The action of metiamide, a specific histamine H2-receptor antagonist, on the acid secretory response to various gastric stimuli in the perfused isolated whole mouse stomach is described. 2. Two kinds of stomach preparations, the non-distended stomach and distended stomach, were used. The distended stomach gave a marked and dose-related acid secretory response to histamine (10(-6) to 10(-3) M), pentagastrin (10(-8) to 10(-5) M), acetylcholine (5 X 10(-5) to 10(-5) M), eserine (10(-5) to 10(-3) M) to dibutyryl cyclic AMP (5 X 10(-5) to 10(-3) M). In the nondistended stomach, dibutyryl cyclic AMP regularly stimulated acid secretion in a dose-dependent manner; in contrast to dibutyryl cyclic AMP, histamine, pentagastrin or acetylcholine did not always stimulate acid secretion. 3. Histamine or pentagastrin but not acetylcholine always caused significant stimulation of acid secretion from the non-distended stomach in the presence of a phosphodiesterase inhibitor such as caffeine, theophylline or the I.C.I. compound, 63197. At the concentration of 10(-4) M, these phosphodiesterase inhibitors markedly potentiated the stimulatory effect of histamine or pentagastrin on acid secretion and the order of effectiveness was 63197 greater than theophylline greater than caffeine. 63197 also produced profound potentiation of histamine- or pentagastrin-stimulated acid secretion in the distended stomach. 4. Metiamide (5 X 10(-5) to 10(-4) M) did not antagonize stimulation of acid secretion by dibutyryl cyclic AMP in the non-distended or distended stomach. 5. In the distended stomach, metiamide (5 X 10(-4) M) produced significant inhibition of histamine-stimulated acid secretion with a linear and parallel displacement of the histamine dose--response curve to the right. Although at this concentration metiamide did not depress maximal acid secretory response to histamine, it caused marked reduction of the maximal acid secretory response attainable with pentagastrin. 6. In the distended stomach, metiamide (5 X 10(-5) M) did not cause significant inhibition of acetylcholine-induced acid secretion. Atropine (5 X 10(-6) M) abolished the stimulatory effect of acetylcholine; it also produced marked inhibition of pentagastrin-stimulated acid secretion but it had little effect on acid secretion induced by histamine. 7. The present results indicate that metiamide inhibited histamine-induced acid secretion by competitive antagonism of the histamine H2-receptor, but its inhibitory effect on pentagastrin-induced acid secretion seemed to be of non-competitive nature. The failure of metiamide to inhibit acid secretion induced by dibutyryl cyclic AMP suggests that cyclic AMP might regulate gastric acid secretion at a site beyond the histamine H2-receptor activation. It is also considered that the present results support the hypothesis that cyclic AMP may be involved in histamine- or pentagastrin-induced acid secretion in the isolated mouse stomach. 8...
