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Hoang 1 MEDICAL PHYSIOLOGY 2005 ENDOCRINE PHYSIOLOGY I. Hormones Highest bound/free radioactive hormone = zero unlabeled hormone present Lowest bound/free radioactive hormone = highest hormone concentration present Rough endoplasmic reticulum = preprohormone & prohormone Golgi apparatus = prohormone & hormone G-Proteins GTP-binding proteins = intrinsic GTPase activity Adenylate cyclase, IP3, and Ca2+-calmodulin A. Adenylate cyclase Hormone bind receptor on cell membrane Gs = stimulatory Gi = inhibitory GDP released from G-protein at -subunit GTP binds to G-protein at -subunit Activate adenylate cyclase Adenylate cyclase converts ATP to cAMP Intrinsic GTPase converts GTP to GDP Inactive G-protein cAMP activates protein kinase A (PKA) Physiologic actions Phosphodiesterase degrade cAMP to 5’-AMP Inhibited by caffeine and theophylline B. IP3 Hormone bind receptor on cell membrane G-protein activates phospholipase C Phospholipase C frees diacylglycerol (DAG) and IP 3 from membrane lipids IP3 recruit Ca2+ from ER IP3 and DAG activate protein kinase C (PKC) PKC phosphorylate proteins C. Ca2+-calmodulin Hormone bind receptor on cell membrane G-protein increase intracellular Ca2+ Open cell membrane calcium channels Release calcium from ER Calcium bind calmodulin Physiologic actions D. Steroid and thyroid hormone Steroid and thyroid hormones diffuse cell membrane Bind cytosolic or nuclear receptor Receptor has conformational change Expose DNA-binding domain Interact with hormone-regulatory elements Transcription initiated mRNA translated in cytoplasm Production of proteins Hoang 2 Hormone Type Derivation Storage Transport Receptor Administration Character-is tic Catechol-a mines Tyrosine Membranebound vesicles Free or loosely associated w/ proteins Cell surface receptors Ineffectively orally in native form; effective when injected AA derived Thyroid Tyrosine Follicles Bound to proteins Intracellular; cross cell membrane Orally AA derived Protein/ Peptide Synthesize as pre-prohomo ne in RER Membranebound granules Unbound, exocytosis upon stimulus Cell membrane NOT orally Polar Hydrophilic Steroid Cholesterol, Esters, synthesized in SER and mitochondria inner membrane No storage, released by diffusion after synthesis Bound to proteins Intracellular and nuclear membrane receptors Orally Hydrophobic Lipophilic G protein-coupled receptors (GPCR) Consist of 7 transmembrane segments GTP-binding domain b/w 5,6 cytoplasmic loop Subunits / modulate signaling Increase K+ channel activity and phospholipase A2 activity C-terminus binds intracellular proteins Diversity of receptors Adrenegic = Epi and NorEpi Muscarinic = Acetylcholine Peptide/Glycoprotein Follicle Stimulating Hormone Angiotensin II Somatostatin Thyroid Stimulating Hormone Vasopressin Parathyroid Hormone Calcium Ionotropic receptors (Ligand-gated ion channel) Consist of membrane spanning subunits that form ion channel Allows cations entry Hoang 3 Calcium = EPI secretion in adrenal Sodium = muscle contraction ACH nicotinic and IP3 receptor Catalytic receptors Extracellular domain = bind hormone May result in receptor dimerization Ligand binds several extracellular domains Activation of intracellular catalytic domain Tyrosine kinase-associated receptors Growth hormone receptor No intrinsic kinase activity Intracellular domain associate with JAK and Src Dimerization to activate tyrosine kinase Receptor guanylyl cyclase Atrial natriuretic peptide (ANP) GC-A receptor Ligand bind to dimerize intracellular guanylyl cyclase domains Becomes activated Convert GTP to cGMP cGMP activate PKG, phosphodiesterase, or ion channels Receptor serine/threonine kinases Receptor tyrosine kinases Insulin receptor, IGF-1 receptor Extracellular domain = -chain Ligand bind to -chain Activated -chain kinase direct tyrosine phosphorylation Insulin receptor substrate-1 Receptor tyrosine phosphatases Intracellular Receptors Steroid hormones The only homodimer when binding to DNA Thyroid hormones Heterodimer Vitamin D3 Heterodimer Bind intracellular receptors that are transcription factors II. Hypothalamus Anterior hypothalamic nucleus Temperature = dissipation of heat Sexual behavior Posterior hypothalamic nucleus Temperature = conservation of heat Paraventricular nucleus (PVN) & Supraoptic nucleus (SON) = magnocellular neurons Arginine vasopressin Oxytocin Arcuate, AH, MPOA, PVN CRH = Corticotrophin releasing hormone TRH = Thyrotrophin releasing hormone LHRH = Lactotrophin releasing hormone GHRH = gonadotrophin releasing hormone SS = somatostatin DA = dopamine Hoang 4 Paraventricular nucleus Hypoglycemia & morning time Stimulate secretion of CRH and AVP Nighttime inhibit hypothalamus CRH and AVP stimulate anterior pituitary to secrete ACTH ACTH stimulate adrenal to secrete cortisol ACTH inhibit pituitary and hypothalamus Cortisol stimulates liver to secrete glucocorticoids = increase blood glucose Highest levels during night Prolactin and Growth hormone Highest levels during day Cortisol Target Hormone Level (ie. liver cortisol) Low High Pituitary Hormone Level Normal Primary failure of target endocrine organ Autonomous secretion of pituitary hormone or resistance to target hormone action (pituitary receptor) (ie. ACTH) Normal Low High Normal range Pituitary failure Autonomous secretion by target endocrine organ III. Pituitary Gland Anterior lobe Linked to hypothalamus via hypothalamic-hypophysial portal system Thyroid-stimulating hormone (TSH) Stimulate synthesis and secretion of thyroid hormones Luteinizing hormone (LH) Stimulates ovulation, formation of corpus luteum, and estrogen/progesterone synthesis Follicle-stimulating hormone (FSH) Stimulates growth of follicles and estrogen secretion Adrenocorticotropic hormone (ACTH) Stimulate synthesis and secretion of adrenal cortical hormones Melanocyte-stimulating hormone (MSH) Stimulates melanin synthesis Hoang 5 -endorphin Growth hormone Stimulate protein synthesis and overall growth Homologous to human placental lactogen and prolactin Pulsatile release Increased by sleep, stress, starvation, and hypoglycemia Decreased by somatostatin, somatomedins, obesity, hyperglycemia, and pregnancy Prolactin Homologous to GH Lactogenesis and breast development Decrease synthesis and release of GnRH and inhibits ovulation / spermatogenesis Secretion inhibited by dopamine from hypothalamus Prolactin stimulate release of dopamine Stimulated by TRH Posterior lobe Derived from neural tissue Nerve cell bodies located in hypothalamic nuclei Supraoptic nuclei = ADH Stimulates water reabsorption by renal collecting ducts Paraventricular nuclei = oxytocin Milk ejection and uterine contraction Used to reduce postpartum bleeding Increased secretion by dilation of cervix and orgasm IV. Growth Hormone Highest concentration during sleep Average = 1.5-1.6 microgram/L in adults Peak = 15 microgram/L Found on chromosome 17 3 variants 20 kDa 22.5 kDa = major variant 45 kDa = combination of two 22.5 kDa segments Derivations of GH Placental Variant GH (PVGH) Same functions as GH Synthesized in placenta Function during fetal period Placental lactogen Similar to GH Weaker affinity to GH receptor 100-1000 fold weaker Prolactin Pituitary produced 19-20% homologous to GH No growth promoting function GH binding protein 40% GH bound (inactive) 60% GH free (active) Bind two GH receptors (dimerization) in liver Increase IGF and IG Binding protein synthesis in liver IGF bound to IGBP with ALS IGF = directly affect growth in bone IGF-1 receptor similar to insulin receptor Hoang 6 Heterotetramer IGF-1 = insulin-like effects Found in growing tissue especially muscle Function in childhood growth and adult maintenance IGF-II receptor = mannose-6-phosphate Clearance for mannose-linked proteins Function in fetal growth Childhood Excessive GH Gigantism Deficient GH Dwarfism Adulthood Acromegaly Growth hormone direct effects Increased muscle mass and decreased adiposity (lean body mass) Decreased glucose uptake IGF-1 direct effects Increased linear growth Increased tissue growth and organ size V. Male Reproduction GnRH 10 amino acids = peptide hormone Pulsated release Chronic infusion = desensitizing effect of GnRH receptors Bind to G-protein linked receptor Activate PLC IP3 increase intracellular calcium concentration DAG activate PKC PKC activate synthesis of and -subunits of LH and FSH -subunit determine functionality since -subunits are identical FSH, LH, hCG, and TRH Dimerization of subunits Release due to calcium increase LH Target Leydig cells Bind G-protein linked receptor Activate adenylate cyclase Adenylate cyclase converts ATP to cAMP Activate PKA PKA stimulate StAR in converting cholesterol to pregnenolone Cytosol to mitochondria to sER Testosterone Bound to SHBG (45%) and albumin (50%) Free testosterone (5%) degraded by liver or attaches to target cell Synthesized and secreted by Leydig cells Does not contain 21-hydroxylase or 11-hydroxylase Stimulated by LH LH stimulate synthesis of cholesterol desmolase Hoang 7 Testosterone inhibit GnRH release and LH release Accessory sex organs contain 5-reductase Convert testosterone (inactive) to dihydrotestosterone (active) Finasteride = 5-reductase inhibitors Differentiation of wolffian ducts and external genitalia Development of male secondary sex characteristics Pubertal growth spurt and libido FSH stimulate Sertoli cells Maintain spermatogenesis Sertoli cells secrete inhibin = inhibit FSH secretion from anterior pituitary Sertoli cells = Mullerian inhibiting hormone (MIH) Mullerian ducts regression Blood-testes barrier Nourishment of developing germ cells Produce seminiferous tubular fluid Remove damaged germ cells Synthesis of androgen-binding protein and inhibin Maintain high levels of testosterone in testes Inhibit FSH secretion from anterior pituitary Leydig cells = Testosterone Wolffian ducts transformation Epididymis, ductus deferens, and seminal vesicles Paracrine effect on development (unilateral) Convert to DHT by 5-reductase Development of penis and scrotum Absence of MIH Mullerian ducts transform Uterus and uterine tubes Absence of testosterone Wolffian ducts regression Development of vagina and female external genitalia Klinefelter syndrome XXY Enlarged breasts, overweight, and infertile Turner’s syndrome XO Nonfunctional ovaries and short stature Testicular feminization XY but androgen insensitivity Male phenotype and ambiguous genitals True hermaphrodite XX with SRY gene due to crossing over Reproductive tract Seminiferous tubules – rete testis – epididymis – vas deferens Seminiferous tubules = immature sperm and incapable of fertilization Epididymis = stored for 2-3 weeks for maturation to become fertile Spermatogonium – Spermatocyte – Spermatid Steroidal effects LH and FSH Stimulate penile growth, pubic hair, and growth spur Testosterone Anabolic effects on muscle Hoang 8 Inhibit breast development Stimulate libido DHT Embryonic development of prostate Descent of testes Phallic growth Balding and pubic hair 17-estradiol Epiphyseal closure Prevent osteoporosis Feedback regulation of GnRH secretion from CNS VI. Female Reproduction Estrogen secretion Low levels before puberty No FSH or LH Increase at puberty (age 12) FSH and LH spikes at night Established at age 13 FSH and LH become monthly surges Decrease to low levels at menopause Constant high levels of FSH and LH due to loss of inhibition from estrogen Menarche First onset of menstrual cycle Thelarche Beginning of breast development Adrenarche (pubarche) Maturation of adrenal gland cortex Development of pubic hair Menstruation Primordial follicle Grow to primary follicle Follicule occurs several cycles before = gonadotropin-independent Primary follicle divides to secondary follicle Form zona pellucida and theca cells Graffian follicle Theca interna produce hormone Cumulus oophorus surrounds oocyte Ovulate into corpus luteum Secrete progesterone Degenerate to corpus albicans Atresia Theca cells = LH LH stimulate StAR via adenylyl cyclase Cholesterol to progesterone Progesterone converts to Androstenedione and testosterone No aromatase in theca cells Granulosa cell = FSH FSH promote aromatase synthesis Androstenedione endocytose from theca cells Converted to testosterone and estradiol via aromatase Estrogen receptors = intracellular (nuclear), membrane, and cytoplasmic receptors Hoang 9 Luteal phase LH receptors synthesized Cholesterol converts to progesterone via LH stimulation Progesterone exported to theca cells Absent in 17-hyroxylase and 17,20-desmolase LH Ovulation Androgen production in theca cells Luteinization and corpus luteum maintenance Progesterone secretion from corpus luteum Granulosa cells FSH Growth and development of ovarian follicles Granulosa cells Estradiol production Increase in LH receptors Proliferative phase Estrogen induce endometrial cell proliferation Increase in Estrogen and progesterone receptors on endometrium Early follicular phase Granulosa cells few Have only FSH receptors Secrete inhibin = inhibit FSH Stimulated by FSH and estradiol Midfollicular phase Granulosa cells have FSH and some have LH receptors Late follicular phase Large number of granulose cells Increase in aromatase Responsive to both LH and FSH Estradiol induce LH surge (ovulatory surge) Progesterone induce collagenase, prostaglandins, and follicular hyperemia Metalloproteinases and plasminogen activator weaken follicle wall Follicle rupture with cumulus cells Evagination of ovum Secretory phase Progesterone induce differentiation of epithelial cells to secretory cells Luteal phase Estrogen and inhibin increases Decreases before menstruation LH and FSH decrease from ovulatory surge Menstrual phase Decline of estrogen and progesterone Activates phospholipase = arachidonic acid Prostaglandins induce vasoconstriction and ischemia Endometrial desquamation and bleeding Shedding of endometrium Due to proteolysis and ischemia Lysis of glandular and stromal cells Degeneration of vascular endothemlium from decreased hormonal support Hoang 10 Estrogen Functions Fetal Sexual differentiation of brain Puberty Adult-Menstruation Growth and development of oviducts, uterus, vagina, and external genitalia Pregnancy Stimulate gonadotropin in follicular phase Increase progesterone receptors Inhibit gonadotropin in luteal phase Increase oxytocin receptors Menopause [Lack of estrogen] Vaginal mucosa dries Osteoporosis Breast development Clear cervical mucus Breasts atrophy Growth spur and fat Closure of epiphyses Endometrial proliferation Increase progesterone receptors Synthesis of SHBG and TBG Increase HDL Decrease LDL and cholesterol Progesterone Functions CNS Increase body temp Decrease GnRH release Mood and behavior Reproductive tract Increased growth and development of oviduct and endometrium Decreased estrogen receptors and uterine contractility of myometrium Decreased oxytocin sensitivity of myometrium Limit prepartum lactogenesis Uterus Lack of progesterone Quiescent Menstruation Increased differentiation and secretion Parturition (delivery) Lactation Dense viscous secretions Postpartum depression Increased differentiation of vagina Decreased proliferation of vagina Hoang 11 Implantation Acromosal reaction via increased intracellular calcium Cortical reaction to harden zona pellucida via increased intracellular calcium Second meiotic division after sperm penetration Hatching Zona pellucida degenerates Apposition Blastocyst implant in endometrium Adhesion Invasion Syncytiotrophoblast divides Multinucleate Forms lacuna Bathed by maternal blood Mature chorionic villus Covered by syncytiotrophoblast Syncytiotrophoblasts Secrete hCG on day 8 Rescues corpus luteum Stimulates production of fetal DHEAS and testosterone Stimulate relaxin from endometrium = quiescent uterus Inhibits hypothalamus and pituitary Maintain low LH and FSH Pregnancy test = detect hCG on day 9 Corpus luteum Secrete progesterone from 2-5 wks of pregnancy Corpus luteum and placenta Secrete progesterone from 5-12 wks of pregnancy Placenta only Secrete estrogen and progesterone Secrete human chorionic somatomammotropin (human placental lactogen) Structurally and anabolically similar to GH Antagonize insulin effects = spare glucose for fetus Cause maternal hyperglycemia Growth of mammary gland Parturition = triggered by fetus Increased prostaglandins Increased oxytocin receptors Increased E/P ratio Decreased progesterone (functions to inhibit contractions) Prolactin function Breast differentiation Duct proliferation and branching Glandular development Milk protein synthesis Lactogenic enzyme synthesis Lactation Suckling stimulus travel via spinal cord to hypothalamus Inhibits dopamine release from arcuate nucleus Leading to prolactin release from lactotrophs (ant. Pituitary) = milk production Inhibits arcuate and preoptic nucleus of hypothalamus Drop in GnRH production = inhibits ovarian cycle Stimulate release of oxytocin from PVN and SON = post. Pituitary Milk release Hoang 12 VII. Adrenal Gland Adrenal Cortex Zona glomerulosa = mineralocorticoids (aldosterone) Hypovolemia stimulate renin secretion Renin convert angiotensinogen to angiotensin I ACE convert angiotensin I to angiotensin II Angiotensin II stimulate zona glomerulosa Increase conversion of corticosterone to aldosterone Aldosterone increase renal sodium reabsorption Hyperkalemia increase aldosterone secretion Zona fasciculate = glucocorticoids (cortisol) Oscillates with circadian rhythm Corticotropin-releasing factor (CRF) stimulate anterior pituitary via cAMP Corticotropes synthesize POMC in production of ACTH ACTH stimulate steroidogenesis in zonae fasciculate and reticularis Increase conversion of cholesterol to pregnenolone Zona reticularis = gonadocorticoids (androgens) Glucocorticoids Increase gluconeogenesis Increased protein catabolism Decreased glucose utilization and insulin sensitivity In adipose tissue Increased lipolysis Increase synthesis of lipocortin Inhibitor of phospholipase A (prostaglandins and leukotrienes) Inhibit IL-2 synthesis and T lymphocyte proliferation Inhibit histamine and serotonin release Mineralocorticoids Increase renal Na+ reabsorption, K+ and H+ secretion 21-carbon steroids Progesterone is precursor 19-carbon steroids Androgenic activity Precursors for estrogens Testes = androstenedione converted to testosterone 18-carbon steroids Estrogenic activity with unsaturated A ring Addison’s disease Adrenocortical insufficiency Hypoglycemia Hyperpigmentation Increased POMC and ACTH = low cortisol feedback Hyperkalemia and metabolic acidosis Cushing’s syndrome Bilateral hyperplasia of adrenal glands Overproduction of ACTH = hypertension Excess cortisol and androgens = hyperglycemia and osteoporosis Central obesity = increased protein catabolism and muscle wasting Conn’s syndrome Aldosterone-secreting tumor Hypertension Hypokalemia Hoang 13 Metabolic alkalosis Decreased renin secretion Congenital 21-Hydroxylase deficiency Decreased cortisol and aldosterone = increased ACTH Virilization in females Early linear growth and pubic hair Increased adrenal androgens Adrenal Medulla Chromaffin Cells = catecholamines (Epi and NE) Majority in blood = Epinephrine (90%) Innervated by sympathetic splanchnic nerve via acetylcholine on nicotinic receptor Influx of calcium Increase synthesis and secretion of Epi and NE via exocytosis into blood Stored in granules Epi and