The acid-peptic diseases are those disorders in which gastric acid and pepsin are necessary, but usually not sufficient, pathogenic factors. Although inherently caustic, acid and pepsin in the stomach normally do not produce damage or symptoms because of intrinsic defense mechanisms. Barriers to the reflux of gastric contents into the esophagus comprise the primary esophageal defense. If these protective barriers fail and reflux occurs, dyspepsia and/or erosive esophagitis may result. Therapies are directed at decreasing gastric acidity, enhancing the lower esophageal sphincter, or stimulating esophageal motility (Chapter 46). The stomach is protected by a number of factors, collectively referred to as "mucosal defense," many of which are stimulated by the local generation of prostaglandins and NO (Wallace, 2008). If these defenses are disrupted, a gastric or duodenal ulcer may form. The treatment and prevention of these acid-related disorders are accomplished by decreasing gastric acidity and enhancing mucosal defense. The appreciation that an infectious agent, Helicobacter pylori, plays a key role in the pathogenesis of acid-peptic diseases has stimulated new approaches to prevention and therapy.
PHYSIOLOGY OF GASTRIC SECRETION
Gastric acid secretion is a complex, continuous process in which multiple central and peripheral factors contribute to a common end point: the secretion of H+ by parietal cells. Neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin) factors all regulate acid secretion (Figure 45–1). Their specific receptors (M3, H2, and CCK2, respectively) are on the basolateral membrane of parietal cells in the body and fundus of the stomach. Some of these receptors are also present on enterochromaffin-like cells (ECL), where they regulate the release of histamine. The H2 receptor is a GPCR (Chapters 3 and 32) that activates the Gs–adenylyl cyclase–cyclic AMP–PKA pathway. ACh and gastrin signal through GPCRs that couple to the Gq–PLC-IP3–Ca2+ pathway in parietal cells. In parietal cells, the cyclic AMP and the Ca2+-dependent pathways activate H+, K+-ATPase (the proton pump), which exchanges hydrogen and potassium ions across the parietal cell membrane. This pump generates the largest ion gradient known in vertebrates, with an intracellular pH of ~7.3 and an intracanalicular pH of ~0.8.
Physiological and pharmacological regulation of gastric secretion: the basis for therapy of acid-peptic disorders. Shown are the interactions among an enterochromaffin-like (ECL) cell that secretes histamine, a ganglion cell of the enteric nervous system (ENS), a parietal cell that secretes acid, and a superficial epithelial cell that secretes mucus and bicarbonate. Physiological pathways, shown in solid black, may be stimulatory (+) or inhibitory (−). 1 and 3 indicate possible inputs from postganglionic cholinergic fibers; 2 shows neural input from the vagus nerve. Physiological agonists and their respective membrane receptors include acetylcholine (ACh), muscarinic (M), and nicotinic (N) receptors; gastrin, cholecystokinin receptor 2 (CCK2); histamine (HIST), ...
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