PHARMACOLOGICAL ASPECTS OF ACID-SECRETION

The secretion of gastric acid is regulated both centrally and peripher ally. The finding that H-2-receptor antagonists are able to reduce or abolish acid secretion due to vagal, gastrinergic, and histaminergic s timulation shows that histamine plays a pivotal role in stimulation of the parietal cell. In the rat, the fundic histamine is released from the ECL cell, in response to gastrin, acetylcholine, or epinephrine, a nd histamine release is inhibited by somatostatin or by the H-3-recept or ligand, R-alpha-methyl histamine. The parietal cell has a muscarini c, M3, receptor responsible for [Ca](i) regulation. Blockade of muscar inic receptors by atropine can be as effective as H-2-receptor blockad e in controlling acid secretion. However, general effects on muscarini c receptors elsewhere produce significant side effects. The different receptor pathways converge to stimulate the gastric H+,K+-ATPase, the pump responsible for acid secretion by the stomach. This enzyme is an alpha,beta heterodimer, present in cytoplasmic membrane vesicles of th e resting cell and in the canaliculus of the stimulated cell. It has b een shown that acid secretion by the pump depends on provision of K+Cl - efflux pathway becoming associated with the pump. As secretion occur s only in the canaliculus, this K+Cl- pathway is activated only when t he pump inserts into the canalicular membrane. Transport by the enzyme involves reciprocal conformational changes in the cytoplasmic and ext racytoplasmic domain. These result in changes in sidedness and affinit y for H3O+ and K+, enabling active H+ for K+ exchange. The acid pump i nhibitors of the substituted benzimidazole class, such as omeprazole, are concentrated in the canaliculus of the secreting parietal cell and are activated there to form sulfenamides. The omeprazole sulfenamide, for example, reacts covalently with two cysteines in the extracytopla smic loops between the fifth and sixth transmembrane and the seventh a nd eighth transmembrane segments of the alpha subunit of the H+,K+-ATP ase, forming disulfide derivatives. This inhibits ATP hydrolysis and H + transport, resulting in effective, long-lasting regulation of acid s ecretion. Therefore, this class of acid pump inhibitor is significantl y more effective and faster acting than the H-2 receptor antagonists. K+ competitive antagonists bind to the M1 and M2 transmembrane segment s of the a subunit of the acid pump and also abolish ATPase activity. These drugs should also be able to reduce acid secretion more effectiv ely than receptor antagonists and provide shorter acting but complete inhibition of acid secretion.