In dispersed mucosal cells from guinea pig stomach, cimetidine as well as each of six chemically related H2 antagonists inhibited binding of [3H]histamine and the histamine-stimulated increase in cellular cyclic AMP. The inhibition by these antagonists of cyclic AMP stimulation was competitive with respect to histamine, and the K(i) values were as follows: tiotidine, 0.04 ± 0.02 μM; ranitidine, 0.15 ± 0.06 μM; etinidine (BL 5641A), 0.22 ± 0.06 μM; cimetidine, 0.81 ± 0.20 μM; SKF 92629, 0.93 ± 0.27 μM; metiamide, 1.41 ± 0.41 μM, and SKF 92408, 3.05 ± 1.02 μM. In inhibiting [3H]histamine binding, the relative as well as the absolute potencies of these antagonists were different from their potencies on inhibiting cyclic AMP stimulation. Higher concentrations of H2 antagonists were required to inhibit [3H]histamine binding than to inhibit cyclic AMP stimulation. Sufficiently high concentrations of each antagonist abolished [3H]histamine binding to gastric cells. Neither cimetidine nor histamine altered the rate of dissociation of bound [3H]histamine from gastric cells. Performing a direct comparison by plotting the log [potency] for inhibition of binding (i.e., K(d)) against the log [potency] for inhibiting cyclic AMP stimulation caused by histamine (i.e., K(i)) revealed that there was no correlation between the two sets of values, and the slope of the regression line was not significantly different from zero. These results agree with our earlier findings with histamine receptor agonists and are compatible with the hypothesis that dispersed gastric cells possess two binding sites that have different affinities for the various H2 antagonists. Occupation of the high-affinity binding sites is sufficient to inhibit the changes in cellular cyclic AMP.
|Original language||English (US)|
|Number of pages||7|
|State||Published - Jan 1 1982|
ASJC Scopus subject areas
- Molecular Medicine