Gastric acid and pepsin in the stomach normally do not produce damage or symptoms of acid-peptic diseases because of intrinsic defense mechanisms. 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 PGs and NO. If these defenses are disrupted, a gastric or duodenal ulcer may form. The treatment and prevention of 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 revolutionized approaches to prevention and therapy of these common disorders.
Barriers to the reflux of gastric contents into the esophagus comprise the primary esophageal defense. If these protective barriers fail and reflux occurs, dyspepsia or erosive esophagitis may result. Therapies are directed at decreasing gastric acidity, enhancing the tone of the lower esophageal sphincter, and stimulating esophageal motility (see Chapter 50).
cAMP: cyclic adenosine monophosphate
CNS: central nervous system
CYP: cytochrome P450
DU: duodenal ulcer
ECL: enterochromaffin-like cell
ENS: enteric nervous system
GERD: gastroesophageal reflux disease
GPCR: G protein–coupled receptor
GRP: gastrin-releasing peptide
GU: gastric ulcer
IP3: inositol 1,4,5-trisphosphate
NO: nitric oxide
NSAID: nonsteroidal anti-inflammatory drug
OTC: over the counter
PK: protein kinase
PLC: phospholipase C
PPI: proton pump inhibitor
PHYSIOLOGY OF GASTRIC SECRETION
Gastric acid secretion is a complex and continuous process: Neuronal (ACh, GRP); paracrine (histamine); and endocrine (gastrin) factors regulate the secretion of H+ by parietal cells (acid-secreting cells) (Figure 49–1). Their specific receptors (M3, BB2, 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 ECL cells, where they regulate the release of histamine. The H2 receptor is a GPCR that activates the Gs–adenylyl cyclase–cyclic AMP–PKA pathway (see Chapters 3 and 39). ACh and gastrin signal through GPCRs that couple to the Gq-PLC-IP3-Ca2+ pathway in parietal cells; GRP uses the same signaling pathway to activate gastrin secretion from G cells. In parietal cells, the cyclic AMP and the Ca2+-dependent pathways activate H+,K+-ATPase (the proton pump), which exchanges ...