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

Abstract

1 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. 2 SCH 32651 inhibited resting acid secretion in proportion to concentrations in serosal solution (0.1–10 μm), the IC₅₀ being 4.4 μm. Cimetidine and atropine at concentrations up to 100 μm were inactive. 3 Serosal application of SCH 32651 inhibited acid secretory responses to histamine (10 μm), methacholine (1 μm) 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 μm, 0.71 μm and 2.9 μm, respectively. In contrast, atropine and cimetidine each at 100 μm, a concentration that entirely abolished responses to methacholine and histamine, respectively, did not affect acid responses to db cyclic AMP plus theophylline. 4 The inhibitory effects of SCH 32651 on resting and histamine-stimulated acid secretion were readily reversible upon washing. 5 SCH 32651 0.1 mm in the mucosal solution also greatly suppressed the resting and stimulated acid secretion. 6 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. 7 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.