Effects of H2-receptor antagonists on 3H-cimetidine binding and histamine-stimulation of cellular cAMP in isolated guinea pig gastric glands.

3H-Cimetidine binding to plasma membranes of isolated guinea pig gastric glands was investigated, and the effects of five H2-receptor antagonists on 3H-cimetidine binding and histamine stimulation of cellular cAMP were compared. Of the five cations tested, Cu++ markedly increased specific 3H-cimetidine binding. 3H-Cimetidine had high affinity (Kd = 0.41 x 10(-6) M) and low affinity (Kd = 12.8 x 10(-6) M) binding sites. Cimetidine and etintidine were potent inhibitors of 3H-cimetidine binding, while famotidine, ranitidine and TZU-0460 were not. Histamine stimulation of cellular cAMP was competitively inhibited by H2-receptor antagonists yielding pA2 values of 6.41 for cimetidine, 6.82 for etintidine, 6.87 for ranitidine, 6.94 for TZU-0460 and 7.60 for famotidine. Because the KB value (log KB = -pA2) of 0.39 x 10(-6) M for cimetidine is close to the Kd value for the high affinity 3H-cimetidine binding site, it is presumed to represent a part of the H2-receptor, and the relative potency of etintidine against cimetidine in inhibiting 3H-cimetidine binding is similar to that in inhibiting histamine stimulation of cellular cAMP. These results suggest that imidazole-derived H2-receptor antagonists (cimetidine and etintidine) and non-imidazole H2-receptor antagonists (famotidine, ranitidine and TZU-0460) compete with histamine at different sites on the H2-receptor of the gastric glands.