PACAP upsets stomach theory.

Gastric acid secretion plays an essential role in the pathogenesis of peptic ulcer disease and gastroesophageal reflux disease. These chronic recurring diseases affect approximately 20–40% of the adult population (1) and result in significant morbidity, lost work, and billions of health care dollars. Although peptic ulcer disease has decreased dramatically, gastroesophogeal reflux disease is increasing in prevalence. Although hydrochloric acid in gastric juice was discovered in 1823 (2), it took three-quarters of a century before most of the major mediators — vagal acetylcholine (ACh), gastrin, and histamine — were identified. However, it would take another 75 years of advances in protein chemistry, immunoassay techniques, isolation of nearly pure cell populations by counterflow elutriation (3), and other cellular and molecular biological methods before the markedly complex regulation of acid secretion would be unveiled in the form summarized below and in ref. 4 and depicted in Figure 1. Visual and chemical stimuli, hypoglycemia, and stress signals that activate secretion originate in the central nervous system, initiating the cephalic phase of gastric control. Hypoglycemic stimuli are also received in the nucleus tractus solitarius along with taste and modulatory stimuli from the peripheral visceral organs. All of these neuronal signals integrate in the dorsal motor nucleus of the vagus and are transmitted to the stomach via vagal efferents that synapse with the enteric nervous system. The enteric nervous system consists of secondary muscarinic neurons in the gastric wall. These neurons loosely innervate mucosal endocrine cells through the release of ACh and possibly one or more neuropeptide transmitters. ACh directly stimulates acid secretion by gastric parietal (P) cells within fundic oxyntic glands; it also acts indirectly on these cells by stimulating the release of gastrin from antral G cells. Regulation of histamine production by enterochromaffin-like cells. Integrated with the cephalic phase of digestion, the peripheral gastric phase of digestion originates in response to the chemical composition and mechanical distension of a meal. Gastrin, released into the circulation from antral G cells in response to luminal aromatic amino acids and pH elevation, acts on enterochromaffin-like (ECL) cells to promote the release of histamine. Histamine, which interacts with histamine type 2 receptors on P cells, serves as the most important direct stimulus for P cells, as evidenced by the effectiveness of histamine type 2 receptor antagonists in the control of acid secretion. The direct action of gastrin on P cells is minimal in the absence of the permissive effect of costimulation by histamine. Similarly, the direct action of ACh at the M3 muscarinic receptor on the P cell is weak and transient compared with its ability to stimulate G cells and (indirectly) ECL cells. In light of the central role of histamine in this pathway, the ECL cell has emerged as a pivotal regulator of acid secretion. A variety of hormones and neurotransmitters negatively regulate acid secretion, serving to check excess acid secretion and to terminate the process after digestion is complete. Somatostatin released from D cells in the antrum and fundus acts in both a paracrine and an endocrine fashion, feeding back to G cells and ECL cells to tonically inhibit the release of gas-