NE produce negative feedback on tyrosine hydroxylase (TH) Acute regulation = increased TH activity Chronic regulation = increased TH synthesis Epinephrine carried in free form (no binding protein) Short half-life = 1-3 minutes Stimulated by hypovolemia, hypothermia, hypoglycemia, trauma, anxiety, and pain Chromaffin granules 0.7 M Epi and NE ATP and ADP Ca2+ Dopamine -hydroxylase Chromogranin A Catecholamine metabolism Liver, kidney, and sympathetic nerve endings COMT and MAO Form endproducts VMA, Metanephrine, and normetanephrine Urine excretion VMA, metanephrine, and normetanephrine Unmetabolized Epi and NE Epi and NE sulfates Catecholamine receptors Adrenergic receptors 1, 2, 1, and 2 = NE 1 = increase phosphoinositide hydrolysis 2 =decrease adenylyl cyclase and cAMP = Epi 1, 2, 3 = increase adenylyl cyclase and cAMP Cross-reactive receptors Continuous release of catecholamine = down-regulates response Via internalization of receptors Sympathectomy = enhance sensitivity and response Acute release of catecholamine = down-regulate response Via desensitization of receptors T3 enhance response via increase in adrenergic receptor and secondary messenger production Hoang 14 Catecholamine receptors Metabolic effects 1 Increase gluconeogenesis Cardiovascular effects Vasoconstriction at splanchnic, renal, cutaneous, and genital vascular beds Other effects Pupil dilation GI and Bladder sphincter contraction Increase blood pressure 2 Decrease insulin secretion and stimulate glucose uptake in muscle and fat 1 2 Increase liver glycogenolysis Increase platelet aggregation Increase heart rate, cardiac contractility, and conduction velocity Increase renin secretion Vasodilation in liver and skeletal muscle vascular beds Increase bladder, bronchial, and gastrointestinal muscle relaxation Increase gluconeogenesis Increase glucagons secretion Decrease glycogen synthase Pheochromocytoma Adrenal chromaffin cell tumor Increase secretion of NE and Epi Severe hypertension and headache Sweating Anxiety Feeling hot Hands and feet are cold Large increase in VMA levels in urine VIII. Thyroid Gland Bilobed and anterior to trachcea Level 5, 6, and 7 vertebrae Thyroid arteries Thyroxine and 3, 5, 3’-Triiodothyronine = T4 (inactive) and T3 (active) Tyrosine combine with iodine (I2) to form MIT and DIT DIT and DIT transform to T 4 (non-calorigenic) DIT and MIT transform to T 3 (calorigenic) Hoang 15 Follicular cells Stimulated = elongated Calorigenesis and growth effects Utilization of energy substrates O2 Consumption Increase heat production and basal metabolic rate Calcitonin Parafollicular cells Calcium regulation Need 1 mg iodide per week Seafood, milk, bread, iodized salt 30 % goes to thyroid 50-70% excreted out via kidneys Thyroid gland use iodide trapping Against concentration and electrochemical gradients Basal level of thyroid hormone synthesis Maintained by sympathetic nervous system Thyroid peroxidase Convert iodide ions to I2 Coupling to form T3, T4, and rT3 Iodinase Combine tyrosine with I2 Thyroid stimulating hormone (TSH) Increases iodide uptake Activates thyroid peroxidase Increases thyroglobulin synthesis Activates iodinase Increases secretion (not storage) Most sensitive monitor of thyroid function Free T4 decrease 50% = TSH increases 100% Negative feedback controlled by free T4 Goiter = enlarged thyroid via stimulation of TSH-receptors Normal euthyroid 90% T4 10% T3 < 0.1% reverse T3 T4 convert to T3 majority In starvation = T4 converts to r T3 (non-calorigenic) Conserve food energy stores Iodide deficiency Total T4and T3 production/secretion decrease More T3 synthesized and secretion relative to T 4 50% T3 and 50% T4 Lack of iodine No T3 or T4 production/secretion T3 and T4 70% bound to thyroxine binding globulin (TBG) 20% bound to transthyretin (TBP) 10% bound to albumin 0.03% total plasma T4 in free state Hoang 16 0.3% total plasma T3 in free state Binding proteins maintain large storage pool of T 4 and T3 Prevent metabolism in liver or excreted in urine Target cell Liver – Kidney – Muscles Entry via diffusion or carrier-mediated transport T3 = nuclear receptor, biologically active, multiple cellular actions Calorigenesis Stimulate appetite Growth effects Bone growth and tooth eruption Stimulate GH and IGF-1 production Nervous system Normal development Neural branching and differentiation Nerve myelination Enhances effects of epinephrine and glucagons = substrates for oxidation Inhibit pituitary (major) and hypothalamus (minor) Hyperthyroidism = increased metabolism Increased appetite Weight loss Heat intolerance Increased sweating Grave’s Disease Autoantibody to TSH-receptor Mimics TSH = agonist Thyroid-stimulating immunoglobulins Increased T3/T4 in plasma Decreased TSH in plasma Goiter Exophthalmos = protrusion of eyes Stimulate extraocular muscles = increased mucopolysaccharides Double vision Hypothyroidism = decreased metabolism Reduced appetite Weight gain Cold intolerance Deceased sweating Autoantibody to iodinase and thyroid peroxidase Decreased T3/T4 in plasma Increased TSH in plasma Goiter Increased production of thyroglobulin Autoantibody to thyroid = Hashimoto thyroiditis Destruction of thyroid follicular cells No production of T3/T4 = no negative feedback to anterior pituitary Increased TSH in plasma No goiter long term Subclinical hypothyroidism Increased TSH Normal T4/T3 Hoang 17 Subclinical hyperthyroidism Decreased TSH Normal T4/T3 Iodide deficiency Decreased T3/T4 secretion in plasma Decreased negative feedback to anterior pituitary = thyrotrophes Goiter Increased thyroglobulin production IX. Calcium and Phosphate Regulation Blood plasma Ca2+ free = 50% biologically active Ca2+-Albumin = 40% Ca2+-Citrate and Ca2+-Phosphate = 10% Normal range = 8.8 – 10.6 mg/100ml Parathyroid Hormone 84 amino acid peptide MW 9,600 Synthesized by chief cells rER Pre-Pro-hormone = 115 aa Pro-hormone = 90 aa Golgi PTH = 84 aa Stored in secretory granules or degraded to amino acids Function to increased plasma Ca2+ Kidney Stimulate calcium reabsorption Distal tubule and loop of Henle Result in decreased excretion of calcium Decrease phosphate reabsorption At proximal and distal tubules Result in increased excretion of phosphate Increase level of free Ca2+ Low phosphate levels = activate renal-1 hydroxylase Convert vitamin D to calcitrol Bone Increase osteocytic osteolysis (osteocytes) = rapid Increase osteoclast activity = long-term Remove Ca2+ and phosphate Amplified via calcitrol Intestine Via calcitrol = increase Ca2+ and phosphate absorption from diet Stimulated by epinephrine via adenylyl cyclase and cAMP Act on bone, kidney, and intestine (indirectly via calcitrol) Induce osteocytic osteolysis Osteocytes remove calcium from bone via canaliculi Inhibited by high plasma calcium levels Ca2+ bind Ca2+-sensing receptors Activate PLC into IP3 and PKC PKC inhibits PTH transcription and release Stimulate degradation of PTH and Pro-PTH Hoang 18 Low plasma Ca2+ levels Stimulate PTH synthesis and secretion 7-dehydrocholesterol converted to Vitamin D3 via UV light Vitamin D3 binds to 2-globulin binding protein Transported to liver Vitamin D3 converted to 25-(OH)-D3 via 25-hydroxylase Transported by 2-globulin to kidney 25-(OH)-D3 converted to calcitrol Transported to bone and intestine by transcalciferin 2-globulin binding protein Renal-1-hydroxylase = convert 25-(OH)-D3 to 1,25-(OH)2D3 Stimulated by vitamin D deficiency, PTH, low renal phosphate levels Renal-24-hydroxyalse = convert 25-(OH)-D3 to 24,25-(OH)2D3 Stimulated by vitamin D sufficiency, low PTH, high renal phosphate levels Vitamin D metabolite [1,25 (OH)2D3] Found in skin and diet Liver, fish, and milk Vitamin D2 Plants and diet Long-term negative feedback on PTH synthesis Inhibit transcription in chief cells Epinephrine Bind b-adrenergic receptor G-protein activate adenylyl cyclase Increase cAMP levels stimulate PTH secretion Pheochromocytoma = hypercalcemia Calcitonin 32 amino acids (MW = 3200) Synthesized by parafollicular cells of thyroid Function to decrease plasma Ca2+ Act primary at bone Inhibit bone resorption Inhibit osteocytic-osteolysis and osteoclast activity Stimulate osteoblasts Weak acting at kidneys Secretion occurs at 10mg/ 100mls plasma Ca2+ Rare in adults due to slow bone remodeling Greater role in children Osteoblast secrete collagen Collagen polymerizes to osteoid matrix with calcium, phosphate, hydroxyl, and bicarbonate ions Hydroxyapatite becomes new bone Primary hyperparathyroidism Parathyroid adenoma = secrete excess PTH Increased Serum Ca2+ = hypercalcemia Serum urinary phosphate excretion Urinary cAMP Decreased Serum P = hypophosphatemia Urinary Ca2+ excretion = increased Ca2+ reabsorption (hypercacinuria long-term) Kidney stones Hoang 19 Secondary hyperparathyroidism Renal failure Increased PTH secretion Bone resorption Decreased Lack of 1,25-(OH)2D3 production Lack of negative feedback to PTH Serum Ca2+ Malignancy-associated hypercalcemia Carcinomas = secrete PTH-related peptide (PTH-rp) Mimic PTH Increased Serum Ca2+ = hypercalcemia Hypoparathyroidism Thyroid surgery or congenital Increased Serum P Decreased Serum Ca2+ and tetany Urinary phosphate excretion Pseudohypoparathyroidism type Ia Defective G protein in kidney and bone End-organ resistance to PTH Hypocalcemia and hyperphosphatemia Elevated PTH levels Rickets (children) /Osteomalacia (adults) Lack of Vitamin D Inability to form 1,25-(OH)2D3 Vitamin D resistance Increased PTH secretion Increased phosphate excretion Increased Ca2+ reabsorption Decreased Absorption of Ca2+ and phosphate Plasma phosphate levels Osteoporosis Decrease in bone mass Estrogen Inhibits PTH stimulated bone resorption Inhibits osteoclasts Promote PTH-stimulated 1,25-(OH)2D3 synthesis Testosterone Cushing Syndrome Excessive glucocorticoids Decreased Ca2+ reabsorption in kidney Decreased Ca2+ absorption in intestine Hyperparathyroidism = increased PTH secretion Hoang 20 Calcium Regulatory Hormones and Action PTH (peptide) Stimulus Vitamin D (peptide) Calcitonin [1,25 (OH)2D3] Decreased serum Ca2+ Decreased serum Ca2+ Decreased serum P Increased PTH Increased serum Ca2+ Increased resorption Increased resorption Decreased resorption Decreased P reabsorption Increased Ca2+ reabsorption Increased P reabsorption Increased Ca2+ reabsorption Increased Ca2+ absorption via vitamin D Increased Ca2+ absorption Increased P absorption Increase Ca2+ Increase Ca2+ Decrease P Increase P Action Bone Kidney Intestine Overall effect on Serum Ca2+ Serum Phosphate X. Plasma Glucose Regulation Islets of Langerhans = interconnected by gap junctions with portal blood supply Alpha cells Secrete glucagon Beta cells Secrete insulin Delta cells Secrete somatostatin and gastrin Pancreatic polypeptide cells Secrete pancreatic polypeptide Blood flows from center to periphery of islet of Langerhans Beta cells influence Alpha and Delta cells Glucagon (Alpha) Peptide hormone Prohormone cleaved to glucagons and GLP (glucagons-like product) GLP-1 and GLP-2 are incretins = stimulate insulin release Acts only on liver Via cAMP Increase blood glucose Increase glycogenolysis Prevent recycling of glucose into glycogen Increase gluconeogenesis Decrease production of fructose 2,6-bisphosphate Decrease phosphofructoskinase Inhibit glucose reuptake in liver Increase blood fatty acid and ketone levels Decrease Ca2+ Hoang 21 Increase lipolysis Ketone production from acetyl-CoA Increase urea production Amino groups incorporated into urea Stimulus Hypoglycemia Decrease glucose in plasma Exercise Sympathetic = NE and Epi Amino acids Inhibition Increase blood glucose Somatostatin Ketones and fatty acids Parasympathetic = acetylcholine Insulin (Beta) A and B chain = joined by two disulfide bridges Proinsulin synthesized as single chain Connecting peptide is cut in storage granules C-peptide cleaved and combines with zinc Measure C-peptide as indication of Beta cells efficiency Secretion from mature granules only Decrease blood glucose Glucose metabolized by beta cells = stimulate insulin secretion GLUT-2 = insulin-independent glucose receptor Increase in intracellular ATP Ca2+ channels out with influx of Ca2+ Promote glycogen synthesis in muscle and liver Inhibit glycogenolysis Decrease gluconeogenesis Increase production of fructose 2,6-bisphosphate Increase phosphofructokinase activity Decrease blood fatty acid and ketone levels Inhibit lipolysis Modest increase in plasma glucose = drastic increase in insulin IV Glucose = biphasic Initial burst of insulin from stored granules Slow release aftermath result from insulin synthesis Oral Glucose = monophasic Glucose stimulate incretins (CCK, GLP-1, GTP) Diabetic with oral glucose Slow increase in glucose Little insulin response Stimulus Increase glucose in plasma Amino acids Cortisol and GH Parasympathetic = acetylcholine GI hormones = Gastrin, secretin, CCK Inhibition Decrease glucose in plasma Exercise Somatostatin from liver Sympathetic = NE and Epi Hoang 22 Glucagon Insulin Decrease glucose uptake Increase glucose uptake Increase glycogenolysis Increase glycogen synthesis Increase gluconeogenesis Decrease gluconeogenesis Increase fatty acid uptake and ketones secretion Decrease fatty acid and ketones Increase urea production Increase fat deposition Increase lipolysis via hormone-sensitive lipase Decrease lipolysis Decrease blood amino acid levels Decrease blood K+ levels Insulin receptor Tetramer of two and two subunits subunit = tyrosine kinase activity Autophosphorylation Insulin-receptor complex become internalized Down-regulates receptors Increase in receptors during starvation Decrease in receptors during obesity Receptor regulation mechanisms Internalization of receptor when insulin binds Recycling of internalized receptor (or degraded) Synthesis of new insulin receptors Insulin translocates inactive glucose transporters to cell membrane to become active GLUT-4 = only insulin-sensitive glucose transporter Normal controls = 5 % of receptors are activated for maximum response Type 2 diabetic = higher insulin concentration for the same maximum response Down regulation of receptors Impairment of postreceptor signaling Hepatocytes GLUT-2 = insulin independent Insulin binds to insulin receptor Stimulates Glucose to G-6-P Glycogen synthesis Glycolysis G-6-P to pyruvate to acetyl CoA Lipogenesis Acetyl CoA to malonyl CoA to free fatty acids to triglycerides Protein synthesis Inhibits G-6-P to glucose Glycogenolysis Glucogenogenesis Lipolysis Fatty acids to ketones Protein metabolism Hoang 23 Secrete LDL into blood for transport to adipose storage Muscle GLUT-4 = insulin dependent Insulin binds to insulin receptor recruit GLUT-4 transporters Stimulates Glucose uptake Glycolysis Glucose to G-6-P Glycogen synthesis Protein synthesis Inhibits Lipolysis Fatty acids to acetyl CoA Protein metabolism Adipocyte GLUT-4 = insulin dependent Insulin binds to insulin receptor recruit GLUT-4 transporters Stimulates Glucose uptake Glycolysis Glucose to G-6-P Pyruvate to acetyl CoA Lipogenesis Malonyl CoA to fatty acids to triglycerides Free fatty acids uptake Lipoprotein lipase synthesis Move to endothelial cells Convert LDL to fatty acids for uptake Inhibits Lipolysis Hormone-sensitive lipase Triglycerides to fatty acids and glycerol Insulin Deficiency Glucose-sparing Liver secrete glucose into blood Glucose is inhibited for uptake in liver, muscle, and adipose Liver = secrete glucose and ketones Uptake amino acids for gluconeogenesis Increased nitrogen into urea synthesis Uptake fatty acids for ketogenesis Blood ketone level increase Adipose = secrete fatty acids Muscle = secrete amino acids Uptake ketones for energy Hypoglycemia Activate VM hypothalamus Increased sympathetic activity Activate alpha (glucagons release) Inhibit beta (decrease insulin release) Increased epinephrine release Muscle Increase glycogenolysis Decrease glucose uptake Adipose Hoang 24 Increase lipolysis Liver Increase glycogenolysis Increase gluconeogenesis Hyperglycemia Insulin deficiency Decreased glucose uptake in cells Hypotension ECF volume contraction Metabolic acidosis Overproduction of ketoacids Hyperkalemia Lack of insulin Decreased potassium uptake in cells Stomatostatin (Delta) Pancreas Inhibit secretion of insulin, glucagons, and gastrin Inhibits absorption of glucose XI. Steroidogenesis Rate limiting step Cholesterol to pregnenolone via P450scc Zona glomerulosa Mineralocorticoid = aldosterone Zona fasciculata Glucocorticoids = cortisol Zona reticularis Androgens = DHEA and androstenedione Acetate converted to mevalonic acid via HMG-CoA reductase Mevalonic acid form cholesterol LDL Excess LDL negative feedback on HMG-CoA reductase Cholesterol esters convert to cholesterol in lipid droplet Cholesterol with SCP2 transport to mitochondrial via StAR Cholesterol converts to Pregnenolone via P450scc, Adx, and AdRex Chronic steroidogenic response Slow induction by cAMP Synthesis of steroidogenic enzymes Occurs hours-days In all steroidogenic tissue Acute steroidogenic response Rapid induction by cAMP Substrate availability Occurs in 15 mins In adrenal and gonads Inhibited by CHX Regulation of Steroidogenesis Hypothalamus CRF and AVP Pituitary ACTH and proopiomelanocorticortin Adrenal Glucocorticoid feedback Hoang 25 Fast feedback Seconds to minutes Proportional to dose and duration Delayed feedback Hours to days Proportional to dose and duration Administration Mechanism by glucocorticoid receptor = inhibit transcription of genes Mineralocorticoid = renin-angiotensin Androgens and adrenarche Lipoid congenital adrenal hyperplasia Inability to convert cholesterol to pregnenolone Enlarged adrenals = cholesterol esters Low steroid hormones Salt-wasting syndrome = lack of aldosterone Males and females both have normal female external genitalia XI. Contraception Reproductive age death Highest relative risk = pregnancy Oral contraceptive Induced abortion No contraception Small absolute risk Contraceptive use Highest = birth control pills Lowest = female condoms Oral contraceptive Venous thrombic embolism Oral contraceptives increase 3 fold Pregnancy increase 6 fold Increase risk of cervical cancer over time of use Contraindications Vascular disease Diabetes Older than 35 Smoker Hypertension Pregnancy Estrogen dependent neoplasia Vasectomy Highly effective No increase in prostate cancer Anti-sperm antibodies Human papilloma virus (HPV) Type 16 = most associated with cervical cancer Intrauterine device (IUD) Highly effective Spermicidal Pregnancy = risk of septic abortion Paragard = 10 years Hoang 26 RESPIRATORY PHYSIOLOGY I. Functional Anatomy Anatomic dead space = 0.15 L Alveolar ventilation = (tidal volume – dead space) x breaths/min Muscles of inspiration Diaphragm Push abdominal contents downward External intercostals Pull ribs up and out Used during exercise Muscles of expiration Passive movement Abdominal muscles Push diaphragm up Internal intercostals muscles Pull ribs down and in Blood flow of pulmonary capillary = 0.75 sec transit time past alveoli Normal = blood equilibrate with alveolar gas in 0.25 seconds Z= 10 End of cartilage bronchi Z = 16 End of terminal bronchiole End of conducting airway Z= 17 Beginning of alveolar air spaces = 3.0 L Beginning of respiratory bronchioles Surfactant = lipid dipalmitoyl phosphatidyl choline Type II alveolar cells Increase compliance Diffusion layers of the alveoli = total