Cellular mechanisms and inhibitors of gastric acid secretion

Hydrochloric acid (HCl) secretion into the gastric lumen is a specialized p rocess driven primarily by H+/K+-ATPase or proton pump, a unique enzyme exp ressed in high quantities by the parietal cells. Physiological regulation o f this secretion involves central signals conveyed by the vagus nerve and l ocal mechanisms mediated by cholinergic and peptidergic fibers of the gastr ic wall, as well as amine or peptide secreting cells located in the fundic and antral epithelia. Among these cells, the enterochromaffin-like (ECL) ce ll plays a major role: it responds to gastrinic, cholinergic and adrenergic stimulations to secrete histamine, which in turn activates an H-2 receptor on the parietal cell. The H-2 receptor is responsible for intracellular pr oduction of cAMP, a second messenger critical for the secretory machinery t o be triggered. The blockade of this receptor by specific antagonists resul ts in a dramatic albeit surmountable inhibition of HCl output. The blockade of the proton pump is an alternative means of inhibition. This can be achi eved by a series of benzimidazole derivatives which specifically accumulate in the parietal cell secretory canaliculus and covalently bind to ATPase e xtracellular sites. The resulting inhibition is stronger and lasts longer t han with the H-2 antagonists. Furthermore, it is effective regardless of th e stimulatory status. Therefore, proton pump inhibitors (PPIs) are of speci al interest in the treatment of acid-related diseases such as gastric and d uodenal ulcer, as well as reflux esophagitis. (C) 1999 Prous Science. All r ights reserved.