Regulation of the Alimentary Canal PDF

Summary

These notes cover the regulation of the alimentary canal, including saliva production, GI hormones, gastric secretions, and peptic ulcer disease. The document is designed for a physiology course at an undergraduate level.

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Regulation of the Alimentary Canal: Dr. Komnenov Page 1 of 16 Regulation of the Alimentary Canal Learning Objectives: 1. Describe the regulation of saliva production in the oral cavity. 2. Describe the role of GI hormones in regulation of...

Regulation of the Alimentary Canal: Dr. Komnenov Page 1 of 16 Regulation of the Alimentary Canal Learning Objectives: 1. Describe the regulation of saliva production in the oral cavity. 2. Describe the role of GI hormones in regulation of the alimentary canal. a. Classify the various GI hormones as hormones with true endocrine function, hormones with paracrine function (paracrines), and hormones synthesized by neurons in the GI tract (neurocrines). Note: Cells that produce the hormones will be covered in Histology lecture and the specific hormones will be mentioned. b. Describe the actions of the following “true endocrine” GI hormones: gastrin, cholecystokinin (CCK), secretin, and glucose-dependent insulinotropic peptide (GIP). c. Describe the control of the release of gastrin, cholecystokinin (CCK), secretin, and glucose-dependent insulinotropic peptide (GIP). d. Describe the source and actions of the following paracrines in the GI system: somatostatin and histamine. Add enterochromaffin-like cell (ECL cell – histamine comes from mast cells in lamina propria and ECL cells in lamina propria)? e. Describe the source and actions of the following neurocrines in the GI system: vasoactive intestinal peptide (VIP), GRP (bombesin), and enkephalins f. Describe the regulation of satiety by GI hormones. 3. Describe the sources and functions of gastric secretions. 4. Describe the three phases of HCl secretion in the stomach a. Describe the cephalic phase of HCl secretion in the stomach. b. Describe the gastric phase of HCl secretion in the stomach. c. Describe the intestinal phase of HCl secretion in the stomach. 5. Describe the inhibition of gastric HCl secretion via negative feedback 6. Describe peptic ulcer disease. a. Distinguish between the two classes of peptic ulcer: gastric ulcers and duodenal ulcers. b. Describe the role of Helicobacter pylori (H. pylori) infection in the formation of peptic ulcers. Outline: (1) Regulation of saliva production (2) GI hormones and regulation of alimentary canal (a) True endocrine hormones (b) Paracrines (c) Neurocrines (d) Regulation of Satiety by GI hormones (3) Gastric secretions (4) Three phases of HCl secretion in the stomach (5) Inhibition of gastric H+ secretion via negative feedback (6) Peptic ulcer disease Regulation of the Alimentary Canal: Dr. Komnenov Page 2 of 16 Regulation of the Alimentary Canal Clinical significance: Zollinger-Ellison syndrome (gastrinoma). The patient presents with worsening diarrhea, abdominal pain and muscle cramping, that can go on for several years. Gastric fluid pH measurement was < 2.0 despite the ongoing intravenous acid suppressant therapy. It was established that the patient has Zollinger-Ellison syndrome, a rare condition caused by gastrinoma-derived gastrin hypersecretion. (1) Regulation of saliva production Salivary secretion is exclusively under neural control by the autonomic nervous system, unlike the other GI secretions which are under both neural and hormonal control. Salivary secretion is increased by both parasympathetic and sympathetic stimulation, although parasympathetic stimulation is dominant. There is parasympathetic and sympathetic innervation of acinar and ductal cells. Stimulation of salivary cells results in increased saliva production, increased Fig. 1- Regulation of saliva secretion by the ANS. − HCO3 and enzyme secretions, and contraction of myoepithelial cells (Fig. 1). Parasympathetic innervation- carried on the facial (cranial nerve VII) and glossopharyngeal (cranial nerve IX) nerves. Activation of muscarinic receptors leads to production of inositol 1,4,5-triphosphate (IP3) and increased intracellular calcium (Ca2+) concentration, which produce the physiologic action of increased saliva secretion, primarily increasing the volume of saliva and the enzymatic