Inhibition of acid secretion in isolated gastric glands by substituted benzimidazoles.

A new class of gastric acid inhibitors, substituted benzimidazoles (H 83/69 and H 149/94), have been tested in an isolated rabbit gastric gland preparation. Acid formation in the glands was stimulated by histamine, dibutyryl cAMP (DBcAMP), and high extracellular K+ concentrations, and the glandular secretory response was measured by changes in oxygen consumption and in accumulation of the weak base [14C]aminopyrine (AP). The substituted benzimidazoles inhibited AP accumulation induced by all stimulants in a dose-dependent noncompetitive manner. In contrast, cimetidine only inhibited histamine-induced AP accumulation. Basal AP accumulation, not affected by cimetidine, was also inhibited by the substituted benzimidazoles, as was the increase in glandular oxygen consumption produced by the addition of histamine and DBcAMP. Basal oxygen consumption was inhibited by about 15%. The substituted benzimidazoles, like AP, are weak bases and were also found to accumulate in the glands. Semiquantitative morphological studies of glands stimulated by histamine plus theophylline did not show any change in the enlarged secretory surface area after stimulation in the presence of inhibitory concentrations of H 149/94 (10(-4) M). The results suggest that substituted benzimidazoles have a mechanism of action different from that of H2-receptor antagonists and indicate a very distal site of action in the events leading to acid formation.