distance of ½ m Alveolar epithelium Basement membrane Interstitial space Capillary basement membrane Capillary epithelium II. Ventilation, Compliance, and Resistance Minute ventilation = tidal volume x breaths/minute Tidal volume = 0.5 L Volume of exhaled air with each breath Vital capacity/ Forced vital capacity = 4.8 L Volume of air that can be exhaled after maximal inspiration Tidal volume + Inspiratory reserve volume + Expiratory reserve volume Residual volume = 1.2 L Volume of air remaining in lungs after maximal expiration Expiratory reserve volume = 1.2 L Maximal volume of air that can be exhaled at end of tidal volume Inspiratory reserve volume = 3.1 L Hoang 27 Volume of air that inhaled at end of a normal inspiration Inspiratory capacity = 3.6 L Maximal volume of air inhaled after normal expiration Tidal volume + Inspiratory reserve volume Functional residual capacity = 2.4 L Volume of air remaining in the lungs at end of normal expiration Expiratory reserve volume + Residual volume Total lung capacity = 6.0 L Total volume of air in the lungs after maximal inspiration Forced expiratory volume Volume of air expired in one second following maximal inspiration = 80 % of FVC FEV1 / FVC = 0.8 Compliance Change in lung volume per change in transpulmonary pressure Greatest compliance in middle pressure range Lowest compliance at high expanding pressures C = Distensibility / Elastic recoil Rest Alveolar pressure = 0 cm H2O No air movement Pleural pressure = -5 cm H2O Lung volume = FRC Mid-inspiration point Alveolar pressure = -1 cm H2O Max air movement Pleural pressure = -7 cm H2O Lung volume > FRC Maximal inspiration Alveolar pressure = 0 cm H2O No air movement in Pleural pressure = -8 cm H2O Lung volume = FRC + tidal volume Mid expiration point Hysteresis Velocity greater at start of expiration than end Alveolar pressure = 1 cm H2O Max air movement out Pleural pressure = -6 cm H2O Lung volume > FRC Rest Airway resistance Bronchial smooth muscle = radius of airway Parasympathetic = constrict and decrease radius Sympathetic = dilate and increase radius via 2 receptors High lung volumes Decrease airway resistance Low lung volumes Increase airway resistance Density and viscosity of gas Low-density helium reduce resistance Highest resistance in medium-sized bronchi III. Gas Exchange Hoang 28 Diffusion rates Dependent on partial pressure differences & diffusion surface area Perfusion-limited exchange Gas equilibrates along length of pulmonary capillary Diffusion of gas increases when blood flow increases Diffusion-limited exchange Gas do not equilibrate along length of pulmonary capillary Seen in fibrosis and emphysema Diffusion of gas increases when capillary length increases Increased lung volumes = expand alveoli = collapse pulmonary vessels P50 = P02 at 50 % saturation 26 mm Hg IV. Oxygen and CO2 Transport Oxygen transport Carried via dissolved in solution and bound to hemoglobin Hemoglobin = 22 Fe2+ binds oxygen reversibly (Fe3+ binds irreversibly) H+ from histidine is released = function in acid/base buffering Increase oxygen-carrying capacity of blood 70x 1 gram Hb = binds 1.39 mL O2 15 grams Hb per deciliters (100 ml) of blood 20.85 mL O2 per dl of blood at 97.5 % Hb saturation 0.3 mL O2 dissolved in blood In tissues (venous blood) 14.4 mL O2 per dl of blood at 75 % Hb saturation Chronic hypoxemia Occurs at high altitudes Increase synthesis of 2,3-DPG DPG bind hemoglobin to unload oxygen in tissues CapacityO2 = (1.39 ml O2/g Hb/dl x [Hb] x % saturation) + (0.003 ml O 2/dl/mm Hg PO2) % Saturation = (HbO2 bound / HbO2 capacity) x 100 % Solubility of O2 at 37oC and 100 mm Hg 0.3 mL O2/dl of blood Hemoglobin-O2 Dissociation Curve Shifts Left Shifts Right Increased pH Decreased pH Decreased PCO2 Decreased temperature Decreased 2,3-DPG Increased PCO2 Increased temperature Increased 2,3-DPG Hemoglobin F Carbon monoxide CO2 transport Hoang 29 Dissolved CO2 Carbaminohemoglobin HCO3- (major form) CO2 in tissues = diffuse to plasma CO2 combines with H2O forming H2CO3 Via carbonic anhydrase Dissociates into H+ and HCO3Chloride shift HCO3- leaves RBC to plasma in exchange with ClHaldane effect Carbamino compound formation weakens affinity to O 2 Unload O2 from hemoglobin in high levels of CO2 Body regulates [H+] NOT pH Buffer systems Phosphate (weak) pK = 6.8 Stronger system in kidneys Protein (strong) Hemoglobin = highest levels in blood Imidazole group = buffer Myoglobin Bicarbonate Open system Lungs = CO2 Kidneys = H+ and HCO3PaCO2 = k x (VCO2/VA) VA (alveolar ventilation) regulate [H+] via its control of PaCO2 V. Pulmonary Circulation Pulmonary pressure much lower than systemic circulation Balanced by a lower resistance than systemic Equal cardiac output for systemic circulation V/Q = 1 at 3rd rib level Q changes more rapidly than V Zone 1 Blood flow lowest at apex of lung Highest V/Q = due to gravity effects Highest PO2 = 132 mm Hg Lowest PCO2 = 28 mm Hg Alveolar pressure > arterial pressure > venous pressure Zone 2 Arterial pressure > alveolar pressure > venous pressure Zone 3 Blood flow highest at base of lung Lowest V/Q = due to gravity effects Lowest PO2 = 89 mm Hg Highest PCO2 = 42 mm Hg Arterial pressure > venous pressure > alveolar pressure Hypoxia Local vasoconstriction in pulmonary blood flow Vasodilation in systemic circulation Fetal pulmonary vascular resistance High = low ventilation in fetal lungs Hoang 30 Shunts Right-to-Left Decrease in arterial PO2 Left-to-Right Increase in PO2 on right side of heart VI. Ventilation/Perfusion Defects Normal V/Q = 0.8 Arterial PO2 = 100 mm Hg Arterial PCO2 = 40 mm Hg Airway obstruction Low V & V/Q No gas exchange Blood flow obstruction Low Q & high V/Q No gas exchange R = respiratory quotient (rate of CO2 production per O2 consumption) R = 0.7 for fat R = 0.8 for proteins R = 1.0 for carbohydrates R = 0.85 for mixed protein, fat, and carbohydrate diet VII. Breathing Regulation Central control of breathing Medullary respiratory center = reticular formation Dorsal respiratory group Nucleus tractus solitarius Rhythmic drive to contralateral phrenic motor neurons Project to VRG Inspiration & generates basic breathing rhythm Afferents = vagus (X) & glossopharyngeal (IX) nerve Efferents = phrenic to diaphragm Ventral respiratory group Nucleus ambiguous & nucleus retroambiguous 2/3 of VRG neurons = expiratory (active) 1/3 of VRG neurons = inspiratory Nucleus ambiguous Vagus nerve Auxiliary respiratory muscles Larynx via recurrent laryngeal nerve Nucleus retroambiguous Stimulate external, internal intercostals, and abdominal expiratory muscles Project to pons and DRG Apneustic center = lower pons of cerebral peduncles Stimulate inspiration Apneusis = deep prolonged inspiratory grasp Tonic diaphragmatic contraction Pneumotaxic center = upper pons of nucleus parabrachialis Inhibit inspiration and stimulate expiration Regulate inspiratory volume and respiratory rate Cortex Voluntary control Slowly adapting pulmonary stretch receptors (PSR) Hoang 31 Smooth muscle of airways = mechanoreceptors Myelinated neurons Stimulated by distention or lung inflation Over-inflation of lungs negative feedback Decreased activity with deflation Decreased activity with increased airway CO2 Continuous activity with sustained inflations Hering-Breuer reflex = decrease in breathing frequency by distention Inspiratory inhibitory Insensitive to chemicals Rapidly adapting pulmonary stretch receptors (RAR) Between airway epithelial cells = mechanoreceptors Stimulated by rate of change of lung volume (I to E, E to I) Some discharge with normal tidal ventilation Myelinated neurons Irritant receptors Stimulated by noxious substances Coughing Inspiratory excitatory Augment inspiration Shorten expiratory duration C-Fibers Unmyelinated slow fibers Between alveolar membrane and capillary Chemosensitive Bronchial C-fibers = bronchial circulation Respond to histamine and prostaglandins Cardiac slowing Increased blood pressure Hyperpnea & coughing Pulmonary C-fibers = pulmonary circulation J receptors Alveolar walls close (juxtaposition) to capillaries Stimulated by engorgement of pulmonary capillaries Result in rapid, shallow breathing Seen in pulmonary edema Respond to histamine, prostaglandins and pulmonary congestion Cardiac slowing Decreased blood pressure Apnea Joint and muscle receptors Activated during limb movements Exercise Chemoreceptors = CO2, H+, and O2 Central chemoreceptors = medulla pH of CSF H+ do not cross blood-brain barrier CO2 diffuse readily through blood-brain barrier CO2 combines with H2O to produce H+ and HCO3Resulting H+ act on central chemoreceptors Chronic high levels of CO2 = desensitization Kidneys increase blood bicarbonate = lower H+ levels in CSF Peripheral chemoreceptors = carotid and aortic bodies Decreased arterial PO2 = stimulate breathing PO2 below 60 mm Hg Denervation possible with inhalation of 100% O2 Hoang 32 Increased arterial PCO2 = stimulate breathing Increased arterial [H+] = stimulate breathing and carotid bodies Carotid bodies = high metabolic rate Greatest blood flow per gram = small arterial-venous difference Exercise Increase in ventilation and perfusion Pulmonary blood flow increases Cardiac output increases Decrease in physiologic dead space No change in arterial PO2 and PCO2 during exercise Strenuous exercise cause lactic acidosis = drop in arterial pH Venous PCO2 increases High altitudes Decreased alveolar PO2 and arterial PO2 (hypoxemia) Stimulate peripheral chemoreceptors Increase ventilation = hyperventilation Respiratory alkalosis = treated by acetazolamide Stimulate erythropoietin = increase RBC production Increased O2-carrying capacity 2,3-DPG increases Pulmonary vasoconstriction = increase pulmonary artery pressure Hypertrophy of right heart VIII. Pathology Fibrosis Restrictive lung disease FEV and FVC reduced Could have higher-than-normal expiratory flow rate Low compliance “Cement lung” Need greater pressure for same volume change Asthma Obstructive lung disease FEV reduced more than FVC FEV/FVC decrease Decreased ventilation Decreased V/Q Easier to breathe at high lung volumes = decrease airway resistance High compliance No elastic tissue = no elastic recoil Inspiration easy but exhalation difficult Albuterol Sympathetic agonist Dilate bronchi via relaxing smooth muscle Chronic obstructive pulmonary disease (COPD) High airway resistance Decreased V/Q Emphysema High compliance Higher FRC = barrel-shaped chest Chronic infection – Airway obstruction – Destruction of alveolar walls Increased airway resistance – Abnormal V/Q – Increased pulmonary vascular resistance Pulmonary hypertension Pulmonary hypertension Smooth muscle hyperplasia and hypertrophy of pulmonary capillaries Hoang 33 Increased pulmonary capillary resistance Right heart backup Low Q Left heart failure Blood back up in pulmonary circulation Increased Q Edema into alveoli Pneumonia Inflammation of lungs due to bacterial/viral infection Consolidation = alveoli become filled with fluid and blood cells Post-praudial dyspnea (“after eating” SOB) Shortness of breath GI tract filled = block diaphragm from contracting Decreased V Blood pool in lungs Edema of alveoli Fen-Phen Weight losing drug via serotonin production and increased a-adrenergic activity Reduce appetite Act on endothelial cells of lungs Serotonin cause vasoconstriction Increased vascular resistance Decreased Q Cheyne-Strokes breathing Respiratory disorder of periodic breathing Cycle = breathes deeply then decrease to almost no breathing Due to slow blood flow (cardiac failure) or increased negative feedback (brain damage) Atelectasis = collapse of alveoli Bronchial obstruction = air in alveoli is absorbed (negative pressure) Lack of surfactant = seen in hyaline membrane disease Hypoxemia Decreased PaO2 or decreased PIO2 = low PaCO2 High altitudes Hypoventilation = high PaCO2 Airway obstruction = asthma Weakness of respiratory muscles Decreased respiratory drive from CNS Diffusion limitation Pulmonary edema Shunts Right-to-left = atrial septal defect Bronchial circulation via thebesian veins Patient inhales 100% O2 1% shunt for every 20 mm Hg difference between P AO2 and PaO2 Metabolic = change in body metabolism resulting in abnormal pH Respiratory = change in breathing resulting in abnormal pH Respiratory academia Pulmonary perfusion inadequacy Insufficient ventilation Severe pulmonary edema Pneumonia Hypoventilation CNS defect Depressants and anesthesia Hoang 34 Cervical spinal cord injury Metabolic academia Retention of acid Ketoacidosis Chronic renal failure Addison’s disease Loss of base GI disorders Acid ingesting Renal tubular acidosis Respiratory alkalemia Hyperventilation = CNS Congestive heart failure Metabolic alkalemia Loss of acid GI disorders Intake of base Excessive minerocorticoid activity Potassium depletion Blood transfusion Normal pH PCO2 [HCO3-] 7.4 40 mm Hg 24 mEq/L [H+] = 40 nEq/L Respiratory acidosis Decrease Increase (primary) Increase (secondary) Metabolic acidosis Decrease Decrease (secondary) Decrease (primary) Respiratory alkalosis Increase Decrease (primary) Decrease (secondary) Metabolic alkalosis Increase Increase (secondary) Increase (primary) IX. Laws Boyle’s Law PiVi = PfVf while temperature is constant Poiseuille’s Law Air flow V = Pr4 / 8l Fick’s Law Diffusion = SA / thickness of membrane Laplace’s Law P = 2 x Surface Tension / radius of alveolus Dalton’s Law Partial pressure = total pressure x fractional concentration Hoang 35 COPD with fatigue, dyspnea at rest, & peripheral edema Low PaCO2 and PaO2 pH = 7.6 Decreased diffusion capacity Hypoxemia V/Q mismatch Increased alveolar ventilation Increased RBC production Increased right atrial pressure Respiratory alkalosis Increased Hematocrit Increased bicarbonate Right heart failure & respiratory acidosis Normal A-a gradient Right heart failure Pulmonary edema Hypoventilation Anaerobic metabolism Metabolic acidosis Increased PaCO2 Increased bicarbonate Respiratory acidosis Normal anion gap Decreased chloride High A-a gradients are associated with oxygen transfer / gas exchange problems. These are usually associated with alveolar membrane or interstitial disease. High gradients result from impaired diffusion or, more commonly, by ventilation-perfusion inequality of the "shunting" variety. Hypoxemia in the face of a normal A-a gradient implies hypoventilation with displacement of alveolar O2 by CO2 or other substance. Hoang 36 Respiratory muscle weakness Decreased tidal volume & vital capacity Increased PaCO2 Hypoventilation Decreased hemoglobin saturation Decreased arterial pH Severe acute asthma Non-anion gap metabolic acidosis Asthma attack Decreased bicarbonate Non-anion gap Hyperventilation Decreased PaCO2 [3 days later] Metabolic acidosis Hypocapnia Respiratory alkalosis Hoang 37 CARDIOVASCULAR PHYSIOLOGY I. Functional Anatomy Endocardium Myocardium (Cardiac muscle) Striated with intercalated discs at Z line Gap junctions Low electrical resistance Maintain cell-to-cell cohesion Sarcomere From Z line to Z line Thick filaments = myosin Thin filaments = actin, troponin, tropomyosin Atrioventricular bundle = conducts impulses from atria to ventricles Resting membrane potential = -85 to –95 millivolts Action potential = 105 millivolts Fast sodium channels Open at initiation of action potential Slow calcium-sodium channels Maintain plateau Calcium stimulate muscle contraction of myofibrils Transverse tubules cause sarcoplasmic tubules to release calcium into reticulum Well developed in ventricles rather than artia Epicardium Cardiac cycle P wave Depolarization of atria Initiates atrial contraction (systole) Contribute to ventricular filling Atrial pressure increases after P wave QRS wave Ventricular depolarization = 0.16 sec after P wave Initiates ventricular contraction (isovolumetric) T wave Repolarization of ventricle Aortic & pulmonic valve close Causes dicrotic notch Atria function as primer pump for ventricles 75 % ventricular filling occurs during diastole before atrial contraction 25 % ventricular filling occurs via atrial contraction Ventricles fill during diastole During systole A-V valves closed Atria fill Beginning diastole Ventricular pressure decreases below atria A-V valves open First 1/3 diastole Rapid filling of ventricles Last 1/3 diastole Hoang 38 Atrial contraction = 25 % of ventricular filling Diastasis = slow ventricular filling Beginning systole Ventricular contraction A-V valves close & pressure builds in ventricles Period of isovolumic contraction = 0.2 to 0.3 seconds of ventricular contraction Middle systole Left ventricular pressure > aortic pressure (80 mm Hg) Right ventricular pressure > pulmonary artery pressure (8 mm Hg) Aortic & pulmonary valves open Period of rapid ejection to period of slow ejection Aortic pressure > ventricular pressure Momentum push into aorta Last systole Period of isovolumic relaxation Ventricular pressure < aortic & pulmonary artery pressure Aortic & pulmonary valves close Ejection fraction = fraction of end-diastolic volume ejected (60 %) End-diastolic volume = 110 to 120 mL Stroke volume = 70 mL End-systolic volume = 40 to 50 mL Systolic pressure Ventricular ejection increases aorta pressure Exceeds diastolic pressure in aorta Opens aortic valve Aorta pressure increases to 120 mm Hg Afterload = pressure in artery exiting ventricle (aorta or pulmonary) Diastole pressure Blood flow to peripheral circulation Arterial pressure decreases to 80 mm Hg Preload = end-diastolic pressure Atrial pressure waves a wave = atrial contraction c wave = ventricular contraction v wave = in-filling of atria from venous return Frank-Starling mechanism Increased venous return = stretches heart muscle Heart pumps with greater force of contraction Heart pumps all blood that comes to it Without allowing excess accumulation of blood in veins Sympathetic Heart rate increase from 72 to 180-200 beats per minute Parasympathetic Mainly affects atria Decrease heart rate and force of contraction of ventricles Inhibit sympathetic stimulation Ion responses Excess potassium Flaccid heart Reduced heart rate Decrease in contractility K+ decreases resting membrane potential = decreased action potential intensity Hoang 39 Excess calcium Spastic contraction Low calcium Flaccid heart Acute increased temperature = increased heart rate Increased permeability of muscle membrane to ions Decreased temperature = decreased heart rate II. Heart Rhythm and Conduction System Sinoatrial node Initiates cardiac impulse Controls rate of heartbeat = pacemaker Discharge faster than other cardiac tissues Membrane potential = -55 to -60 mV Due to fast sodium channels = slow leakage of sodium into cell fiber Until potential reaches -40 mV Calcium-sodium channels activated Rapid entry of sodium and calcium = action potential Potassium channels open = potassium escape cell Membrane potential return to resting potential Internodal pathway = conduct impulses from sinus node to A-V node Atrioventricular (A-V) node Delays impulses from atria to ventricle = 0.09 seconds Allows atria to empty into ventricles Delay resulting from: 1. Resting membrane potential is less negative in A-V node & bundle than normal cardiac muscle 2. Fewer gap junctions between cells in A-V node & bundle = greater resistance A-V bundle = conducts impulse from A-V node to ventricles Purkinje fibers = left and right bundles conduct impulses to all