component. Parasympathetic activity to the salivary glands is increased by food, smell, and nausea and by conditioned reflexes (i.e., Pavlov’s salivating dogs), and is decreased by fear, sleep, and dehydration. Regulation of the Alimentary Canal: Dr. Komnenov Page 3 of 16 Sympathetic innervation - originates in thoracic segments T1 to T3 with preganglionic nerves that synapse in the superior cervical ganglion. Activation of β- adrenergic receptors on the acinar and ductal cells leads to stimulation of adenylyl cyclase and production of cyclic adenosine monophosphate (cAMP), with the ultimate goal to increase saliva secretion. (2) GI hormones GI mucosa releases the GI hormones into the portal circulation initially. They then enter the systemic circulation and exert their actions on target cells. Four “official” GI hormones are: gastrin, cholecystokinin (CCK), secretin and glucose-dependent insulinotropic peptide (GIP) (Table 1). (a) Gastrin Secreted in response to a meal Actions: a. Increases H+ secretion by the gastric parietal cells b. Stimulates growth of gastric mucosa by stimulating the synthesis of RNA and new protein. Patients with gastrin-secreting tumors have hypertrophy and hyperplasia of the gastric mucosa. Stimuli for secretion of gastrin a. Site of secretion: G cells of the gastric antrum in response to a meal b. The most potent stimuli for gastrin secretion are phenylalanine and tryptophan amino acids c. Other stimuli: distention of the stomach, vagal stimulation (mediated by gastrin-releasing peptide (GRP)) Inhibition of gastrin secretion a. Negative feedback loop exists in the lumen of the stomach and will inhibit gastrin secretion once H+ has accumulated and the stomach contents are sufficiently acidified b. Somatostatin inhibits gastrin release (b) CCK Homologous to gastrin Released from the I cells of the duodenal and jejunal mucosa Regulation of the Alimentary Canal: Dr. Komnenov Page 4 of 16 Actions: a. Stimulates gall bladder contraction and causes relaxation of the sphincter of Oddi for secretion of bile b. Stimulates pancreatic enzyme secretion c. Potentiates secretin-induced stimulation of pancreatic HCO3 –secretion d. Stimulates growth of the exocrine pancreas e. Inhibits gastric emptying Stimuli for release: a. Small peptides and amino acids b. Fatty acids and monoglycerides (Note: triglycerides do not stimulate the release of CCK because they cannot cross intestinal cell membranes) Table 1. – Four GI hormones – sites and stimuli for secretion and actions (c) Secretin Actions: a. Reduces the amount of H+ in the lumen of the small intestine by stimulating pancreatic HCO3- secretion b. Stimulates HCO3- and H2O secretion by the liver and increases bile production c. Inhibits H+ secretion by gastric parietal cells Stimuli for release: a. Secretin is released by the S cells of the duodenum in response to both H+ and fatty acids in the lumen of the duodenum Regulatiion of the Alimentary Canal: C Dr. Komnenov K Page 5 of 16 (d d) GIP Actions: a. Sttimulates inssulin release.. Note: Oral glucose is m more effectivve than inttravenous gllucose in acttivating GIP to cause inssulin release, and thus gluucose utilizaation nhibits H+ seccretion by gaastric parietaal cells b. In Stimu uli for releasse: a. GIIP is secreted by duodennum and jejuunum b. Faatty acids, am mino acids and a orally addministered gglucose all ppotently stim mulate GIIP secretion Fig.. 2- Classificcation of neurral peptides as hormmones, paraacrines andd neurocriness Paracrines (Fig. 2) Somatosttatin and hisstamine: released from eendocrine ceells in the GII mucosa, diiffuse short distaances to act on target cellls. (a a) Somatosttatin ut the GI tracct in response to H+ in thhe lumen. Thhis Is secrreted by cellls throughou secrettion is inhibiited by vagall stimulationn Masteer inhibitor: Inhibits I the release r of all GI hormonnes nhibits gastricc H+ secretio In on Regulation of the Alimentary Canal: Dr. Komnenov Page 6 of 16 (b) Histamine Secreted by mast cells of the gastric mucosa Increases gastric H+ secretion via two mechanisms: directly, and by potentiating the effects of gastrin and vagal stimulation Neurocrines (Fig. 2) Synthesized by the neurons in the GI tract, diffuse across the synaptic cleft to the target cells GI neurocrines are: vasoactive intestinal peptide (VIP), GRP (bombesin), and enkephalins (a) VIP Released