Effects of SCH 32651 on resting and stimulated acid secretion in guinea-pig isolated fundic mucosa.

Effects of SCH 32651, a novel antisecretory and cytoprotective agent, on resting and stimulated acid secretion by the guinea-pig isolated fundic mucosa were studied. SCH 32651 inhibited resting acid secretion in proportion to concentrations in serosal solution (0.1-10 microM), the IC50 being 4.4 microM. Cimetidine and atropine at concentrations up to 100 microM were inactive. Serosal application of SCH 32651 inhibited acid secretory responses to histamine (10 microM), methacholine (1 microM) or dibutyryl cyclic AMP (0.5 mM) plus theophylline (1 mM) in a concentration-dependent manner. The IC50S against histamine, methacholine and db cyclic AMP plus theophylline were 4.2 microM, 0.71 microM and 2.9 microM, respectively. In contrast, atropine and cimetidine each at 100 microM, a concentration that entirely abolished responses to methacholine and histamine, respectively, did not affect acid responses to db cyclic AMP plus theophylline. The inhibitory effects of SCH 32651 on resting and histamine-stimulated acid secretion were readily reversible upon washing. SCH 32651 0.1 mM in the mucosal solution also greatly suppressed the resting and stimulated acid secretion. In the presence of histamine treatment, SCH 32651 concomitantly caused a marked rise in K+ entry into the mucosal solution in parallel to a decline in the appearance of H+ in the same solution. The various events demonstrated by SCH 32651 in the present study are shared by omeprazole, a potent antisecretory agent working through inhibition of gastric H+/K+-ATPase. We conclude that SCH 32651 as a potent antisecretory agent seems to act directly on the parietal cell, near or at the site of H+/K+-ATPase which is a final step in the acid secretory process triggered by various stimuli.