parts of ventricles Lie under endocardium Rapid transmission of impulse High permeability of gap junctions at intercalated discs Atrial and ventricular syncytia Separated and insulated from one another Fibrous barrier that acts as insulator Force atrial impulses to enter ventricles through A-V bundle Parasympathetic = Vagal (acetylcholine) Decrease rate of sinus node discharge Decrease excitability of fibers between atrial muscle and A-V node Increase permeability of potassium in sinus node and A-V fibers = hyperpolarization Decreased membrane potential of sinus nodal fibers to -65 to -75 mV Sympathetic (norepinephrine) Increase rate of sinus node discharge Increase cardiac impulse conduction rate Increase force of contraction of atria and ventricles Increase permeability to sodium and calcium Increase resting membrane potential = more excitable Ventricular escape Lack of impulses from atria Purkinje fibers develop own rhythm at 15-40 beats per minute Hoang 40 III. Electrocardiogram Depolarization Electrical current flows from base toward apex of heart Normal P-Q = 0.16 seconds Normal Q-T = 0.35 seconds Einthoven’s law Electrical potential of any limb equals the sum of potentials of the other two limb leads Abnormal waveforms QRS Increased voltage Hypertrophy of heart Decreased voltage Old myocardial infarctions (decreased cardiac muscle mass) Fluid in pericardium = pleural effusion Prevents voltage from reaching body surface Pulmonary emphysema Prolonged conduction Hypertrophied and dilated hearts (one or both ventricles) Longer distance for impulse to travel Blockade of impulses in Purkinje system T Inverted Ischemia IV. Heart Sounds First heart sound Closure of A-V valves Beginning of ventricular systole Ventricular contraction Louder with higher pitch Second heart sound Closure of aortic and pulmonary valves Semilunar valves End of ventricular systole Third heart sound Maximal ventricular dilation End of rapid ventricular filling In-rushing of blood into ventricles Beginning of middle third of diastole Fourth heart sound Atrial contraction Abnormal = due to stiff heart Failure of ventricle to fill during rapid ventricular filling Large blood volume left in atrium Acceleration of blood into ventricles cause sound Last third of diastole Pathologic valvular disease Rheumatic fever Stenotic valves Insufficient valves Heart murmurs Hoang 41 Aortic stenosis Left ventricular hypertrophy Chronic increase in blood volume Chronic increase in left atrial pressure Due to hypervolemia Angina pectoris pain Aortic regurgitation Increased stroke volume Left ventricular hypertrophy Decreased diastolic pressure Increased blood volume V. Cardiac Arrhythmias Pathological ECGs Etiology ECG Signs First-degree block Longer PR interval (normal rate and rhythm) Second-degree block: Mobitz Type I (Wenckebach block) PR – Long PR – Longer PR – No PR – cycle starts over Second-degree block: Mobitz Type II Normal PR – P wave but no QRS – cycle starts over Third-degree block P at regulate rate & rhythm QRS-QRS at its own rate & rhythm Wolff-Parkinson-White Syndrome Shortened PR due to delta wave Bundle Branch block Right bundle branch = Wide QRS with dip in middle Left bundle branch = Wide QRS with little or no dip Atrial Fibrillation Irregular R-R intervals No detectable P waves (cancel each other out) Atrial Flutter Several P waves with normal QRS-T complex (2-3:1) Tachycardia Increased in heart rate greater than 100 beats per minute Increased body temperature Sympathetic stimulation Due to blood loss Digitalis intoxication = biphasic T waves (normal T wave followed by inverted T wave) Bradycardia Decreased heart rate less than 60 beats per minute Carotid sinus syndrome Artherosclerotic plaque stimulate vagus A-V blocks Inhibits impulses from SA node Inflammation or ischemia of A-V node or bundle Compression of A-V bundle Strong vagal stimulation Hoang 42 Atrial paroxysmal tachycardia Inverted P wave Tachycardia originate in atrium Supraventricular tachycardia Ventricular paroxysmal tachycardia Originate in ventricles Ventricular fibrillation Impulse stimulates ventricular muscles Then stimulate itself Portions of ventricles contract at same time and other relax Atrial fibrillation Enlarged atrium caused by heart valve lesions Atrial flutter Single large wave front travels around atria Atria contract at 250 to 300 times per minute Small amount of blood can be pumped VI. Circulation: Pressure, Resistance, and Distensibility Principles Vasoconstriction must be accompanied by vasodilation Blood flow to tissue is proportional to tissue needs Velocity of flow is inversely proportional to vascular cross-sectional area Lowest velocity in capillaries Highest in aorta Blood flow Q = P / R Poiseuille’s Law Vascular Resistance = [Viscosity x Length] / Radius 4 Distensibility = Volume / [Pressure x Original Volume] Vascular compliance = Volume / Pressure = Distensibility x Volume Veins = 24x as compliant as arteries Delayed compliance First increase in pressure when there is an increased in volume Delayed stretch of vessel Then decreased in compliance Allows continuous pulsatile flow of blood Hematocrit = 40 Percentage of RBC in blood Total blood volume 84 % in systemic circulation 64 % in veins 13 % in arteries 7 % in systemic arterioles and capillaries 7 % in heart 9 % in pulmonary vessels Pulse pressure = systolic pressure – diastolic pressure Increase pulse pressure can be caused by Increased stroke volume Decreased arterial compliance (arteriosclerosis) Aortic valve stenosis Patent ductus arteriosus Aortic regurgitation Pulmonary circulation has lower pressure than systemic circulation Pulmonary = 25 mm Hg & 8 mm Hg Systemic = 120 mm Hg & 80 mm Hg Hoang 43 Pulmonary vascular resistance < systemic vascular resistance Increased right atrial pressure = increased peripheral venous pressure Increased venous resistance = increased peripheral venous pressure Blood reservoirs Spleen Liver Large abdominal veins Venous plexus beneath skin VII. Microcirculation Precapillary sphincters Smooth muscle fibers encircle vessel Capillary wall Thin, single layer of endothelial cells Porous Vasomotion = blood flows intermittently through capillaries Blood flow through capillaries is discontinuous Diffusion = transfer of substances between plasma and interstitial fluid Influenced by pore size, molecular size, & concentration difference Interstitium = spaces between cells Collagen fiber bundles Proteoglycan filaments Fluid filtration through capillary membrane Capillary hydrostatic pressure = force fluid outward through capillaries Average of 17 mm Hg Interstitial fluid hydrostatic pressure = force fluid inward Interstitial fluid colloid osmotic pressure = osmosis of fluid outward Averages of 8 mm Hg Plasma colloid osmotic pressure == osmosis of fluid inward Averages of 28 mm Hg Edema = outward pressure exceeds inward pressure VIII. Local Control of Blood Flow Tissues autoregulate blood flow Supply nutrients Remove waste Determine heat loss = control body temperature Greater rate of metabolism = greater blood flow High in thyroid and adrenal Low in resting skeletal muscles Decreased oxygen availability = increases local blood flow Occurs in cyanide poisoning, carbon monoxide, pneumonia Acute control Seconds to minutes Vasoconstriction or vasodilation Increase local blood flow Accumulation of vasodilator metabolites Lack of nutrients = glucose, amino acids, or fatty acids Beriberi Hoang 44 Lack of oxygen Increased tissue metabolic rate Long-term control Days, weeks, or months Due to change in physical size and metabolic need Angiogenesis = increase tissue vascularity Stimulated by low oxygen Ischemic tissues Tissues growing rapidly Tissues with excessively high metabolic rates Angiogenic factors Vascular endothelial growth factor (VEGF) Fibroblast growth factor (FGF) Angiogenin Rarefraction = decrease tissue vascularity Humoral control Norepinephrine/epinephrine Vasoconstrictors via -adrenergic receptors Epinephrine cause be vasodilator via -adrenergic receptors Angiotensin II Vasoconstrictor Form in response to volume depletion or decreased blood pressure Vasopressin (ADH) Vasoconstrictor Form in response to decreased blood volume or increased plasma osmolarity Endothelin Vasoconstrictor from endothelial cells after damage Eta & Etb receptors on capillaries = constriction Etb receptors on endothelial cells = relaxation Prostaglandins PGE2 Vasodilator and vasoconstriction Fever and pain PGF2a Vasoconstrictor Uterine contraction PGI2 Vasodilation TxA2 Vasoconstrictor Platelet aggregation Bradykinin Vasodilator Can cause edema Histamine Vasodilator from mast cells and basophils Increase capillary permeability Nitric oxide (via nitric oxide synthase) Calcium dependent nNOS Neurons and macula densa eNOS Endothelial cells in caveoli Calcium independent iNOS Macrophages and microglia Hoang 45 Vasoconstrictors Calcium Vasodilators Potassium Magnesium Sodium Increased osmolarity of blood Increased [H+] Increased [CO2] Constrictors Hormone Receptor Norepinephrine & epinephrine -adrenergic Angiotensin II AT1 Vasopressin V1a Endothelin Et a & Et b2 Prostaglandin E2 EP1 & EP3 Thromboxane A2 TP Dilators Hormone Receptor Epinephrine -adrenergic Endothelin Et b1 Prostaglandin I2 IP Prostaglandin E2 EP2 & EP4 Nitric oxide Soluble guanylate cyclase Bradykinin BK Histamine H1 Reactive hyperemia Blood supply blocked to tissue Then unblocked Blood flow increases 4-7 times normal Due to accumulation of vasodilator metabolites & oxygen deficiency Active hyperemia Tissue metabolic rate increases Hoang 46 Accumulation of vasodilator substances & oxygen deficiency Local vasodilation = decreased total peripheral resistance Increased venous return = blood flow increases to compensate Arterial pressure Increase in arterial pressure = increase in blood flow Metabolic theory of autoregulation Arterial pressure increases too great Excess oxygen and nutrients to tissue Constriction of vessels Blood flow decrease to normal levels Myogenic theory of autoregulation Increased arterial pressure = stretch blood vessels Cause smooth muscle of vessels to contract Stretched blood vessels release endothelium-derived relaxing factor (NO) Dilate upstream larger arteries Decreased arterial pressure = relaxes smooth muscle Decrease vascular resistance Maintain normal blood flow even at lower blood pressure Vasoactive hormones Histamine Arteriolar vasodilation & venous vasoconstriction Increase Pcapillary = increased filtration out of capillaries = local edema Bradykinin Arteriolar vasodilation & venous vasoconstriction Increase Pcapillary = increased filtration out of capillaries = local edema Serotonin Arteriolar vasodilation Released in vessel damage Migraine headaches Prostaglandins Vasodilator & vasoconstrictor IX. Regulation of Cardiac Output and Venous Return Cardiac output Amount of blood pumped into aorta per minute Peripheral circulation blood Normal adult = 5 L/min Venous return Amount of blood flows back to right atrium per minute Venous return resistance Average resistance between peripheral vessels and heart Increased by sympathetic stimulation Frank-Starling Law of the Heart Increased in venous return = increased in diastolic filling pressure = greater contractile force of ventricles Due to stretching of cardiac muscle Pump out all excess venous return Cardiac output = venous return Factors controlling venous return also control cardiac output Increased venous return 1. Stretch sinus node Increased rhythmicity of node Hoang 47 Increased heart rate to pump extra blood 2. Bainbridge reflex Increase in atrial pressure Impulses go to vasomotor center then back to heart via sympathetic and vagus nerves Increased heart rate & contractility Prevent damming of blood in veins, atria, and pulmonary circulation Ohm’s Law Decreased total peripheral resistance = increased cardiac output Increased total peripheral resistance = decreased cardiac output Cardiac output curve Increases plateau Increased sympathetic stimulation Decreased parasympathetic stimulation Cardiac hypertrophy Decreases plateau Myocardial infarction Cardiac valvular disease with stenosis Abnormal cardiac rhythm Measured by Fick’s principle CO (L/min) = [O2 absorbed in lungs (mL/min)] / [Arteriovenous O 2 Diff (mL/liter of blood)] Cardiac oxygen consumption increases via: Increased afterload (aortic pressure) Increased heart size Increased contractility Increased heart rate Stroke work = primary source of energy is fatty acids Pathologic cardiac output Beriberi Lack of thiamine Increased vasodilation = decreased total peripheral resistance = increased cardiac output Arteriovenous fistula Shun between artery and vein Decreased total peripheral resistance = increased cardiac output Hyperthyroidism Increased oxygen use = release vasodilatory products Total peripheral resistance decreases = increased cardiac output Anemia Decreased total peripheral resistance = increased cardiac output Lack of oxygen delivery = increased vasodilation Decreased viscosity of blood from low RBC count Contractility Intrinsic ability of cardiac muscle to develop force at given muscle length Estimated via ejection fraction = 0.55 AKA inotropism Positive inotropic effects = increase contractility Increased heart rate Post-extrasystolic potentiation Sympathetic stimulation Increases Ca2+ entry during plateau of action potential Increase Ca2+ pump activity of SR Cardiac glycosides = digitalis Inhibit Na+-K+ ATPase = increase contraction strength Intracellular [Na+] increases = inhibit Ca2+-Na+ exchange Increases Ca2+ Hoang 48 Negative inotropic effects = decrease contractility Parasympathetic stimulation Decrease Ca2+ entry = decrease contraction strength Effects of Stimulation on CV Physiology Cardiac Output Venous Return Contractility Sympathetic Mean Systemic Pressure Parasympathetic - Increased Total Peripheral Resistance - - Decreased Total Peripheral Resistance - - Hemorrhage - Excess Blood Volume - Parasympathetic effects Negative chronotropic effect Decreases heart rate via phase 4 Decreases If of Na+ Negative dromotropic effect Decreases conduction velocity through AV node Increases PR interval Sympathetic effects Positive chronotropic effect Increases heart rate via phase 4 Increase If of Na+ Positive dromotropic effect Increases conduction velocity through AV node Decreases PR interval Autonomic Effects on Heart Sympathetic Parasympathetic Effect Receptor Effect Receptor Heart Rate 1 Muscarinic Conduction velocity (AV Node) 1 Muscarinic Contractility 1 Muscarinic Hoang 49 X. Nervous Regulation of Circulation Vasomotor centers Area C-1 Vasoconstrictor Norepinephrine Upper medulla Area A-1 Vasodilator Project to C-1 and inhibit vasoconstrictor activity Lower medulla Area A-2 Sensory Medulla and lower pons Tractus solitarius Receive from vagus and glossopharyngeal nerves Reflex control (i.e. Baroreceptor reflex) Sympathetic regulation = rapid Norepinephrine -adrenergic receptors Vasoconstriction Arterioles constricted Increased total peripheral resistance Increased blood pressure Veins constricted Increase effective blood volume Increased cardiac output Heart enhance in cardiac pumping Increased heart rate Sympathetic stimulation Inhibition of parasympathetics Arterial baroreceptor reflex control system Stretch receptors on carotid sinus and aortic arch Carotid sinus – Herring’s nerve – glossopharyngeal nerve – tractus solitarius Aortic arch – vagus nerve – tractus solitarius Increased pressure – increased impulse firing of baroreceptor – inhibition of vasoconstrictor center Excite vagal center Vasodilation of veins and arterioles Decreased heart rate and contraction strength Decreased peripheral vascular resistance = decreased cardiac output Decreases arterial pressure Decreased baroreceptor activity = increased sympathetic activity Baroreceptor system plays minor role in chronic control System reset within 1-2 days to exposed blood pressure levels Cardiopulmonary reflex Stretch receptors on atrial and pulmonary arteries Detect increase in heart and pulmonic circulatory pressure Due to change in volume Increased atrial stretch = decreased sympathetic activity of kidney & ADH secretion from hypothalamus Renal vasodilation of afferent arterioles Increases glomerular capillary pressure Increase glomerular filtration rate = increased volume excretion Decrease tubular reabsorption of sodium Release of atrial natriuretic peptide Hoang 50 Abdominal compression reflex Stimulation of sympathetic vasoconstrictor system = increased tone of abdominal muscles Compress venous reservoirs = increased effective blood volume Central nervous system ischemic response Cerebral ischemia Decreased blood flow to vasomotor center of lower brain stem Maximum increase in arterial pressure (250 mm Hg) Due to lactic acid buildup and increased CO2 Potent sympathetic vasoconstriction of organs (i.e. kidneys stop urine production) Cushing reaction Increased pressure in cranial vault Could compress blood vessels in brain CSF pressure = arterial pressure Initiate central nervous system ischemic response Increase arterial pressure to 250 mm Hg Maintain blood flow to vital centers Orthostasis Gravitational acceleration of blood to lower extremities Compensation to decreased venous return Vis a fronte = sucking action of right atrium on venous system Vis a tergo = positive pressure transmitted from capillaries to venous bed Intrapleural pressure Abdominal pressure Venous valves & skeletal muscle pump Respiratory waves = small rhythmic changes in arterial pressure Increase in arterial pressure during early expiration Decrease in arterial pressure during the remainder of the cycle Vasomotor waves = large rhythmic changes in arterial pressure Oscillation of baroreceptor reflex Oscillation of chemoreceptor reflex Oscillation of CNS ischemic response XI. Long-Term Regulation of Arterial Pressure via the Kidneys Renal output of salt and water = intake of salt and water Two determinants of long-term arterial pressure 1. Renal output of salt and water 2. Level of salt and water intake Renal-body fluid feedback system Arterial pressure rises excessively high Pressure natriuresis Kidney excrete sodium Pressure diuresis Kidney excrete water Extracellular fluid volume and blood volume decreases Blood pressure return to normal Arterial pressure decreases excessively Kidney reduce rate of sodium and water excretion Increased total peripheral resistance Do not elevate long-term arterial pressure Unless fluid intake and renal function changes Normal arterial pressure =120 / 80 mm Hg Hoang 51 Hypertension Diastolic greater than 90 mm Hg Systolic greater than 140 mm Hg Mean arterial pressure = 93 mm Hg Volume loading effects and results Hypertension Increased total peripheral resistance Complete return of extracellular fluid volume, blood volume, & cardiac output back to normal Renin-angiotensin system Decreased arterial pressure Renal JG cells secrete renin Catalyze angiotensinogen to angiotensin I Angiotensin I convert to angiotensin II via ACE ACE present throughout body Predominately in lungs & kidneys Angiotensin II constricts arterioles and veins & decreases salt and water secretion in kidneys Increase total peripheral resistance Decrease vascular capacity = increase venous return Degraded by angiotensinase Arterial pressure increase to normal Angiotensin II effects on