from the neurons in the mucosa and smooth muscle of the GI tract Action: Produces relaxation of GI smooth muscle, including the lower esophageal sphincter Similar to secretin, VIP stimulates HCO3- secretion and inhibits H+ secretion Secreted by pancreatic islet cell tumors and is presumed to mediate pancreatic cholera (b) GRP (bombesin) Released from vagus nerve that innervates the G cells Action: Stimulates gastrin release from G cells (c) Enkephalins (Met-enkephalin and Leu-enkephalin) Secreted from the nerves in the mucosa and smooth muscle of the GI tract One of the three opioids produced by the innate opioid system Stimulates contraction of GI smooth muscle, particularly the lower esophageal, pyloric, and ileocecal sphincters Inhibits intestinal secretion of fluid and electrolytes. This action forms the basis for the usefulness of opiates in the treatment of diarrhea. Regulation of the Alimentary Canal: Dr. Komnenov Page 7 of 16 Fig 3- Production of GI hormones by different parts of the GI tract Regulation of Satiety by GI hormones 2 hypothalamic centers regulate satiety and hunger: (a) Satiety center (inhibits appetite) located in the ventromedial nucleus of the hypothalamus (b) Feeding center (stimulate appetite) located in the lateral hypothalamic area of the hypothalamus Anorexigenic neurons release proopiomelanocortin (POMC) in the hypothalamic centers, causing decrease in appetite, and orexigenic neurons oppose this action by releasing neuropeptide Y, which stimulates appetite Leptin is secreted by fat cells. It stimulates anorexigenic neurons, and inhibits orexigenic neurons, thus decreasing appetite. Ghrelin increases appetite by stimulating orexigenic neurons and inhibiting anorexigenic neurons. Clinical significance: Zollinger-Ellison Syndrome (gastrinoma). The patient presents with worsening diarrhea, abdominal pain and muscle cramping, that have been going on Regulatiion of the Alimentary Canal: C Dr. Komnenov K Page 8 of 16 fo or several yeears. Gastric fluid pH meeasurements was < 2.0 ddespite the onngoing in ntravenous acid a suppresssant therapy.. It was estabblished that the patient hhas Zollingerr- Ellison E syndrrome (ZES), a rare condiition caused by gastrinomma-derived ggastrin hy ypersecretioon. Due too the action of gastrin, patients p with ZES presennt with hyperrplasia of gaastric mucosa. m This becomes ev vident with an a imaging pprocedure (suuch as compputed to omography scan), s presennting as thick kening foldss of the gastrric body and// or fundus. Endoscopy E caan also be usseful in diagnnosis, as it ccan reveal ullcerations. T The persistenntly lo ow pH measu t gastric flluid can be eexplained byy the action oof gastrin onn H+ urement of the seecretions (stiimulates it). Radioologic localizzation of gasstrinomas whhen ZES is ssuspected is challenging but paramount in determining g tumor stagge and identiffying optimaal managem ment strategiees. Somatostatin receptor sciintigraphy is currently thhe most sensitive methodd for primaryy tu umor localization and ev valuation of metastatic m diisease 1. Fig. 4- Gasstric cell types and their secretory prroducts (3) Gastric G secrettions (a a) Gastric ceell types andd their secrettions Four gastric g cell ty ypes: parietaal cells, chieef cells, G ceells, and muccous cells (Fig.4). The body of the sttomach conttains oxynticc glands (funundic or gastrric glands) thhat empty y their secrettory products, via ducts, into the lum men of the stoomach (Fig. 5). Regulatiion of the Alimentary Canal: C Dr. Komnenov K Page 9 of 16 The openings of th he ducts on the t gastric mucossa are called d pits, which are lined with epithelial e cellls. Deeper in n the gland are mu ucous neck cells, c parietaal (oxyntic) cells, and chief (peptic) cells. The parietal p cellss have two seecretory produucts, HCl and d intrinsic faactor. The ch hief cells haave one secreetory produuct, pepsinog gen. The an ntrum of thee stomach coontains the pyloriic glands, whhich are configured similaar to the oxynntic glands (fundic ( or Fig. 5- SStructure off the gastric gastricc glands) bu ut with deepeer pits. oxyntic ggland (fundiic or gastric gland) sshowing the various cell The pyloric gland ds contain twwo cell types:: types linning the glannd the G cells and thee mucous ceells. The G cells secrete s gastrin, not into the t pyloric dducts but intoo the