Cellular mechanisms and inhibitors of gastric acid secretion

Hydrochloric acid (HCl) secretion into the gastric lumen is a specialized process driven primarily by H(+)/K(+)-ATPase or proton pump, a unique enzyme expressed in high quantities by the parietal cells. Physiological regulation of this secretion involves central signals conveyed by the vagus nerve and local mechanisms mediated by cholinergic and peptidergic fibers of the gastric wall, as well as amine or peptide secreting cells located in the fundic and antral epithelia. Among these cells, the enterochromaffin-like (ECL) cell 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 production of cAMP, a second messenger critical for the secretory machinery to be triggered. The blockade of this receptor by specific antagonists results in a dramatic albeit surmountable inhibition of HCl output. The blockade of the proton pump is an alternative means of inhibition. This can be achieved by a series of benzimidazole derivatives which specifically accumulate in the parietal cell secretory canaliculus and covalently bind to ATPase extracellular sites. The resulting inhibition is stronger and lasts longer than with the H(2) antagonists. Furthermore, it is effective regardless of the stimulatory status. Therefore, proton pump inhibitors (PPIs) are of special interest in the treatment of acid-related diseases such as gastric and duodenal ulcer, as well as reflux esophagitis.