kidney 1. Constrict efferent arterioles Diminishes blood flow and filtration 2. Stimulate renal tubules to increase reabsorption of sodium and water 3. Stimulate adrenal glands to secrete aldosterone Aldosterone increases renal salt and water reabsorption Especially in collecting tubule Renal hypertension Causes = excessive salt and water retention Renal arterial stenosis Constriction of afferent arterioles Increased resistance to fluid filtration through glomerulus Excessive angiotensin II formation One-kidney Goldblatt hypertension One kidney removed Constrictor on renal artery of remaining kidney Systemic arterial pressure increases Renal arterial pressure increases back to normal levels Due to renin-angiotensin system Phase 1 = vasoconstriction type Transient Phase 2 = volume-loading type Total peripheral resistance increased Essential hypertension Unknown cause Kidney require high arterial pressure to maintain intake and output balance Rapid blood pressure control mechanism (seconds) Baroreceptor feedback mechanism CNS ischemic mechanism Chemoreceptor mechanism Intermediate blood pressure control mechanism (minutes) Renin-angiotensin vasoconstrictor mechanism Hoang 52 Stress relaxation of vasculature mechanism Capillary fluid shift mechanism Long-term blood pressure control mechanism (hours to months) Renal-body fluid feedback mechanism XII. Congestive Heart Failure Heart failure Inability of the heart to maintain CO sufficient to support vital organs Rapid compensation via sympathetic system Increased MSFP, contractility, heart rate Vasoconstriction of peripheral blood vessels Chronic response via renal mechanisms (RAS) Sodium retention and increased blood volume Compensated failure Recovery of cardiac output to normal levels after heart damage Decompensated failure Compensatory responses fail Longitudinal tubules of SR fail to accumulate calcium Increased blood volume overstretch sarcomeres Decreases cardiac contractility Edema of heart muscle Systolic heart failure Poor pumping leads to defect in expulsion of blood Decreased ejection fraction Diastolic heart failure Impairment of ventricular filling Leads to high venous pressure upstream from ventricle Often concomitant with systolic heart failure Hypertension – left ventricular hypertrophy Diagnostic tests ECG Lower QRS amplitude = MI Prolonged QRS = conduction block Arrhythmias Chest X-ray Echocardiogram Cardiac catheterization Blood testing Secondary effects of heart failure Effects of therapy or contributing factors Exercise testing ACE inhibitors First therapy in systolic dysfunction Beta-blockers Second therapy in systolic dysfunction Diuretics Decrease load tension on heart Inotropic agents Increase contractility and CO Hoang 53 RENAL PHYSIOLOGY I. Body Fluid Compartments Total body water 60% of body weight Muscle & skin have most of the water Blood & kidneys have highest water % to body weight Skeleton & adipose have lowest water % to body weight 42 L of water in a 70-kg adult Water intake Majority from food then drink Minor production from oxidation Water output Majority in urine then insensible water lost Insensible skin & insensible lungs Minor from feces and macroscopic sweat Intracellular fluid = 40% of body weight (28 L) Extracellular fluid = 20% of body weight (14 L) Interstitial fluid = 15% of body weight Plasma = 4% of body weight Lymphatic fluid = 1% of body weight Decrease % fat = Increased water % of body weight Obesity = low body water to weight ratio Females has more subcutaneous fat than men Older babies have more fat than newborns Indicator-Dilution principle Used to measure compartmental volumes Substance A is injected into compartment 1 Substance A disperse equally to equilibrium Volume 1 = [Volume A x Concentration A] / Concentration 1 Total body volume = antipyrine – D2O – HTO Plasma volume = Evan’s blue, radioiodinate human serum albumin (RISA) Extracellular volume = inulin, radiosulfate, radiosodium Molarity (M) = moles of solute / liter of solvent One mole = 6 x 1023 particles Electrochemical equivalence (mEq/L) = M x valence One equivalent = weight in grams that associate with 1 gram of H + Osmolarity (osm/L) = Molarity x number of particles per molecule Osmotic pressure of a solution through a semipermeable membrane Osmolality (osm/kg) = Molality x number of particles per molecule Water moves rapidly across cell membrane Intracellular almost always equal extracellular fluid compartment Addition of hypertonic solution to ECF Increased ECF osmolarity Osmosis to ECF ECF volume > ICF volume Addition of isotonic solution to ECF No change in osmolarity Hoang 54 Increased in ECF volume Addition of hypotonic solution to ECF Decreased ECF osmolarity Osmosis to ICF ECF volume < ICF volume Capillaries Filtration = Kf x [ Pc – Pif – c + if ] Hydrostatic pressure & osmotic/oncotic pressure Osmotic pressure () = [solutes] x R x Temperature Edema Intracellular edema Depression of metabolic systems Lack of adequate nutrition to cells Sodium leak into interior of cells Osmosis of water into ICF compartment Extracellular edema Abnormal leakage from plasma to interstitial space Lymphatic insufficiency or blockage Excessive blood flow or heart failure Cirrhosis or loss of protein Blockage of interstitial proteins reuptake into lymphatic system Factors preventing edema = 17 mm Hg Low compliance of tissues Increased interstitial fluid = increases interstitial hydrostatic pressure Lymph flow can increase 50 fold Decreases interstitial protein concentration = decrease interstitial colloid pressure Intracellular Extracellular Na+ 145 mM Cl- 108 mM HCO3- 25 mM Proteins 200 mg/dl 15 mg/dl Ca2+ 10-4 mM 1 mM Mg2+ 40 mM 2 mM K+ 140 mM 4.5 mM Intracellular Total = 400 mM but 300 mosm/L due to associative affects 98% of K+ is intracellular Highest ion in cell Extracellular Total = 300 mM and 300 mosm/L Major cation is Na+ NaCl dictates volume of ECF compartment Hoang 55 Asymmetry in solute composition b/w ECF & ICF Gibbs-Donnan Effect Non-diffusible ion present only on one side of membrane i.e. Non-diffusible protein anions of blood plasma Resulting in slightly greater concentration of cations in plasma than ICF Resulting in slightly greater concentration of anions in ICF than plasma Electroneutrality of solutes conserved in each compartment Number of diffusible cations greater in blood plasma (ECF) than ICF Oncotic pressure Osmotic pressure generated by large solutes Proteins Balanced by hydrostatic pressure Primary active transport = Ionic pumps Membrane proteins Transport ions against concentration gradient Na/K ATPase pump 2 K+ into cell = 3 Na+ out of cell Favors passive diffusion of Na + into cell across luminal membrane Favors passive diffusion of K+ out of cell into tubular lumen Consume ATP to establish asymmetric distribution Secondary active transporter Transport solute against concentration gradient Use Na+ gradient generated from Na/K-ATPase Antiporters Na+ inward = counter-ion outwards to ECF Symporters Na+ & accompanying ion into ICF RBC Permeable to urea RBC burst when placed in same osmolar urea solution (hypotonic) Impermeable to sucrose RBC maintain normal volume (isotonic) “To exert an osmotic pressure across a membrane, a solute must not permeate that membrane” II. Renal Anatomy Function of kidney Monitor and regulate volume/concentration of body fluids Excrete waste products & drugs Make glucose – ammonia – bicarbonate Maintain acid base balance Synthesize renin – erythropoietin – 1,25-OH-VitD Function of nephron Modification of filtrate Filtration, secretion, reabsorption, excretion Anatomy Retroperitoneal Encased in fat Cortex Covered by fibrous capsule Medulla Pyramids Inner medulla = papilla Collecting duct – calyces – renal pelvis – ureter – bladder Hoang 56 All glomeruli = located in cortex Cortical glomeruli = 90% at outer 2/3 of cortex Juxtamedullary glomeruli = 10% at inner 1/3 of cortex Larger with higher GFR Macula densa Junction of thick ascending loop of Henle & distal convoluted tubule Distal nephron = distal convoluted tubule + collecting duct Blood supply = aorta – renal artery Renal blood flow = 22% of cardiac output Segmental – interlobar – arcuate – afferent – glomerular – efferent – peritubular (90%) or vasa recta (10%) In series = 2 resistance beds & 2 capillary beds Vasa recta = specialized peritubular capillaries & parallel to loop of Henle Afferent arterioles = muscular Contain granular cells = synthesize renin Renal corpuscle Glomerular capillary = no VSM Contain mesangial cells Structural support Contractile Regulation of surface area Synthesis – phagocytic – immune functions Epithelium Podocytes Foot processes create slit pores Each pore covered by diaphragm Bowman’s capsule Surrounds glomerulus Juxtaglomerular apparatus Macular densa + extraglomerular mesangium + terminal afferent arteriole Functional importance = tubule communicate with blood vessels Tubule membrane transport Asymmetric Na/K ATPase on basolateral surface (peritubular) Variable Na+ permeability on apical surface (lumen) Proximal tubule Thick microvilli Leaky tight junction Ascending loop of Henle Tight tight junction Distal nephron (distal tubule + collecting duct) Tight-tight tight junction Collecting duct Principal cells & intercalated cells Renal innervation Sympathetic to arterioles & proximal and thick ascending loop of Henle No significant parasympathetic innervation Some non-adrenergic, non-cholinergic nerves (NANC) NO neurotransmitter Chemoreceptors Composition of urine Mechanoreceptors Hoang 57 Degree of perfusion of renal tissue III. Glomerular Function & Renal Clearance Renal blood flow = [ Renal artery pressure – Renal vein pressure ] / Total renal vascular resistance Resistance vessels Interlobular arteries Afferent arterioles Efferent arterioles Glomerular filtration barrier Fenestrated endothelium (50-100 nm) Glomerular basement membrane Filtration slit diaphragms bridging between adjacent foot processes Podocytes cytoplasmic processes Glomerular capillary wall Strong negative charge Polyanionic molecules on surface of endothelial cells, podocytes, & within GBM Negatively charged molecules filtered less Mesangium Mesangial cells and surrounding matrix Structural support Urinary excretion rate = Filtration rate – Reabsorption rate + Secretion rate Glomerular filtration rate (GFR) GFR = 80-200 ml/min or 115-290 L/day 20% of renal plasma flow Increase body weight = Increase GFR Glomerular filtrate = identical to plasma except it has no protein Rate of filtration of X = plasma [X] x GFR Assume X is freely filtered Rate of excretion of X = urine [X] x Urine flow rate (V) Renal clearance Volume of plasma which all substance X is removed / unit time CX = [ Ux/Px ] x V Fractional clearance Fractional clearance of X = [ CX/Cinulin ] FC > 1 when secretion FC = 1 when no reabsorption or secretion FC < 1 when reabsorption Glucose All filtered & all reabsorbed via active transport Seen in urine when Tmax is exceeded Diabetes mellitus = plasma [glucose] abnormally high Renal glycosuria = Tm abnormally low Phosphate All filtered but some reabsorbed via active transport at proximal tubule Tm is low = PO4 usually seen in urine CPO4 / Cinulin = 0.2 20% is excreted H 2O Filter 125 ml/min but excrete 1-2 ml/min Passively reabsorbed Water reabsorbed = urinary [inulin] increases Hoang 58 Uinulin / Pinulin = 1 when no water reabsorbed Uinulin / Pinulin = 2 when 50% filtered water reabsorbed Uinulin / Pinulin = 100 when 99% filtered water reabsorbed Free water (solute-free) ClearanceH2O = Urine flow rate V – Cosm Cosm = Urineosm x Urine flow rate V / Plasmaosm Urineosm < Plasmaosm Positive free-water clearance Net excretion of free-water Hypo-osmotic urine Urineosm > Plasmaosm Negative free-water clearance Net absorption of free-water Hyperosmotic urine Urea Waste product of protein metabolism Produced in liver Excreted by kidney Freely filtered & passively reabsorbed via concentration gradient Require transporter to cross membrane Reabsorbed in proximal tubule and inner medullary collecting duct Secreted in thin ascending limb of loop of Henle Concentration gradient determined by water reabsorption Water reabsorbed = urinary [urea] increases Urine flow rate decreases = urea excretion decreases Curea / Cin = 0.6 Protein Filter 2 g/day but 5-6 kg flow through kidney per day 99% reabsorbed in proximal tubule Para-aminohippuric acid (PAH) Non-endogenous Freely filtered Secretion via peritubular capillaries Proximal tubule CPAH = renal plasma flow rate (RPF) CPAH / Cin = 5 Creatinine Freely filtered Secreted but not reabsorbed Ccr / Cin = 1.1 Measuring renal plasma flow Fick principle RPF = Urinary [X] x Urine flow rate V / ( Arterial [X] – Venous [X] ) Invasive Urinary clearance method PAH as ideal marker Freely filtered & actively secreted 10-20% remains in renal vein Due to vasa recta of juxtamedullary nephrons No secretion of PAH in medulla “Effective” RPF = CPAH = Urinary [PAH] x Urine flow rate V / Plasma venous [PAH] Underestimates RPF by 10-20% Measuring GFR Inulin & iothalamate Hoang 59 Non-endogenous ideal marker Rate of filtration via plasma = rate of excretion via urine PIn x GFR = UIn x V Clearance = GFR = [UIn / PIn ] x V Because inulin is freely filtered, no secreted or reabsorbed Creatinine Endogenous non-ideal marker Freely filtered but is also secreted Ccreatinine > Cinulin Excretion is constant and equals production Plasma creatinine is constant = 1 mg/dl If GFR decreases ½ = Plasma [creatinine] increase 2 fold to compensate Production is inconstant in pregnancy, aging, muscle wasting, & maturation Cockcroft-Gault formula Females is less than males Incorporate age, weight, & gender MDRD equation Incorporates race in addition to previous formula Females produce less; blacks produce more GFR = Renal plasma flow x Filtration fraction FF = GFR/RPF 0.2 = 120 ml/min / 600 ml/min GFR = Kf x Net filtration pressure 1. PG = 60 mm Hg (promotes filtration) 2. G = 33 mm Hg (oppose filtration) 3. PB = 18 mm Hg (oppose filtration) 4. B = 0 mm Hg Methods to increase G Increase renal plasma flow = increase filtration fraction Increase renal blood flow = decrease glomerular colloid osmotic pressure Methods to increasing PG Increase arterial pressure Decrease afferent arteriolar resistance Increase efferent arteriolar resistance Excretion Reabsorption Glucose Filtered Proximal tubule Phosphate Filtered Proximal tubule Water Filtered Everywhere Urea Filtered Secreted in thin ascending Henle Proximal tubule Inner medullary collecting duct Protein Filtered Proximal tubule PAH Filtered Secreted via peritubular capillaries Not reabsorbed Creatinine Filtered Secreted Proximal tubule Hoang 60 Neurohumoral systems of GFR Sympathetic stimulation Constrict renal arterioles = decrease renal blood flow & GFR Norepinephrine & epinephrine Constrict afferent & efferent arterioles = decrease renal blood flow & GFR Endothelin Constricts renal arterioles = decrease renal blood flow & GFR Endothelium-derived nitric oxide (EDNO) Decrease renal resistance = increase renal blood flow & GFR Prostaglandins (PGE & PGI) Decrease vasoconstrictor effects of sympathetic = increase renal blood flow & GFR Angiotensin II Constricts efferent arterioles more than afferents Increase PG & decrease renal blood flow Low [Ang II] Constricts both afferent & efferent arterioles = decreases RPF (& GFR) Constrict efferent arterioles more = increases P GC (& GFR) Net zero effect on GFR Decrease sodium excretion Stimulate sodium transport in proximal tubule Via Na/H-antiporter Stimulate aldosterone release Increase sodium reabsorption in collecting duct High [Ang II] Intense renal vasoconstriction = decreases GFR Atrial natriuretic peptide Stimulated by volume overload (stretch fibers) Increase RPF & PGC Vasodilator on afferent arterioles Vasoconstrictor on efferent arterioles Tubuloglomerular feedback Decreased bp = decreased NaCl sensed by macula densa cells Decreased afferent arteriolar resistance Increase PG = increased GFR Increased renin release from JG cells of afferent & efferent arterioles Increase Ang II = constricts efferent arterioles to increase P G & GFR Myogenic autoregulation Blood pressure increase = blood vessels auto-constricts Increase vascular resistance = decrease renal blood flow & GFR Blood pressure decrease = blood vessels dilate Decrease vascular resistance = increase renal blood flow & GFR High protein diet Increase [amino acids] in blood Reabsorbed in proximal tubule using co-transport of sodium Decreased NaCl to macula densa = decreased afferent arteriolar resistance Increase GFR Hyperglycemia Increase sodium reabsorption via co-transport at proximal tubule Tubuloglomerular feedback = increase GFR Glucocorticoids Increase renal blood flow & GFR Fever Increase renal blood flow & GFR Hoang 61 Aging Reduction in functional nephrons Decrease renal blood flow & GFR IV. Renal Hemodynamics & Glomerular Function Kidney 0.5 % of body weight 25 % of cardiac output Regulates erythropoietin release Stimulated by low pO2 via interstitial renal cells Regulates RAS – water balance – countercurrent exchange Renal blood flow Flow = P / Resistance Resistance vessels Interlobular artery (cortical radial) & afferent artery Efferent artery Glomerular filtration Size, charge, and shape Exclude large, globular, and anionic molecules Filter small, deformable, and cationic molecules Proteins phagocytosed by mesangial cells 99 % filtered is reabsorbed in proximal tubule Glomerular filtration rate determinants 1. Renal plasma flow (RPF) 2. Filtration rate of each glomeruli 3. Number of functioning glomeruli Glomerular filtration fraction determinants Transcapillary hydrostatic pressure gradient Glomerular capillary ultrafiltration coefficient (Kf) Oncotic pressure of blood at glomerulus Due to nonfilterable plasma proteins Renal plasma flow Increase RPF = increased filtration Via decreased afferent or efferent arteriolar resistance Transcapillary hydrostatic pressure gradient Increased capillary blood pressure = increased filtration Increase filtration fraction = increased GFR Afferent arteriole constriction Decreases glomerular blood pressure Decreased GFR Efferent arteriole constriction Increases glomerular blood pressure Increased GFR Constriction of afferent & efferent equally No change in glomerular blood pressure Decreased RPF Glomerular capillary ultrafiltration coefficient Kf Increase surface area No effect on GFR if filtration pressure equilibrium was already present Increase GFR if filtration pressure disequilibrium is present Controlled by contractile intraglomerular mesangial cells Contain receptors = respond to hormone & drugs Synthesize vasoactive substances Oncotic pressure of glomerular capillary A Hoang 62 Decreased glomerular oncotic pressure = increase transcapillary pressure gradient Increased GFR Fluid Flux = P x water permeability x total area P = hydrostatic & colloid osmotic pressure Kf = water permeability x total area Self-limiting during filtration Single nephron GFR (SNGFR) Filtration pressure Area between P and curves V. Tubular Processing Secretion = peritubular capillaries into tubules Simple diffusion into renal interstitium Active or passive transport across tubular epithelium into lumen Reabsorption = from tubules into peritubular capillaries Transported across renal tubular epithelial membrane into interstitial fluid