circulaation. The mucou us neck cellss secrete muucus, HCO3−, and pepsinnogen. Mucuus and HCO3− have a protective, neutralizing g effect on thhe gastric muucosa. b) Mechanissm of gastricc H+ secretio (b on A majjor function of the pariettal cells is seecretion of H HCl, which aacidifies the gastricc contents to o between pH H 1 and 2. Physio ologically, th he function of o this low ggastric pH is to convert iinactive pepsinnogen, which h is secreted d by the nearrby chief cellls, to its actiive form, peppsin, a prottease that beggins the proccess of proteein digestionn. (i) Cellullar mechanissms Thhe apical meembranes coontain H+-KK+ ATPase annd Cl− channnels, and the basolatera al membran nes contain NNa+-K+ ATP Pase and Cl−- − HCCO3 exchan ngers. The cells contain carbonic anhhydrase. Cl secretion occurs as fo HC ollows (Fig. 6): 1. H2CO3 disssociates intoo H+ and HC CO3−. The H+ is secretedd with Cl− innto the lumen of the stomaach, and the HCO3− is abbsorbed intoo the blood. 2. At the apiccal membran ne, H+ is seccreted into thhe lumen of tthe stomach via the H+-K+ ATPase. Cl− follows H+ into the lum men by diffuusing throughh Cl− channels inn the apical membrane. Regulatiion of the Alimentary Canal: C Dr. Komnenov K Page 10 of 16 3. At the basolateral membranee, HCO3− is absorbed d from the cell into th he blood via a Cl−-HHCO3− exchangerr. The H 3− is absorbed HCO responsiblle for the “alkaline tide” t (high pH) that caan be observed ini gastric venous blo ood after a meal. Even ntually, this HCO3− will be secreted baack into Fig. 6- Meechanism off HCl secretiion by gastriic the GI tracct in parietal ceells pancreaticc secretions. 4. In combination, the ev vents occurriing at the apical and basoolateral membranees of gastric parietal cellss result in neet secretion oof HCl and nnet absorption n of HCO3−. ances that allter H+ secreetion (ii) Substa Th hree substances stimulate H+ secretioon by gastricc parietal cellls: a) Histaminee (a paracrinee), b) ACh (a neeurocrine), annd c) Gastrin (a hormone) Figg. 7- Agents thaat stimulate and inhibit H+ seccretion by gastric parietaal cellls Regulation of the Alimentary Canal: Dr. Komnenov Page 11 of 16 Each substance binds to a different receptor on the parietal cell and has a different cellular mechanism of action (Fig. 7). In addition, there are indirect effects of ACh and gastrin via stimulation of histamine release. a) Histamine Released from enterochromaffin-like (ECL) cells in the gastric mucosa and diffuses to the nearby parietal cells, where it binds to H2 receptors, which are coupled to adenylyl cyclase by a Gs protein. When adenylyl cyclase is activated, there is increased production of cAMP, which activates protein kinase A, leading to secretion of H+ by the parietal cells. Cimetidine blocks H2 receptors and blocks the action of histamine on parietal cells. b) ACh Released from vagus nerves innervating the gastric mucosa and binds directly to muscarinic (M3) receptors on the parietal cells. Phospholipase C is activated, which liberates diacylglycerol and IP3 from membrane phospholipids, and IP3 then releases Ca2+ from intracellular stores. Ca2+ and diacylglycerol activate protein kinases that produce the final physiologic action: H+ secretion by the parietal cells. Atropine blocks muscarinic receptors on parietal cells and, accordingly, blocks the action of ACh. ACh also increases H+ secretion indirectly by stimulating ECL cells to release histamine, which then acts on the parietal cells as described earlier. c) Gastrin Secreted into the circulation by G cells in the stomach antrum. Gastrin reaches the parietal cells by an endocrine mechanism, not by local diffusion within the stomach. Thus, gastrin is secreted from the stomach antrum into the systemic circulation and then delivered back to the stomach via the circulation. Gastrin binds to cholecystokinin B (CCKB) receptors on the parietal cells. (Note: The CCKB receptor has equal affinity for gastrin and CCK, whereas the CCKA receptor is specific for CCK.) Regulation of the Alimentary Canal: Dr. Komnenov Page 12 of 16 Like ACh, gastrin stimulates H+ secretion through the IP3/Ca2+ second messenger system. The stimuli that trigger gastrin secretion from the G cells are distention of the stomach, presence of small peptides and amino acids, and stimulation of the vagus nerves. Like ACh, gastrin also stimulates H+ secretion indirectly by causing release of histamine from ECL cells. The rate of H+ secretion is regulated by the independent actions of histamine, ACh, and gastrin, as well as by interactions among the three agents; this interaction is called potentiation. This phenomenon of potentiation has consequences for the actions of the various drugs that inhibit H+ secretion. i) For example, because histamine potentiates the actions of ACh and gastrin, H2 receptor–blocking agents such as cimetidine have a greater effect than expected: They block the direct action of histamine, and they also block the histamine-potentiated effects of ACh and gastrin. ii) In another example, ACh potentiates the actions of histamine and gastrin. A consequence of this potentiation is that muscarinic-blocking agents such as atropine block the direct effects of ACh and the ACh- potentiated effects of histamine and gastrin. (4) Three phases of HCl secretion in the stomach Three phases of HCl secretion: cephalic, gastric, and intestinal i) The cephalic phase - accounts for approximately 30% of the total HCl secreted in response to a meal. Stimuli: smelling and tasting, chewing, swallowing, and conditioned reflexes in anticipation of food. Two mechanisms promote HCl secretion in the cephalic phase (Fig. 8): (1) direct stimulation of the parietal cell by vagus nerves, which release ACh and (2) indirect stimulation of the parietal cells by gastrin. In the indirect path, vagus nerves release GRP at the G cells, stimulating gastrin secretion; gastrin enters the circulation and stimulates the parietal cells to secrete HCl. Regulatiion of the Alimentary Canal: C Dr. Komnenov K Page 13 of 16 Fig. 8- Regulatio on of HCl secretion s du uring cephaalic and gasstric phases ii) The gastric phasee - accounts for approxim mately 60% % of the total HCl secreteed in responnse to a meaal. The stimuuli for HCl seecretion in thhe gastric phhase are distention of the t stomach and the pressence of breakdown products of proteiin, amino accids and sma all peptidess. Four physiiologic mechhanisms are involvved in the gaastric phase: (1) Diistention cauuses direct vaagal stiimulation off the parietal cells. (2) In ndirect stimu ulation of thee paarietal cells via v gastrin reelease. (3) Diistention of the t stomach an ntrum and inv volves local reflexes that sttimulate gasstrin release. (4) Diirect effect of o amino acid ds and sm mall peptidess on the G ceells to FFig. 9- Effecct of eating oon acid secreetion stiimulate gastrrin release. In I ad ddition to theese physiolog gic mechaniisms, alcohool and caffein mulate ne also stim gaastric HCl seecretion. Regulation of the Alimentary Canal: Dr. Komnenov Page 14 of 16 iii) The intestinal phase accounts for only 10% of HCl secretion and is mediated by products of protein digestion. (5) Inhibition of gastric H+ secretion via negative feedback The major inhibitory control of HCl secretion is decreased pH of the gastric contents. With food in the stomach, as H+ is secreted, much of it is buffered; the gastric contents are acidified, but not as much as they would be if there were no buffers. When the food moves to the small intestine, the buffering capacity is reduced, and further H+ secretion reduces gastric pH to even lower values. This lower pH then inhibits gastrin secretion, which decreases H+ secretion. Somatostatin inhibits gastric H+ secretion through both direct and indirect pathways:  In the direct pathway, somatostatin binds to receptors on parietal cells that are coupled to adenylyl cyclase via a Gi protein, adenylyl cyclase is inhibited, and cAMP levels are reduced; in this way, somatostatin antagonizes the stimulatory effect of histamine on H+ secretion.  In the indirect pathways, somatostatin inhibits both histamine release from ECL cells and gastrin release from G cells; the net result is to reduce the stimulatory actions of histamine and gastrin. In similar fashion to somatostatin, prostaglandins also antagonize histamine’s stimulatory action on H+ secretion by activating the Gi protein and inhibiting adenylyl cyclase. (1) Peptic ulcer disease An ulcerative lesion of the gastric or duodenal mucosa. Caused by the erosive and digestive action of H+ and pepsin on the mucosa (normally protected by the layer of mucus and HCO3−). For a peptic ulcer to be created there must be (1) loss of the protective mucous