83 Gastric Physiology

The stores food and facilitates through The gastric phase begins when food reaches the a variety of secretory and motor functions. Important stomach and lasts until the stomach is empty. It accounts secretory functions include the production of acid, for 60% of the total acid secretion. The gastric phase of pepsin, intrinsic factor, mucus, and gastrointestinal hor- acid secretion has several components. Amino acids and mones. Important motor functions include food storage small peptides directly stimulate antral G cells to secrete (receptive relaxation and accommodation), grinding and , which is carried in the bloodstream to the pari- mixing, controlled emptying of ingested food, and peri- etal cells and stimulates acid secretion in an endocrine odic interprandial “housekeeping.” fashion. In addition, proximal gastric distention stimu- Hydrochloric acid (HCl) stimulates both mechani- lates acid secretion via a vagovagal reflex arc, which is cal and biochemical breakdown of ingested food. In abolished by truncal or highly selective vagotomy.Antral an acidic environment, pepsin and HCl facilitate pro- distention also stimulates antral gastrin secretion.Acetyl- teolysis. Gastric acid also inhibits the proliferation of choline stimulates gastrin release, and gastrin stimulates ingested bacteria and stimulates secretin release when release from ECL cells. Enterochromaffin-like it enters the duodenum. Parietal cells secrete HCl cells play a key role in the regulation of gastric acid secre- when one of three membrane receptor types is stimu- tion. A large part of the acid-stimulatory effects of both lated by acetylcholine (from vagal nerve fibers), gastrin acetylcholine and gastrin are mediated by histamine

(from G cells), or histamine (from enterochromaffinlike released from mucosal ECL cells. This explains why H2- [ECL] cells). Somatostatin from mucosal D cells inhibits blockers are effective inhibitors of acid secretion, even gastric acid secretion. The enzyme H+/K+-ATPase is the though histamine is only one of three parietal cell stimu- proton pump that is stored within the intracellular lants. The mucosal D cells release somatostatin, which tubulovesicles and is the final common pathway for inhibits histamine release from ECL cells and gastrin gastric acid secretion. Although electroneutral, this is an release from D cells. The function of D cells is inhibited energy-requiring process, because the hydrogen is by Helicobacter pylori infection and leads to an exagger- secreted against a gradient of at least 1 millionfold, ated acid secretory response. which explains why the parietal cell is the most mito- The intestinal phase of gastric secretion is poorly chondria-dense mammalian cell (about one third by understood and is thought to be mediated by an unknown volume). During acid production, K+ and Cl− are also hormone from the proximal small bowel mucosa in secreted into the secretory canaliculus through separate response to luminal chyme.This phase starts when gastric channels. emptying begins and continues as long as nutrients Food ingestion is the physiologic stimulus for acid remain in the proximal small intestine. It accounts for secretion. The acid secretory response occurs in three about 10% of meal-induced acid secretion. phases: cephalic, gastric, and intestinal. The cephalic or Interprandial basal acid secretion is 2 to 5mEq of HCl vagal phase begins with the thought, sight, smell, and/or per hour, about 10% of maximal acid output, and it is taste of food. These stimuli activate several cortical and greater at night. Basal acid secretion probably con- hypothalamic sites, and signals are transmitted to the tributes to the relatively low bacterial counts found in the stomach by the vagal nerves. Acetylcholine is released, stomach. Basal acid secretion is reduced 75% to 90% by leading to stimulation of ECL cells and parietal cells. The vagotomy or H2-receptor blockade. cephalic phase accounts for 30% of total acid secretion Pepsinogen secretion from chief cells is primarily stim- in response to a meal. ulated by food ingestion; acetylcholine is the most impor-

