + 𝜋𝑐 ) for fluid OUT of capillary net filtration = 𝐾𝑓[(𝑃𝑐 + 𝜋𝑡 ) − (𝑃𝑡 + 𝜋𝑐 )] where Kf varies by tissue Describe the role of the precapillary resistance in controlling hydrostatic pressure within the capillary changes in precapillary resistance inversely effect Pc if R , Pc , if R , Pc Describe the role of compliance in regulating venous volume. active: due to changes in vascular smooth muscle, result in changes in entire venous compliance curve passive: changes in position on same compliance curve due to changes in transmural pressure Describe a feedback control system sensor – mechanism to detect the level of the parameter integrator – analyzes info from the sensor and decides if adjustments are necessary; effects adjustment by means of the: effector – mechanism to affect the variable under control Discuss the factors affecting baroreceptor nerve activity sensors arterial baroreceptors – located in walls of carotid sinus and aortic arch cardiopulmonary baroreceptors – located in atria, ventricles, and pulmonary vessels o arterial and venous much more sensisitive to small changes in P than arterial reinforce SS triggered by arterial atrial cells release atrial naturiuretic peptide, which does… something o ventricular tend to reinforce arterial except…may be responsible for “vicious cycle” (see below) carotid and aortic chemoreceptors – respond to changes in CO2 and O2 central chemoreceptors – if O2 delivery to brain becomes too compromised, in SS activity – cerebral ischemic pressor responses o vasoconstriction to shunt blood to brain o responsible for hypertension associated with head injuries integrator – probably the vasomotor center in the medulla effectors – PS and SS autonomics basal state is SS, PS!! o that is, in baroreceptor activity INHIBITS vasomotor center SS, PS Discuss the compensatory responses to hemorrhage. Discuss the "vicious cycle" orthostatic intolerance – inability to stand without fainting probably due to dramatically blood volume (bed rest and space flight) o more susceptible to the blood volume shifts that accompany upright posture prolonged orthostasis contractility , preload reflex bradycardia & SS cardiac output & vasodilation exercise oxygen consumption = blood flow x (arterial – venous)O2 can O2 consumption by blood flow or extraction of O2 (or both) response to exercise central command o volition or “will” to exercise in PS activity arterial baroreflex o reset to higher level reinforce in pressure o how? no one knows skeletal metaboreflex and mechanoreflex o metabolites accumulate stimulate afferent nerves in arterial pressure and HR – metaboreflex o some of these afferents are mechanosensitive & stimulate with contraction – mechanoreflex o works via SS & vasopressin activity during graded exercise initially o PS tone in cardiac output o small in SS muscle metaboreflex as exercise progresses o PS due to central command and resetting of arterial baroreflex o SS due to resetting of arterial baroreflex and muscle metaboreflex hyperthermia majority of cardiac output directed to the skin o in cardiac output & redistribution of blood flow vasodilation due to SS (PS not present in limbs) exercise more difficult in hot environment because you only have so much blood, has to be divided between muscle (actively metabolizing) and skin (heat loss)