barrier, (2) excessive H+ and pepsin secretion, or (3) a combination of the two. What prevents the gastric contents from eroding and digesting the mucosal epithelial cells? (1) mucous neck glands secrete mucus, which forms a gel-like protective barrier between the cells and the gastric lumen. Regulation of the Alimentary Canal: Dr. Komnenov Page 15 of 16 (2) gastric epithelial cells secrete HCO3−, which is trapped in the mucus. Should any H+ penetrate the mucus, it is neutralized by HCO3− before reaching the epithelial cells. Should any pepsin penetrate the mucus, it is inactivated in the relatively alkaline (high HCO3−) environment. Protective factors, in addition to mucus and HCO3−, are prostaglandins, mucosal blood flow, and growth factors (Fig. 10). Fig. 10- Balance of protective and damaging factors on gastroduodenal mucosa Damaging factors, in addition to H+ and pepsin, are H. pylori infection, nonsteroidal anti-inflammatory drugs (NSAIDs), stress, smoking, and alcohol consumption. Peptic ulcers are classified as either gastric or duodenal (a) Gastric ulcers Form primarily because the mucosal barrier is defective, which allows H+ and pepsin to digest a portion of the mucosa. A major causative factor in gastric ulcers is the gram-negative bacterium H. pylori Clinical Significance: Helicobacter pylori infection. H. pylori colonize the gastric mucus and release cytotoxins that damage the gastric mucosa. The bacteria colonize the gastric mucus (often in the antrum), attaches to gastric epithelial cells, and releases cytotoxins (e.g., cagA toxin) that break down the protective mucous barrier and the underlying cells. H. pylori colonizes the gastric mucus because it contains the enzyme urease, which converts urea to NH3 that alkalinizes the local environment, permitting the bacteria to survive in the otherwise acidic gastric lumen. Regulation of the Alimentary Canal: Dr. Komnenov Page 16 of 16 A diagnostic test for H. pylori is based on its urease activity. In the test, the patient drinks a solution containing 13C-urea, which is converted to 13 CO2 and NH3 in the stomach; the 13CO2 is absorbed into blood, expired by the lungs, and measured in a breath test. Surprisingly, in persons with gastric ulcers, net H+ secretory rates are lower than normal because some of the secreted H+ leaks into the damaged mucosa. In gastric ulcer disease, the secretion rate of gastrin is increased as a result of the reduced net H+ secretion (recall that gastrin secretion is inhibited by H+). (b) Duodenal ulcers More common than gastric ulcers; form because H+ secretory rates are higher than normal. If excess H+ is delivered to the duodenum, it may overwhelm the buffering capacity of the Brunner’s gland secretions and of the HCO3− in pancreatic juice. Acting with pepsin, this excess H+ digests and damages the duodenal mucosa. H. pylori infection also causes duodenal ulcer, but its role is indirect. One consequence of H. pylori colonizing the gastric mucus is inhibition of somatostatin secretion from D cells in the gastric antrum. Because somatostatin normally inhibits gastrin secretion from G cells, “inhibition of inhibition” results in increased gastrin secretion, which leads to increased H+ secretion by gastric parietal cells. In this way, there is an increased H+ load delivered to the duodenum. The gastric H. pylori infection spreads to the duodenum and inhibits duodenal HCO3− secretion. Normally, duodenal HCO3− secreted by the Brunner’s gland is sufficient to neutralize the H+ load delivered from the stomach. However, in this case, not only is excess H+ delivered to the duodenum, but less HCO3− is secreted to neutralize it. In summary, neutralization of H+ in the duodenum is insufficient, the duodenal contents become abnormally acidic, and there is an erosive action of H+ and pepsin on the duodenal mucosa. In persons with duodenal ulcers, baseline gastrin levels may be normal, but gastrin secretion in response to a meal is increased. The increased gastrin levels also exert a trophic effect on the stomach, which increases parietal cell mass References: 1. Anderson B, Sweetser S. Zollinger-Ellison Syndrome: A rare cause of chronic diarrhea and abdominal pain. J Gastroenterol Hepatol. (2017) 32(7):1281 2. Costanzo, LS. Physiology, 6th ed., Chapter 8, Elsevier: Philadelphia, PA, 2018.

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