Then through peritubular capillary into blood Transcellular route = through cell membranes Active or passive transport Paracellular route = through junctional spaces between cells Ultrafiltration = bulk flow into peritubular capillaries Mediated by hydrostatic & colloid osmotic pressure Reabsorption rates are variable for different substances Glucose & amino acids = completely reabsorbed NaCl & bicarbonate = highly reabsorbed but changes depending on body needs Urea & creatinine = poorly reabsorbed Proximal tubules High capacity (65%) for reabsorption Water, Na+, Cl-, K+, & electrolytes Loop of Henle Descending thin segment Highly permeable to water 20% of glomerular filtrate volume is reabsorbed Resulting in hyperosmotic tubular fluid Ascending thin segment & thick segment Impermeable to water Permeable to Na+, Cl-, & K+ Resulting in dilute tubular fluid Early distal tubule (“diluting segment”) Form justaglomerular complex Feedback control on GFR & blood flow Impermeable to water & urea Reabsorb ions Dilutes tubular fluid = 100 mOsm/L Late distal tubule & cortical collecting tubule Principal cells 2/3 of total cells in segment Absorb Na+ & water into cell Secrete K+ into lumen Intercalated cells 1/3 of total cells in segment Absorb K+ into cell Secrete H+ into lumen Controlled by aldosterone Hoang 63 Permeability to water Controlled by ADH Impermeable to urea Medullary collecting ducts Permeability to water Controlled by ADH Highly permeable to urea Secretes H+ against concentration gradient VI. Sodium Transport & Balance Na/K-ATPase is present in basolateral membrane All segments of nephron Proximal convoluted tubule 60-70% sodium reabsorption Early PCT Sodium reabsorption via Na/H antiporter Na+ into cell Down concentration gradient created by Na/K ATPase 3 Na+ out of cell 2 K+ into cell + H out into lumen Sodium-linked bicarbonate, glucose, phosphate, amino acids & chloride reabsorption Na symporter More bicarbonate than chloride is reabsorbed Increase [Cl-] downstream in late PCT Reabsorption of CO2 H+ bind to HCO3- = form H2CO3 Split into CO2 and water CO2 reabsorbed into cell Reform carbonic acid via carbonic anhydrase Late PCT Na/H exchanger Na+ from lumen into cell H+ from cell into lumen H+ binds with protein anion Neutral H-anion diffuse back into cell Cl/Anion exchanger Cl- from lumen into cell Anion from cell into lumen H+ binds with protein anion Neutral H-anion diffuse back into cell Paracellular transport [Cl-] higher in lumen than plasma Net chloride diffusion into peritubular fluid Via chemical gradient Result in net positive charge in luminal fluid Stimulate sodium, Ca2+, Mg2+, & K+ reabsorption Via paracellular transport Net NaCl reabsorption between cells (leaky tight junctions) Avoid entering cells Thin descending loop of Henle No sodium reabsorption Water reabsorption via aquaporins Osmolarity gradient Hoang 64 Thick ascending loop of Henle 25% sodium reabsorption Na/Cl/K exchanger Na+, 2Cl-, & K+ from lumen into cell Via low intracellular [Na+] & [Cl-] Against high intracellular [K+] Chloride channel in basolateral membrane Cl- from cell into peritubular capillaries + K channel K+ from cell into lumen Result in net positive charge in lumen Stimulate Ca2+, Mg2+, & other cations reabsorption No water reabsorption No aquaproins in apical membrane Early distal convoluted tubule 5-7% sodium reabsorption Na/Cl co-transporter Na & Cl from lumen into cell Na+ exit cell to peritubular fluid via Na/K-ATPase Cl- exit cell to peritubular fluid via chloride channel Water cannot cross apical membrane Only section that can generate hypotonic luminal fluid (dilute urine) No aquaporins in apical membrane Late convoluted tubule & collecting duct 1-4% sodium reabsorption Via principal cell 2/3 of total cells in collecting duct Function in Na/K/H2O transport Sodium channel = epithelial Na+ Channel (eNaC) Na+ diffuse from lumen into cell Via negative intracellular charge Created by Na/K-ATPase Create negative charge in lumen Stimulate K+ diffusion from cell into lumen Via K+ channel Hormonal regulation Aldosterone Early Open exisiting ENaC Late Stimulate ATP production = activate intracellular proteins & transcription Form new Na/K-ATPase on basolateral membrane Determinants of aldosterone release Primary mechanism = increase plasma [angiotensin II] Renin release = rate limiting step Increased PK Increased ACTH Decreased PNa Decreased plasma ANP ANP has tonic inhibition on aldosterone Angiotensin II Regulation of release Renin release = rate limiting step Renin Synthesized in granular cells of afferent arteriole = part of JGA Hoang 65 Determinants of renin release Decreased renal perfusion pressure Via baroceptors in afferent arteriole -adrenergic sympathetic stimulation Occur when blood pressure falls Decrease in NaCl at macula densa Occur when GFR falls Regulation of release Directly sense volume = indirectly relates to sodium content Do not sense sodium concentration Inhibited by Ang II Atrial natriuretic peptide Increase GFR Increase UNaV Rapid Direct inhibition of sodium reabsorption Proximal tubule & collecting duct Decreased aldosterone release Determinants of ANP release Atrial stretch from volume expansion via sodium increased Nitric oxide Increase GFR Direct inhibition of sodium reabsorption Proximal tubulte & collecting duct Systemic vasodilator cGMP 2nd messenger Determinants of NO release High salt intake Prostaglandins Inhibit sodium reabsorption Thick ascending loop of Henle & collecting duct Stimulation of prostaglandin release Increase in volume Endothelin Vasoconstrictor Increase sodium excretion Different from other natriuretic hormones (vasodilators) Bartler’s Syndrome Seen in newborns Mutation of Na/Cl/K exchanger or K+ channel of thick ascending loop of Henle Build-up of K+ intracellular compartment Inhibit Na/K-ATPase Decreased NaCl reabsorption = decreased urinary sodium excretion Increased urine Na & K concentrations Decreased serum K concentration & blood pressure Hemorrhage Less than 10% blood loss BP maintained by SNS & Ang II Between 10-25% blood loss ADH + SNS + Ang II ADH = vasoconstrictor Greater than 25% blood loss Maximal vasoconstriction Shock & renal failure Hoang 66 Septic Shock Endotoxin = increase NO release Massive vasodilation Underfilled circulation Volume depletion Cause sodium retention = increase effective circulating volume 3rd spacing = edema VII. Potassium Regulation Potassium Intracellular ion = 150 mEq/L Plasma [K+] = 4 mEq/L Low plasma [K+] = hyperpolarize cell Less excitable = “flaccid paralysis” High plasma [K+] = depolarization Spastic paralysis Excretion Renal = 90% GI = 10% K+ uptake into cells Insulin Epinephrine = -adrenergic agonist Aldosterone ECF alkalosis K+ into cell = H+ out of cell K+ secretion out of cells -adrenergic stimulation Exercise Increased plasma osmolality Cell lysis = physical injury ECF acidosis K+ out of cell = H+ into cell Proximal convoluted tubule 67% reabsorption of K+ K+ exit cell to peritubular space Via K+ channel & K/Cl-cotransport + K channel for emergency secretion only Early PCT Na+ reabsorption cause H2O to diffuse via paracellular transport Solvent drag = water diffusion drag K+ reabsorption via paracellular transport Concentration gradient Late PCT Early bicarbonate reabsorption cause lumen to be positively charged K+ diffuse via paracellular transport Electric gradient Thick ascending loop of Henle 20% reabsorption of K+ Na/2Cl/K-cotransport K+ transport to peritubular fluid via K-channel K-channel secrete K+ into lumen to recycle for pump (50% of total reabsorption) K+ reabsorb by paracellular diffusion (50% of total reabsorption) Driven by luminal positive voltage Hoang 67 Distal nephron Reabsorption with low K+ intake Excretion with high K+ intake Distal K+ secretion = primary determinant of K + excretion Principal cells Regulate UK & V (urine flow rate) Not by GFR or rate of reabsorption Cortical collecting tubule: Intercalated cell K/H-ATPase K+ from lumen into cell K+ transported to peritubular fluid via K-channel H+ from cell into lumen H-channel H+ out of cell when K+ reabsorption is not needed Cl/HCO3-antiporter Cl- into cell HCO3- out of cell Cortical collecting tubule: Principal cell Aldosterone-regulated-channels ENaC Na+ from lumen reabsorbed into cell + K pump K+ from cell secreted into lumen K/Cl-cotransporter K+ & Cl- from cell secreted into lumen + K pump on basolateral membrane K+ from cell transported into peritubular fluid K+ recruit from peritubular fluid into cell via Na/K-ATPase CK/Uin < 1.0 Net reabsorption Excreted K+ from secretion (not filtration) in distal nephron Secretion across luminal membrane = passive Increasing K+ secretion of collecting tubule Increased intracellular [K+] Increase plasma [K+] = increase aldosterone secretion Increase ECF pH Induction of Na/K-ATPase via aldosterone Increased K+ from cell into lumen Increase luminal membrane permeability via aldosterone Increase negativity of lumen Increase Na+ reabsorption Increase luminal concentration of non-reabsorbable anions i.e. Phosphate or bicarbonate Increase tubular fluid flow rate Diuretics result in K+ wasting Potassium does not “escape” aldosterone unlike sodium Conn’s syndrome result in hypokalemia VIII. Calcium, Phosphate, & Magnesium Regulation Excess calcium Nausea – vomiting – polyuria – dehydration – hypotension – coma Excess phosphate Calcium deposits in skeletal tissues, cardiac system, & arteries Hoang 68 Deficient phosphate ATP deficiency – muscular weakness – respiratory failure Plasma calcium Protein (albumin) bound = 40% Bicarbonate complex = 10% Ionized in solution = 50% Only kind that is filterable & active Calcium Proximal tubule = 70% Paracellular diffusion into interstitial fluid Via lumen positive electrical gradient Transcellular transport (minor) Thick ascending limb of loop of Henle = 20% Paracellular diffusion Via lumen positive electrical gradient Resulting from Na/2Cl/K-cotransport & recycling of K+ Increased Na+ reabsorption = increased paracellular Ca2+ reabsorption Loop diuretics = inhibit Na/2Cl/K-cotransporter Increase urinary calcium excretion Distal tubule = 9% Paracellular diffusion = minor Transcellular transport = major Calcium channel = apical Intracellular negative gradient & low intracellular ionized calcium concentration Via electrochemical gradient Ca-ATPase & Na/Ca-exchanger = basolateral Collecting ducts = 1% Thiazide diuretics = increase calcium reabsorption Inhibit Na/Cl-symporter of distal tubule Inhibit NaCl entry into cell = increase intracellular negativity gradient Increases apical calcium entry & stimulate basolateral calcium exit Increased sodium excretion = decreased intravascular volume Stimulates Na/2Cl/K-symporter of loop of Henle Increased sodium reabsorption = increase calcium reabsorption Phosphate Essential buffer in urine for proton excretion Bone = 86% of body’s total [phosphate] ICF = 14% of body’s total [phosphate] ECF = 0.03% of body’s total [phosphate] Protein bound = 10% Free ionized = 90% Proximal tubule = 90% 2Na/Pi-Symporter Via sodium gradient = intracellular negative potential gradient Distal tubule = 10% Phosphate loading or hypocalcemia Increased PTH Cause parathyroid gland hyperplasia = increased PTH secretion Decreased calcium sensitivity to inhibit PTH release Increased phosphate excretion Increased calcium reabsorption Hoang 69 Phosphate depletion or hypercalcemia Decreased PTH Decreased phosphate excretion Magnesium Proximal tubule = 15% of filtered magnesium Thick ascending limb of loop of Henle = 70-80% of filtered magnesium Distal tubule = 10% of filtered magnesium IX. Neurohormonal Regulation Aldosterone Secreted by adrenal cortex Act on principal cells of cortical collecting tubule Stimulate Na/K-ATPase = increases sodium reabsorption & potassium secretion Excess aldosterone = hypokalemic alkalosis Angiotensin II Activated by renin & ACE in RAAS Stimulate aldosterone secretion Constrict efferent arterioles = decrease RPF Reduce hydrostatic pressure peritubular capillaries = reduce renal blood flow to increase FF Increase absorptive force of peritubular capillaries & sodium and water Direct stimulation Na+ reabsorption at proximal tubules & TAH Antidiuretic hormone Secreted from posterior pituitary gland Increase water permeability of distal tubules, collecting tubules, & collecting ducts Atrial natriuretic peptide Secreted by cardiac atria Stimulated by distension of atrium from plasma volume expansion Decrease sodium & water reabsorption At proximal tubule & distal nephron Parathyroid hormone Increase calcium reabsorption Predominantly in distal tubule & ascending loop of Henle Decrease phosphate reabsorption Stimulate renin release & Ang II formation Nitric oxide Increase sodium excretion Increase GFR Direct inhibition of sodium reabsorption on distal nephron & proximal tubule Prostaglandins Stimulated by increased ECF volume Inhibit sodium reabsorption At TAL & collecting duct Sympathetic nervous system Constricts afferent & efferent arterioles Reduce GFR Increase sodium reabsorption at proximal tubule & ascending loop of Henle Stimulate renin release & Ang II formation Hoang 70 Summary of Direct Neurohormonal Effects Hormone Source Site of action Filtration Secretion K+ H+ Reabsorption Na+ Aldosterone Adrenal cortex Distal nephron TAH Angiotensin II ECF Proximal tubule TAH Na+ H2O indirectly ADH Post. Pituitary Distal nephron H2O SNS Peripheral System (-Adrenergic) Proximal tubule TAH Distal nephron Parathyroid Hormone Parathyroid gland Distal tubule TAH ANP Cardiac atria Proximal tubule Distal tubule Collecting duct GFR Na+ H2O Nitric Oxide Endothelial cells Proximal tubule Distal tubule Collecting duct GFR Na+ GFR Na+ Ca2+ PO43- X. Urinary Concentration & Dilution Serum osmolarity Regulate between 285 mOsm/kg and 288 mOsm/kg Serum osmolarity = (2 x Na) + (BUN / 2.8) + (glucose / 18) Urine osmolarity Regulated by the level of ADH Concentration of urine High ADH level Increased water permeability of distal tubule & collecting duct Dilution of urine Low ADH level Function Proximal tubule Tubule fluid does not change osmolarity Thin descending limb of loop of Henle Basal level of water reabsorption Increased via ADH Urea reabsorbed going toward medullary Thick ascending limb of loop of Henle Absorb Na+ & Cl- in absence of water Active transport TF is maximally concentrated at papillary tip TF becomes diluted in the loop TF becomes hypotonic to plasma at end of TAH Hoang 71 Fluid entering distal tubule is hypoosmotic to plasma Impermeable to water Distal convoluted tubule = connecting segment Na+, Cl-, & Ca2+ reabsorption H2O reabsorption via ADH Cortical collecting duct Na+ & Cl- reabsorption H+ & HCO3- balance H2O reabsorption via ADH Medullary collecting duct H2O reabsorption via ADH Sodium reabsorption via ENaC Urea Proximal tubule Reabsorbed Thin descending loop of Henle Urea efflux to interstitum in inner medulla Thin ascending loop of Henle Urea influx into TF Passive efflux of sodium into interstitium Thick ascending loop of Henle Impermeable to urea Active efflux of sodium into interstitium via Na/2Cl/K-symporters Dilute TF to 200 mOsm by end of TAL = TF is hypotonic Distal convoluted tubule Water reabsorption via ADH-stimulated aquaporins Only occur in water restriction Sodium reabsorption via Na/Cl-symporters TF is further hypotonic (100 mOsm) by end of distal tubule Cortical & outer medullary collecting tubule Water reabsorption via ADH-stimulated aquaporins Occur in water restriction [Urea] = increases Impermeable to urea Inner medullary collecting tubule Permeable to urea = high concentration gradient Efflux into interstitium Urea cycling Urea reabsorbed in inner medullary collecting tubule Urea diffuse from interstitium into thin descending & ascending limb of loop of Henle Recycle back to inner medullary collecting tubule Requirements for forming concentrated urine High level of ADH High osmolarity of renal medullary interstital fluid Countercurrent multiplier Create high osmolarity in renal medulla Active transport of sodium with co-transport of K+, Cl-, et cetera From ascending limb of loop of Henle into medullary interstitium Active transport of ions from collecting ducts into medullary interstitium Diffusion of urea from inner medullary collecting ducts into medullary interstitium Diffusion of minute amounts of water from collecting tubules Countercurrent exchange of vasa recta = preserves hyperosmolarity of renal medulla Vasa recta blood flow = low Blood more concentrated in medulla Hoang 72 Highly permeable to water & solutes Water diffuse into vessel when ascending back to cortex Osmoreceptor-ADH feedback system ECF osmolarity increases above normal Stimulate osmoreceptors of anterior hypothalamus Signal release of ADH in posterior pituitary ADH increase water permeability Late distal tubules, cortical collecting tubules, & medullary collecting ducts Increased water reabsorption = excrete concentrated urine Antidiuretic hormone (ADH) Synthesized in supraoptic & PVN of hypothalamus Release from posterior pituitary V1 receptor = vasoconstriction of blood vessels & endothelial cells V2 receptor = intercalation of pre-formed aquaporin-2 G-protein stimulate AC = increased intracellular [cAMP] Stimulate PKA = phosphorylation cascade Fusion of aquaporin-2 with luminal membrane of principal cells Water reabsorption Stimulated by increased plasma osmolarity, decreased blood pressure or volume Thirst Stimulated by angiotensin II, increased osmolarity, decreased blood pressure or volume Pathological urinary concentrating ability Central diabetes insipidus Inability to produce/release ADH from posterior pituitary Nephrogenic diabetes insipidus Inability of kidney to respond to ADH XI. Regulation of Acid-Base Balance ECF [H+] = 0.000 000 04 Eq/L = 40 nEq/L Normal arterial blood pH = 7.4 Normal venous & interstitial fluids = 7.35 Nonvolatile acids Sulfuric acid Phosphoric acid Organic acid Volatile acid CO2 Regulation Buffer systems of body fluids Bicarbonate buffer system pH = 6.1 + log [HCO3-] / [0.03 x PCO2] Proteins of cells Phosphate buffer system Respiratory system Acidosis Hyperventilation = decrease PCO2 Decrease carbonic acid in blood = decreased [H+] Kidneys Excretion of titratable acids H+ (phosphoric acid) Hoang 73 Reabsorption of filtered HCO3About 100% filtered PT = 80% TAL = 15% CCD = 5% About zero % is excreted Production of new HCO3Excretion of ammonium Alkalosis Excess bicarbonate ions Bicarbonate reacts with available H+ to be reabsorbed Excess HCO3- left in urine is excreted Acidosis Excess hydrogen ions All filtered bicarbonate is reabsorbed Excess hydrogen ions are excreted Minimal urine pH = 4.5 Buffers of tubular fluid Phosphate buffer HPO42- & H2PO4For each H+ buffered = 1 bicarbonate is reabsorbed Ammonia buffer Ammonia (NH3) & ammonium (NH4+) Synthesized from glutamine Form 2 NH4+ into urine & 2 HCO3- into blood “New” bicarbonate generation Renal glutamine metabolism Stimulated by acidosis & hypokalemia Renal acid-base secretion & reabsorption Proximal tubule & TAL of Henle Apical membrane Na/H-exchanger (2/3 of hydrogen secretion) H-ATPase (1/3 of hydrogen secretion) Basolateral membrane Na/K-ATPase High intracellular sodium concentration Na/3HCO3-symport Via electrical gradient = negative intracellular potential HCO3/Cl-antiport Proximal tubule & Thick ascending