201 202 Part XII. Gastrointestinal Disorders tant mediator. Somatostatin inhibits pepsinogen secre- is mediated in a paracrine fashion by somatostatin tion. Pepsinogen I is produced by chief cells in acid- released from antral D cells. Gastrin also is trophic to producing glands; pepsinogen II is produced by chief cells gastric parietal cells and to other gastrointestinal mucosal in both acid-producing and gastrin-producing antral cells. Important causes of hypergastrinemia include per- glands. Pepsinogen is cleaved to the active pepsin enzyme nicious anemia, acid-suppressive medication, gastrinoma, in an acidic environment and is maximally active at a pH retained antrum following distal gastrectomy and Bill- of 2.5. The enzyme catalyzes the hydrolysis of proteins roth II surgery, and vagotomy. and is denatured at alkaline pH. Activated parietal cells Somatostatin is produced by D cells located through- secrete intrinsic factor in addition to HCl. Intrinsic factor out the gastric mucosa. The major stimulus for somato- binds to luminal vitamin B12, and the complex is absorbed statin release is antral acidification; acetylcholine from in the terminal ileum via mucosal receptors. vagal nerve fibers inhibits its release. Somatostatin inhibits acid secretion from parietal cells, gastrin release Gastric Mucosal Barrier from G cells, and histamine release from ECL cells. The primary effect of somatostatin is mediated in a paracrine fashion, but an endocrine (bloodstream) effect is pos- The stomach’s durable resistance to autodigestion by sible also. caustic HCl and active pepsin is multifaceted.When these Gastrin-releasing peptide (GRP) in the antrum stimu- defenses break down, ulceration occurs. The mucus and lates both gastrin and somatostatin release by binding to bicarbonate secreted by surface epithelial cells form an receptors on the G and D cells. Nerve terminals end near unstirred mucous gel with a favorable pH gradient. Cell the mucosa in the gastric body and antrum, which are rich membranes and tight junctions prevent hydrogen ions in GRP immunoreactivity. When GRP is given peripher- from gaining access to the interstitial space. Hydrogen ally it stimulates acid secretion, but when it is given cen- ions that occasionally break through are buffered by the trally into the cerebral ventricles of animals, it inhibits alkaline tide created by basolateral bicarbonate secretion acid secretion, apparently via a pathway involving the from stimulated parietal cells. Any sloughed or denuded sympathetic nervous system. surface epithelial cells are rapidly replaced by migration Ghrelin is a small peptide that is produced primarily in of adjacent cells via a process called restitution. Mucosal the stomach. Ghrelin is a potent secretagogue of pituitary blood flow is crucial in maintaining a healthy mucosa by growth hormone but not adrenocorticotropic hormone, providing nutrients and oxygen for the cellular functions follicle-stimulating hormone, luteinizing hormone, pro- involved in cytoprotection. “Back-diffused” hydrogen is lactin, or thyroid-stimulating hormone. Ghrelin appears buffered and rapidly removed by the rich blood supply. to be an orexigenic regulator of appetite. When ghrelin When barrier breakers such as bile or aspirin lead to is elevated, appetite is stimulated, and when it is sup- increased back-diffusion of hydrogen ions from the pressed, appetite is suppressed. The gastric bypass oper- lumen into the lamina propria and submucosa, there is ation is associated with suppression of plasma ghrelin a protective increase in mucosal blood flow. If this pro- levels and appetite. tective response is blocked, gross ulceration can occur. Important mediators of these protective mechanisms include prostaglandins, nitric oxide, intrinsic nerves, Gastric Motility and Emptying and peptides such as calcitonin gene–related peptide and gastrin. Misoprostol is a commercially available Gastric motor function has several purposes. Interpran- prostaglandin E analogue that prevents gastric mucosal dial motor activity clears undigested debris, sloughed damage in chronic nonsteroidal anti-inflammatory drug cells, and mucus. When feeding begins, the stomach users. In addition to these local defenses, there are impor- relaxes to accommodate the meal. Regulated motor tant protective factors in swallowed saliva, duodenal activity breaks down food into small particles and con- secretions, and pancreatic and biliary secretions. trols the output into the duodenum. The stomach accom- plishes this via coordinated smooth muscle relaxation Gastric Hormones and contraction of the proximal, distal, and pyloric gastric segments. Smooth muscle myoelectric potentials are Gastrin is produced by antral G cells and is the major translated into muscular activity, which is modulated by hormonal stimulant of acid secretion during the gastric extrinsic and intrinsic innervation and hormones. phase. A variety of molecular forms exist: the large The intrinsic innervation consists of ganglia and nerves majority of gastrin released by the human antrum is G17. constituting the with a variety of Luminal peptides and amino acids are the most potent neurotransmitters. Important excitatory neurotransmit- stimulants of gastrin release, and luminal acid is the most ters include acetylcholine, the tachykinins, substance P, potent inhibitor of gastrin secretion. The inhibitor effect and neurokinin A. Important inhibitory neurotransmit- 83. Gastric Physiology 203 ters include nitric oxide and vasoactive intestinal peptide. Specialized cells in the muscularis propria, interstitial Serotonin has been shown to modulate both contraction cells of Cajal, also are important modulators of gastroin- and relaxation. A variety of other molecules affect motil- testinal motility.They amplify both cholinergic excitatory ity, including GRP, histamine, neuropeptide Y, norepi- and nitrergic inhibitory input to the smooth muscle of the nephrine, and endogenous opioids. stomach and intestine.