limb of loop of Henle Hoang 74 Collecting duct: A-cell Apical membrane = both pumps use ATP to make steep pH gradients K/H-ATPase Secrete H+ into lumen H-ATPase Basolateral membrane HCO3/Cl-antiporter Chloride depletion = inable to reabsorb bicarbonate Cl-channel Passive diffusion of chloride out of cell into interstitium Via electrical gradient Collecting duct: Acid-secreting intercalated cell Collecting duct: B-cell Apical membrane HCO3/Cl-antiporter Chloride into cell = bicarbonate into lumen Driven by chloride concentration gradient Can increase luminal pH to 8 Basolateral membrane H-ATPase Cl-channel Collecting duct: Bicarbonate-secreting intercalated cell Hoang 75 Renal generation of bicarbonate Proximal tubule Glutamine metabolize to 2 NH4+ & 2 HCO3Low potassium concentration stimulate ammonia production Bicarbonate return to systemic circulation via renal veins NH3 diffuses into lumen to reform ammonia Medullary thick ascending limb of loop of Henle NH4+ reabsorbed into interstitial space to collecting duct Via Na/2Cl/K-symporter NH4+ is mimic potassium Collecting duct NH3 diffuse to luminal fluid & excreted Hypokalemia Stimulate ammonia production and excretion Increase bicarbonate generation Signal collecting duct to stop secretion of potassium = principal cell Via K/Cl-symporter & K-channel Signal collecting duct to reabsorb potassium = -intercalated cell Via K/H-antiporter Long-term chronic acidemia Significant increase in acid excretion Short-term acute academia Little or no increase in net acid excretion XII. Nephropathy of Diabetes Mellitus Diabetes mellitus Chronic hyperglycemia Polyuria – polydipsia – infection – weight loss Type 1 Insulin deficiency Type 2 Insulin resistance due to defective receptors Macrovascular disease Coronary arteries – carotid arteries – peripheral vasculature Microvascular disease Retinopathy & nephropathy Hoang 76 Neuropathy Mono- & polyneuropathy Autonomic neuropathy Renal complications of diabetes mellitus Vascular disease Increased infection Hyperglycemia & inflammatory thrombosis Atonic bladder = inable to empty bladder Prone to infection Renal ischemia & failure Glomerular ischemic damage = hypertension & renal failure Renal failure = 2nd leading cause of death in Type 1 diabetes mellitus Chronic hyperglycemia Glomerular basement membrane glycosylation Decreased negative potential = decreased GBM selectivity Leaky membrane = proteinuria Mesangial proliferation Increased pore size Hypertension Hyperfiltration Intraglomerular hypertension Glomerular damage Thicken GBM & mesangial proliferation Obliteration of capillary loops Death of nephrons Loss of surface area Chronic renal failure Stage I = Early hypertrophy-hyperfunction 100% progression to stage II Treatment to control hyperglycemia & blood pressure Hypertrophy = enlargement of kidneys Expanded blood volume due to hyperglycemia Hyperfunction = increased GFR Expanded blood volume due to hyperglycemia Stage II = Glomerular lesions without clinical disease 40% progession to stage III Treatment same as stage I “Silent phase” Normal bp – no proteinuria – no microalbuminuria Histological changes Thickened GBM Proliferated mesangial matrix Stage III = Incipient diabetic nephropathy Dipstick for protein = negative Minimal albumin excretion = microalbuminuria Special dipstick for MAU = cheapest test available Elevated MAU requires second testing for confirmation 24 hour urine collection = gold standard Mild hypertension “Turning point” Stage IV = Clinical diabetic nephropathy 100% progession to stage V Dipstick-detectable albuminuria Hoang 77 Decreased GFR Measured via clearance of creatinine Hypertension Retinopathy always present Stage V = End-stage renal disease Azotemia Uremia & olgiuria Treatment = dialysis or transplantation Histological findings Nodular diabetic glomerulosclerosis Kimmelstiel-Wilson nodules XIII. Renal Disease & Failure Acute renal failure Abrupt loss of kidney function due to hemodynamics Vasoconstriction of renal blood flow & plasma flow Decreased RPF & GFR Oliguria = low urine flow Anuria = no urine flow Acute tubular necrosis = tubular obstruction cause tubular damage Can reduce urine Can increase urine Polyuria = tubular injury result in decreased sodium reabsorption Occur even in low GFR Category of acute renal failure 1. Prerenal: decreased renal perfusion Hemorrhage – diarrhea – post partum ARF – hypotension 2. Renal: caused within kidney Ischemic damage – surgery – radiocontrast – toxins 3. Obstructive: occlusion of renal system or vessels Treatment Increase volume & urine flow Hemodialysis Chronic renal disease Progressive fall in renal function & GFR Leads to end stage renal disease Dialysis or renal transplant Compromised sodium excretion & conservation Edema & ECF volume expansion = congestive heart failure Low sodium intake = becomes volume depleted Compromised water concentration & dilution Hyponatremia or hypernatremia Compromised potassium regulation Hyperkalemia = cardiac arrhythmias Compromised mineral metabolism Deficiency in 1,25-OH-Vitamin D Abnormal levels of Ca2+ & PO43Hyperparathyroidism Osteomalacia Increased serum phosphate concentration due to decreased GFR Increase binding of phosphate with calcium Decrease serum ionized [calcium] Stimulate PTH = demineralization of bones Hoang 78 Uremia Dysfunctional waste excretion = systemic poisoning Anemia Deficient erythropoetin Acidosis Deficit in reabsorption and generation of bicarbonate Aging kidney Decline in GFR Male @ age 40 = females @ age 60 Falling RAAS Decreased aldosterone Sodium depletion Diminished natriuretic response to sodium loading Increased sodium sensitivity of blood pressure Hypertension Increased systolic Diminished sensitivity to ADH Case 1 = High salt intake No significant in GFR or blood pressure Decreased Na+ reabsorption Increase tubuloglomerular feedback High salt intake Thirst-receptors Increase ECF osmolarity Increase water intake Increase plasma volume Macula densa sense high salt levels Decrease SNS stimulation Decrease renin secretion Dilate renal arterioles Decrease angiotensin II Increase secretion of ANP Decrease Na+ reabsorption Dilate efferent arterioles Decrease aldosterone Decrease H2O reabsorption K+ & H+ retention Hoang 79 GASTROINTESTINAL PHYSIOLOGY I. Gastrointestinal Anatomy Mouth – esophagus – stomach – small intestine – large intestine – colon – anus Esophageal muscle Striated = upper 1/3 Striated & smooth = middle 1/3 Smooth = lower 1/3 Intestinal wall Serosa Longitudinal muscle layer Interstitial Cells of Cajal = non-neural cells Circular muscle layer Submucosa Mucosa Muscularis mucosae lies within deep mucosa GI smooth muscle Muscle fibers connected through gap junctions Function as syncytium Resting membrane potential = -56 mV Depolarization Stretching Acetylcholine (parasympathetic nervous system) Hormones Hyperpolarization Norepinephrine & epinephrine (sympathetic nervous system) Enteric nervous system Lies within gastrointestinal wall Esophagus to internal anal sphincter Composition Myenteric plexus (Auerbach’s plexus) Between circular & longitudinal muscle layers Increase muscle tone Increase contractile intensity Increase rate of contraction Increased conduction velocity Neuron density = 50,000/cm2 gut surface Submucosal plexus (Meissner’s plexus) In submucosa Integrate sensory signals from gastrointestinal epithelium Regulation of secretion, absorption, and contraction (via myenteric plexus) Plexuses are interconnected Increased motility = increased secretion Gastrointestinal movements Myenteric reflex = Peristalsis by myenteric plexus Distention cause contraction ring to move forward Simultaneous receptive relaxation of gut Law of the gut = myenteric reflex + unidirectional movement toward anus Gastrointestinal blood flow Splanchnic circulation = gut + spleen + pancreas + liver Drain into liver via portal vein GI blood flow = proportional to local activity Hoang 80 Vasodilators CCK – gastrin – secretin – kallidin – bradykinin Tissue hypoxia = increase blood flow by 50% Parasympathetic = increase blood flow Sympathetic = decrease blood flow Autoregulatory escape = local metabolic vasodilators elicited by ischemia redilate arterioles II. Secretory Principles of Alimentary Tract Contact of food with epithelium stimulate secretion Tactile stimulation Chemical irritation Gut wall distention Parasympathetic stimulation increase rate of glandular secretion Salivary glands Esophageal glands Gastric glands Pancreas Brunner’s glands of duodenum Secrete alkaline mucus with bicarbonate Also stimulated by tactile and chemical irritants & GI hormones (secretin) Sympathetic stimulation has dual effect on glandular secretion Sympathetic alone increase secretion Sympathetic superimposed on secretion decreases blood flow to gland = decrease secretion Acetylcholine Pepsinogen by chief cells HCl by parietal cells Mucus by mucous cells Gastrin HCl by parietal cells Digestive enzymes by pancreas Pepsinogen by chief cells Histamine HCl by parietal cells GI Hormones Gastric inhibitory peptide (GIP) Secreted by duodenum & jejunum Stimulated by fatty acids, amino acids, & oral glucose Stimulate insulin release Inhibits P-cell secretion of HCl Vasoactive intestinal peptide (VIP) Homologous to secretin Released from mucosal nerves Relaxation of GI smooth muscle Stimulate pancreatic bicarbonate secretion Inhibit gastric HCl secretion Gastrin-releasing peptide (GRP) Stimulated by vagus Released from mucosal nerves Stimulates gastrin release from G-cell Enkephalins Released from mucosal nerves Stimulate GI smooth muscle contraction (sphincters) Hoang 81 Inhibit intestinal secretion of fluid & electrolyttes III. Salivary Secretion & Regulation Daily = 1-1.5 L of saliva secreted Active process High concentrations of K+ & HCO3Low concentrations of Na+ & ClControlled mainly by parasympathetic signals Salivatory nuclei via taste & tactile stimuli of tongue, mouth, & pharynx Function of saliva Facilitator Chewing – swallowing – speech – taste Protector Dilute, neutralize and destroying acids & bacteria Digestor Salivary amylase Lingual lipase Salivon Acini – intercalated ducts – striated duct – excretory duct – major excretory duct Synthesize and secrete primary secretory fluid Isotonic to blood plasma Becomes hypotonic to major excretory duct = saliva Ranges from 150 mOsm/L to 225 mOsm/L Active reabsorption of NaCl Active secretion of K+ & HCO3Hypotonicity = osmotic lysis of bacteria Aldosterone = stimulate reabsorption of NaCl to create hypotonic saliva High [carbonic anhydrase] at acini Form H2CO3 = H+ reabsorbed into capillaries & HCO3- secreted in saliva Bicarbonate from blood & acinar and intercalated duct cells Increases salivary pH for optimum enzyme activity = pH 7.0 Neutralization of bacterial and acids from food Increased rate of salivary secretion = increased pH due to high bicarbonate Ion Parotid Saliva Blood Plasma Na+ 85 mM 145 mM Cl- 40 nM 110 mM K+ 20 mM 10 mM HCO3- 70 mM 24 mM Composition of saliva Serous Primary electrolytes Na+, K+, HCO3-, ClSecondary electrolytes Hoang 82 Ca2+ Stimulate salivary amylase SCNBacteriostatic agent Organic Mucin Glycoprotein for lubrication during swallowing Stimulated by K+ & attach to teeth Amylase (Ptyalin) Hydrolyze polysaccharides to maltose, glucose, & dextrins Split 1,4-glucosidic linkage Activation by chloride Stimulation by calcium Optimum pH = 7.0 Lingual lipase Hydrolyze triglycerides to 2 free fatty acids & 1 monoglyceride Optimum pH = 7.0 Lysozyme Antibacterial = degrade bacterial cell walls Lactoferrin Adsorb Fe2+ & Fe3+ Compete with bacteria = antibacterial IgA Antibacterial Secreted by salivon Autonomic nervous system Parasympathetic & sympathetic = stimulate secretion of saliva Parotid – submaxillary – sublingual glands Regulation by cerebrum, buccal cavity receptors, olfactory receptors Parasympathetic nervous system = CN VII & IX Secretion of serous saliva via cGMP & PIP 2 Vasodilation Via neurotransmitter on vascular smooth muscle Via bradykinin production from stimulation of secretory segment cells = long term Myoepithelial constriction of basket cells around salivary gland Acetylcholine Sympathetic nervous system Mucous (organic) secretion from mucous cell via cAMP Vasoconstriction Myoepithelial constriction of basket cells around salivary gland Norepinephrine Condition reflex secretion of saliva Include cerebrum & memory Unconditioned reflex secretion of saliva Do not include cerebrum IV. Gastric Secretion & Regulation Stomach function Denaturation Expose peptide linkages Tight-tight junctions between cells = no absorption occur Secretion of intrinsic factor Essential for life Hoang 83 Digestion Gastric secretory cells Parietal cell Only in body and fundus Secrete HCl & Intrinsic Factor Chief cell Only body and fundus Secrete pepsinogen Mucous cells = protect stomach Mucous neck cell Secrete alkaline fluid with mucus Mucous cells of cardiac and pyloric glands Secrete alkaline fluid with mucus Surface epithelial cells of stomach mucosa Secrete alkaline fluid with insoluble mucus Regulation of secretory cells Acetylcholine Secreted by postganglionic parasympathetic nervous system (PSNS) Stimulate Auerbach’s plexus & Meissner’s plexus Does not stimulate G-cells Gastrin Hormone secreted by G-cells of pyloric antrum Released by gastrin-releasing peptide (GRP) 17 amino acid peptide = terminal tetrapeptide active fragment Stimulate body and fundus Cephalic phase of secretion Caused by taste, smell, chewing, swallowing reflexes = psychic factors Stimulate vagus efferents to stomach Efferent vagi stimulate Auerbach’s & Meissner’s plexuses Plexuses stimulate G-cells, chief cells, & parietal cells G-cells secrete gastrin Gastrin stimulate parietal cells to secrete HCl and IF Gastric phase of secretion Caused by distention of stomach = lasts as long as food is present in stomach Vago-vagal reflex (long reflex) Distention stretch nerves = influx of sodium into nerve cause stimulation Vagal afferents transmit to efferents Stimulate G-cells to secrete gastrin Gastropancreatic reflex Distension of stomach = signal vagal efferents Stimulate exocrine pancreas secretion of digestive enzymes Local reflex Mediated by Meissner’s plexus Local cholinergic reflex cause acid production Caused by chemicals in food Secretagogues in foods bind receptors in pyloric antrum Meissner’s plexus stimulate G-cells via GRP G-cell secrete gastrin to stimulate parietal cells Secretagogues = amino acids, alcohol, caffeine, & calcium Intestinal phase of secretion Caused by food in intestine stimulating gastric pouch Stimulation of duodenal mucosa cause secretion of Big Gastrin Stimulate stomach secretion Control of secretion Hoang 84 Excess H+ from parietal cells inhibit G-cells Excess H+ stimulate D-cells to release somatostatin Somatostatin inhibit G-cell gastrin secretion = paracrine effect Enterochromaffin-like cells (ECI) secrete enterogastrones From intestine inhibiting stomach Secretin, CCK, gastric inhibitory peptide, & vasoactive intestinal peptide Direct inhibition of G-cells of pyloric antrum Excess H+ stimulate S-cell to secrete secretin into blood Inhibit G-cell from secreting gastrin Enterogastric inhibitory reflex Excess H+ stimulate nerves in mucosa & submucosa Stimulate sympathetic celiac plexus to secrete norepinephrine Inhibit Meissner’s plexus secretion of GRP = inhibit gastrin & HCl secretion Signals from colon & small intestine inhibit stomach motility & secretion Gastric juice Secretions from parietal cells, chief cells, & mucous cells Alkaline = neutralize parietal cell HCl acid Histamine Secreted by histaminocytes = gastric mucosal mast cells Gastrin & acetylcholine receptors Located adjacent to parietal cells Potent stimulator of parietal cells via cAMP Paracrine hormone Multiplicative effect on acid secretion Obligatory agent = acts directly on parietal cells Acetylcholine & gastrin stimulate histaminocyte to secrete histamine Ach & gastrin potentiate histamine effect on parietal cell Formed from histadine via histidine decarboxylase Parietal cell secretion Maximum acidity = 150 mEq/L (pH 0.9) pH increases during meal to pH 2 due to dilution & regurgitation H/K-ATPase = antiporter on apical membrane ATP from oxidative metabolism & anaerobic glycolysis HCO3/Cl-antiporter on basolateral membrane Isosmotic with blood plasma Organic gastric secretion Pepsin Endopeptidase stored in chief cells as pepsinogen Activation via HCl & pepsin Ach, gastrin, histamine, & H+ stimulates chief cell secretion Cleave basic-aromatic peptide bonds = form peptides Optimal pH = 2-3 Mucopolysaccharide Alkaline fluid with gel-like structure Create 1.0-1.5 mm thick barrier Protects stomach from mechanical & chemical injury Denatures pepsin & neutralize H+ due to high pH Secretion stimulated by mechanical and chemical irritations & vagus R-protein Synthesized by secretory segment cells of salivary glands Binds B12 (extrinsic factor) after pepsin free it from protein complex in stomach Gastric intrinsic factor (GIF) Hoang 85 Synthesized by parietal cell & released when stimulated Binds remaining B12 in stomach Pancreatic proteases degrade R-protein in small intestine GIF bind remaining B12 GIF-B12 complex bind high-affinity receptor in ileum brush border membrane to be absorbed Required for heme biosynthesis V. Exocrine Pancreas Functions Neutralize gastric juice = pH 3.3 in stomach increases to pH 6.1 in small intestine Small volume secretion Digestive carboxypeptidases secreted by pancreatic acinar cells Endopeptidase = form peptones & oligopeptides Trypsin – chymotrypsin – elastase Trypsinogen activated by enterokinase on intestinal epithelium Trypsin activate all other endopeptidases Exopeptidase = form amino acids Carboxypeptidase A – carboxypeptidase B Trypsin inhibitor Form 1:1 combination with trypsin = inactivation Protect pancreas from autolysis Lipase = form glycerol, fatty acids, & monoglycerides Degrade fats Amylase = form maltose, detrin, & glucose Activated by chloride Stimulated by calcium Large volume secretion Water & electrolytes secreted by intercalated ducts Sodium & potassium concentrations equal that of plasma Bicarbonate increases as secretion rate increases = always higher than plasma Intercalated cells = high concentration of carbonic anhydrase Neutralize gastric contents Chloride decreases as secretion rate increases = always lower than plasma [HCO3-]pancreas + [Cl-]pancreas = [HCO3-]plasma + [Cl-]plasma Neural regulation of pancreatic secretion Cephalic phase via efferent vagus Stimulate secretion of enzymes (small volume secretion) Gastropancreatic reflex Secretion stimulated by distended stomach via long reflex Afferent to efferent vagus fibers Hormonal regulation of pancreatic secretion Secretin Secreted from duodenal mucosa S-cells Stimulate pancreas to secrete large volume (bicarbonate) Stimulate growth of exocrine pancreas Inhibit G-cells & acid secretion Inhibit gastric motility Respond to duodenal pH 4.5 or less Protect duodenum by stimulating secretion of alkaline juice (no enzymes) Via intercalated cells of pancreas Stimulated by H+, peptides, fats, triglycerides, & amino acids Via cAMP Hoang 86 Cholecystokinin Secreted from duodenal mucosa I-cells Stimulate pancreas to secrete small volume (enzymes) Potentiates secretin stimulation of pancreatic bicarbonate Stimulate growth of exocrine pancreas & gallbladder mucosa Relaxation of sphincter of Oddi Cause contractions of gallbladder Stimulated by peptides, amino acids, fatty acids, & monoglycerides Triglycerides do not cross mucosal cell membrane = no stimulation of CCK Gastrin Secreted from pyloric antrum G-cells Stimulated by gastric distension Gastrin induce pancreatic secretion of digestive enzymes with little aqueous juice Gastrin induce P-cells secretion of acid VI. Liver & Gallbladder Bile Synthesized by hepatocytes continuously Secreted into bile canaliculus to biliary system Provide osmotic force for production & flow of bile Hepatic duct – common bile duct – sphincter of Oddi – ampulla of Vater Recirculation in enterohepatic circulation = 4-12 times per day Proximal & middle small intestine = reabsorbed passively Distal ileum = reabsorbed actively Most abundant organic anion secreted into canaliculi Active transport of inorganic ions NaCl provide osmotic force Function of bile Solubilize biliary lipids Lipid digestion & absorption Lipid-soluble xenobiotics excretion Toxins & waste products excretion Cholesterol homeostasis Gut immunologic function Composition of bile Lipids = lecithin & cholesterol Major component NaCl = via active transport Bile acids = primary detergents & major organic solutes HCO3- = minor Proteins & bilirubin conjugated with glucuronic acid Produced in reticuloendothelial system Bile acids Primary bile acids = cholic & chenodeoxycholic acid Secondary bile acids = deoxycholic, lithocholic, & ursodeoxycholic via intestinal bacteria Steriod nucleus & aliphatic side chain C-terminus conjugated to glycine or taurine Increase hydrophilicity – lowers pKa – resists degradation High bile acids Inhibits bile acid synthesis from cholesterol Inhibits cholesterol synthesis Actively secreted against concentration gradient 100 fold greater than in plasma High canaliculi osmolarity = water flow passively into canaliculi Bile acid dependent flow Hoang 87 Electrolytes Actively secreted into bile Hepatocytes secrete bicarbonate into canaliculus Water & NaCl follows passively = bile acid independent flow Preventing kidney stones Increased bile acid secretion = increases lipid secretion Lecithin secretion is always higher than cholesterol Mixed micelle = increase solubility of free cholesterol 2 million fold Formation of kidney stones Biliary cholesterol & lecithin forms unilamellar vesicles Unilamellar vesicles coalesce into multilamellar vesicles Becomes cholesterol crystals = eventually gallstones Metastable zone = supersaturated cholesterol in bile but no crystals form Low cholesterol (but higher than normal in micelle stage) High lecithin High bile salts Gallbladder Store bile during fasting Neural control Vagal stimulation cause contraction = cephalic phase Hormonal control CCK released from intestinal mucosa (fat or protein) Gallbladder contraction & relaxation of sphincter of Oddi Stimulate pancreatic secretion of enzymes (small volume) Secretin released from intestinal mucosa (protons, fats, & proteins) Stimulate biliary epithelium to secrete bicarbonate Stimulate pancreatic secretion of biocarbonate (large volume) Actively absorbs water & electrolytes from stored bile Sodium actively reabsorbed with water following passively Bicarbonate go with sodium = pH decreases in gallbladder Identical osmotic pressure between gallbladder bile & hepatic bile and plasma VII. Carbohydrate Digestion & Absorption Small intestine Villus function in absorption Crypt function in secretion Tight junctions between each enterocyte Duodenum = minor in absorption Function in neutralization and regulation of chyme movement Jejunum & ileum = major in absorption Carbohydrates Salivary amylase & pancreatic amylase hydrolyze starch into dextrins & maltooligosaccharides -Dextinase on brush border membrane degrade -limit dextrins into glucose Glucoamylase on brush border degrade maltooligosaccharides into glucose Disaccharides degrade into specific monosaccharides on brush border Lactase make galactose & glucose Sucrase make fructose & glucose Hoang 88 Only monosaccharides are absorbed into enterocytes Glucose via SGLT-1 = sodium-dependent active transporter Water absorb with sodium and glucose/galactose Galactose via SGLT-1 Fructose via GLUT-5 = sodium-independent transporter Monosaccharides transport across basolateral membrane into portal blood GLUT-2 = sodium-independent transporter Glucose – galactose – fructose Water exit via aquaporins on basolateral membrane Disaccharides are not transported or absorbed in small intestine Lactose is degraded by lactase on intestinal border Lactase deficiency = lactose intolerance Lactose intolerance = autosomal dominant Deficiency in lactase Increased concentrations of lactose in intestinal lumen Increased osmotic effect = draws water into lumen Cause osmotic diarrhea Microflora degrade lactase = fermentation Produce hydrogen gas = distention & bloating Decreased pH of stool = acid stool Detection Disaccharide tolerance test Lactose tolerant = increased plasma glucose from lactose breakdown Peroral jejunal mucosa biopsy & enzyme assay Breath hydrogen test Adult onset Worldwide & most common Secondary lactose intolerance Intestinal insult cause shut down of lactase 3 day enterocyte turnover period Congenital Rare No breast-feeding Osmotic diarrhea Lactose intolerance Sorbitol ingestion Malabsorption VIII. Protein Digestion & Absorption Carboxypeptidase = pancreatic zymogens Recognize C-terminus of proteins Secreted by pancreas acinar cell CCK from intestinal epithelial endocrine cell Stimulated by proteins and fats Vagus stimulation Trypsinogen activated to trypsin via enterokinase Trypsin activates other zymogens Trypsinogen – chymotrypsinogen – proelastase = endopeptidases Procarboxypeptidase A & B = exopeptidases Digestion & absorption (via villus) Gastric pepsin & HCl denature and hydrolyze protein Hoang 89 Pancreatic C-terminal proteases breakdown protein Degrade into free amino acids, peptides, & dipeptides Peptides breakdown further via apical membrane amino-peptidases Apical membrane H+ dependent active transporter of amino acids & dipeptides Dipeptide transport is more efficient than free amino acid transport Intracellular dipeptides degraded into amino acids Via intracellular enterocyte aminopeptidase Only amino acids are transported by basolateral membrane amino acid transporters Enterocyte Glutamine = major energy source of small intestine Spare glucose IX. Lipid Digestion & Absorption Major classes of lipids Triglycerides Hydrolyzed by lingual & pancreatic lipase Degrade to 2 free fatty acids & 2-mono-glyceride Phospholipids Hydrolyzed by pancreatic phospholipase A2 Lecithin degrade to 1 free fatty acid & 2-lysolecithin Cholesterol esters Hydrolyzed by pancreatic cholesterol esterase Degrade to 1 free fatty acid & cholesterol Step 1: Emulsification Occur in stomach antrum & duodenum Fats become fat droplets Intact TG, lecithin, cholesterol esters Some fatty acids, monoglycerides, lysolecithin, & cholesterol Fats stimulate CCK release from I-cell Contraction of gallbladder Pancreatic enzyme secretion (small volume) & potentiates secretin on bicarbonate secretion Growth of exocrine pancreas & gallbladder mucosa Inhibit gastric motility = slows gastric emptying Exocrine pancreas secrete trypsinogen, pro-colipase, & lipase Trypsinogen converts to trypsin via duodenal enterokinase Pro-colipase converts to colipase via trypsin Colipase = positive charge Displace bile from triglycerides & facilitate lipase binding Lipase = negative charge Gallbladder release bile salts Unconjugated & deconjugated = not useful in metabolism Conjugated = useful form for metabolism of fats Negative charge at pH 7.5 Step 2: Hydrolysis Hydrolysis on droplet surface Lipase hydrolyze triglyercides to 2 fatty acids & 2-monoglycerides Long-chain fatty acids = C17 or more Short and medium chain fatty acids = C7 or less & C8-C16 Bile salts become deconjugated via microflora Reabsorbed in distal ileum via enterohepatic circulation Step 3: Packaging Long-chain fatty acids packaged into mixed micelle Contains conjugated bile & phospholipids with vitamins K, D, E, & A Step 4: Absorption Hoang 90 Short & medium-chain fatty acids with 2-monoglycerides absorb directly into portal blood system Mixed micelle contact intestinal villus due to hydrophilic surface of micelle Diffusion of 2-monoglycerides, lysolecithin, cholesterol, & Vitamins K, D, E, & A Free fatty acid transporter required for FFAs Bile salts stay in lumen until distal ileum via Na+-dependent active transport Step 5: Chylomicron formation & transport Long-chain FFA activated with CoA = FFA-CoA sER = monoglyceride pathway 2 FFA-CoA join with 2-monoglyceride to form triacylglyceride Packaged into chylomicron in cytoplasm with ApoA & ApoB rER = Phosphatidic acid pathway Form phospholipids Packaged into chylomicron in cytoplasm Lysolecithin + vitamins + cholesterol = packaged into chylomicron Chylomicron transport to golgi Chylomicrons absorbed into lymphatic system of villus Cholesterol can also form VLDL Short & medium-chain FFA reform triacylglycerides Diffuse directly from enterocyte into portal vessel X. Fluids & Electrolytes Water Output Ingest 2000 mL/day Secrete 1500 mL/day saliva Secrete 2000 mL/day gastric juice Secrete 500 mL/day bile Secrete 1500 mL/day pancreatic juices Secrete 1500 mL/day intestinal juices Reuptake Absorb 8500 mL/day in small intestine Absorb 400 mL/day in colon Excrete 100 ml/day of water Jejunum enterocyte SGLT-1 Active apical transport of sodium, water, & glucose/galactose Glucose bind first – then sodium – then water (40%) Sodium exit enterocyte via GLUT-5 Apical transport of fructose alone GLUT-2 Basolateral transport of glucose, fructose, & galactose Water diffuse into enterocyte Passively via SGLT-1 water channel = 25% 6 L = channel + coupled Passive diffusion through membrane = 35% (3L) Water exit enterocyte via aquaporin 4 & 3 Jejunum epithelial cell Crypt of Lieberkuhn Secrete chloride via CFTR = cAMP Sodium follows via electrical gradient Enters through basolateral membrane via Na/K/2Cl-transporter Water diffuse into lumen Hoang 91 Enters through basolateral membrane via AQP4 Ileum Secrete bicarbonate for titration Secretory diarrhea Cholera = toxin-mediated Neoplastic causes Cholera toxin-induced secretory diarrhea Excess secretion of chloride and water Toxin Inhibits GS-GTP degradation Increased cAMP = increased chloride permeability via CFTR Stimulate excess secretion of VIP from enteric nervous system Activate adenylate cyclase Treatment Oral rehydration therapy Increases villus absorption via SGLT-1 in crypt High sodium, glucose, & chloride Crypt secretions are independent of villus reabsorption Simultaneous events Iron absorption in duodenum & upper jejunum Via heme transporter Iron circulate in Fe3+ state XI. Propulsion & GI Movement Myogenic control Mediated by basic electrical rhythm (BER) BER = slow waves (basal electrical rhythm) Cyclic depolarization of muscle membrane Propogated aborally via nexuses to adjacent cells Interstitial cells of Cajal Form networks connecting GI musculature Pacemakers for intestinal electrical slow waves Slow wave of GI muscles Phase 0 = K+ out Resting membrane potential Phase 1 = Ca2+ in Upstroke depolarization Phase 2 = K+ out Transient repolarization Phase 3 = K+ out & Ca2+ in Plateau phase Phase 4 = K+ in Repolarization BER frequency Stomach = 3 waves / min Duodenum = 11 waves / min Ileum = 8 waves / min Colon = 3-6 waves / min Sympathetic nervous system Hoang 92 Slows GI motility Superior cervical ganglion & prevertebral ganglia Parasympathetic nervous system Increase GI motility Vagal nerve & pelvic nerve Enteric motor neurons = final pathway to GI musculature Inhibited by VIP & NO Excited by substance P & acetylcholine Muscle contractions Peristalsis = bolus propulsion Ring of contraction moves abroad Segmental = bolus mixing Ring of contraction is stationary Oropharyngeal phase Voluntary initiation of swallow Sealing of nasopharynx Protection of airway Clearing of bolus Oropharyngeal dysphagia Difficulty initiating swallow Nasopharyngeal regurgitation Pulmonary aspiration Residual Esophageal peristalsis Primary peristalsis = initiated by swallowing Lower esophageal sphincter relaxes as bolus arrives then contract at the end Secondary peristalsis = esophageal distension Lower esophageal sphincter relaxes longer and contracts later LES = primary barrier against gastroesophageal reflux Decrease LES pressure = increased reflux Secretin – CCK – progesterone – VIP – GIP Fat Increase LES pressure = decreased reflux Gastrin – Substance P – ADH – Ang II Protein Neural blockade = minimal effect on LES pressure Primary myogenic in origin Atropine (anti-cholinergic) decrease LES pressure slightly Ca2+ decrease LES pressure effectively LES relaxation Mediated by non-cholinergic, non-adrenergic (NANC) motor neurons VIP & NO Stomach functional motor regions Reservoir = body & fundus Tonic contractions Receptive relaxation to minimize change in pressure Antral pump = antrum Phasic contractions Break foods into 1 mm before emptying into duodenum Ileal brake = Lipids in distal small intestine delay gastric emptying Pacemaker region = greater curvature of corpus Determine max frequency – propagation velocity – propagation direction Hoang 93 Gastric emptying factors Increase Isotonic solutions Low caloric content Small particle size Erythromycin (Motilin agonist) Solid foods Decrease Hypertonic solutions High caloric cotent Large particle size Lipids Stress Liquid foods Vagotomy Liquids = increased emptying due to lost of receptive relaxation reflex Discomfort threshold decreased Solids = decreased emptying due to lost of antral pump Gallbladder CCK decrease sphincter of Oddi pressure & increase gallbladder contraction Morphine increase pressure and frequency of contractions Contraction is coordinated with onset of MMC in antro-duodenal region Migrating motor complex = fasting state Intestinal housekeeper Seen during interdigestive state Has phase of irregular contractile activity (phase II) before phase of regular contraction (phase III) Migrates with decreasing velocity from duodenum to ileum Return bile acids to enterohepatic circulation during interdigestive state Ileus phase I Contractile quiescence Ileus phase II Less than 100% of slow waves trigger peristaltic contractions Ileus phase III 100% of slow waves trigger peristaltic contractions Feeding state = no MMC MMC switch to segmenting motility = keep food stationary Colon movments Mixing movements Haustral migration Mass movments Colonic smooth muscle Innervated by vagus Cholinergic & non-cholinergic Sympathetics inhibit colonic contraction & frequency Anal sphincter Allows defaction via dilation of internal sphincter Provide continence via contraction of external sphincter Aganglionosis Internal anal sphincter inable to relax = cause pain External anal sphincter is still able to contract Hoang 94 XII. Gastrointestinal Pathology Gastric ulcers Mucus barrier impaired H+ secretion lower than normal But still injures gastric mucosa Gastrin level is high in blood due to lower-than-normal acid concentration Duodenal ulcers Higher than normal H+ secretion Increased number of gastric P-cells Due to trophic effect of gastrin Result in higher-than-normal gastrin levels in response to a meal Zollinger-Ellison syndrome Triad Non-beta islet cell tumors = gastrinomas Gastric acid hypersecretion Severe ulcer disease Hypergastrinemia = 1,000 pg/mL Induce ECL (histamine) & P-cells (HCl) secretion Trophic effects = prominent gastric mucosal folds Gastrinomas 1/3 originate outside pancreas Second portion of duodenum = most common 1/3 of patients develop diarrhea 50% are malignant Peptic ulcer disease = developed in 95% of patients First portion of duodenum = most common location of ulcers Diagnose by fasting serum gastrin of 1000 pg/mL or higher Treatment H2-receptor antagonists Omeprazole = H/K-ATPase inhibitor Stomatistatin analog = inhibit gastrin release Surgical removal of gastrinoma Proximal vagotomy Pernicious anemia Atrophic gastric mucosa of body of stomach Achlorhydria or hypochlorhydria Most common cause of hypergastrinemia Steatorrhea Malabsorption of lipids Pancreatic disease = cystic fibrosis or pancreatitis Hypersecretion of gastrin = inactivates pancreatic lipase Deficiency of bile acids = ileal resection Decreased intestinal cells = tropical sprue Inability to synthesize apoprotein B = inable to absorb chylomicrons Scleroderma LES hypotension due to decreased smooth muscle tone (lower 1/3 esophagus) Achalasia Loss of ganglion cells Degeneration of dorsal motor nucleus & vagal fibers Simultaneous contraction = spasms Treated with nitrates & calcium channel blockers or pneumatic dilation Diffuse esophageal spasm LES inable to relax Nutcaracker esophagus Hoang 95 High contractions with long duration Normal peristaltic rhythm Hypertensive LES Normal peristalsis Exaggerated post-relaxation contraction of LES Non-ulcer dyspepsia Lost of receptive relaxation More sensitive to gastric distension & pain Familial visceral myopathy Degenerative disease of smooth muscle Can’t contract & push foodstuffs through intestines Leads to pseudo-obstruction Neuropathic pseudo-obstruction Normal smooth muscle tissue Abnormal innervation of muscle = irregular contractions No phase I – II – III Treated with prokinetic agents = erythromycin Gallbladder diseases Primary biliary cirrhosis Destroys small bile ducts Inable to absorb fat soluble vitamins and cholesterol homeostasis Crohn’s disease Disease of distal ileum Interrupt enterohepatic circulation of bile acids Inable to absorb fats & fat soluble vitamins Gallstones = fat fertile forty female Cholesterol stones 80% cholesterol Composed of mucin glycoproteins & calcium Nucleation promoters = high biliary proteins & mucin glycoproteins & stasis Nucleation inhibitors = apolipoproteins Black pigment stones Bilirubin & mucin glycoproteins Brown pigment stones Calcium & bilirubin with cholesterol and proteins Symptoms Biliary colic pain Cholecystitis Gallbladder gangrene & perforation Pancreatitis Cholangitis Treatment Increase bile acid secretion = dissolution of gallstones Chenodeoxycholic acid Ursodeoxecholic acid Decrease cholesterol secretion Lithotripsy Cholecystectomy Gold-standard Cholestasis leads to hepatic retention & intestinal deficiency Retention of bile acids = hepatocyte injury Retention of bilirubin = jaudice Retention of cholesterol = xanthomata Deficiency of bile acids = malabsorption of triacylglycerols & vitamins K, D, E, & A Hoang 96 XIII. Helicobacter Pylori Infection H. pylori cause chronic active gastritis Leads to duodenal ulcer – gastric ulcer – gastric cancer – MALT lymphoma Higher incidence in non-Caucasian groups Whites = 19-30% Blacks = 54% Hispanics = 59% Seropositivity decreasing = decreasing antibodies to H. pylori Diagnosis Serology test Breath test = false negatives Stool antigen test Treat patients who are to be treated with antibiotics Treat only patients who test positive for H. pylori BMT = 14 days LAC = 14 days OAC = 10 days Do not treat in non-ulcer dyspepsia Treating GERD cause more heartburn Secondary Messengers cGMP Parasympathetic Acetylcholine PLC/PIP2 Sympathetic Epinephrine Histamine cAMP Secretin (pancreatic large volume) CCK (pancreatic small volume) cGMP IP3
