Interaction of histamine with gastric mucosal cells. Effect of histamine agonists on binding and biological response

In dispersed cells from guinea pig fundic mucosa, histamine and each of eight chemically related analogues inhibited binding of [³H]histamine and caused a 2- to 18-fold increase in cellular cyclic AMP. The rank order of potencies of these agonists on both processes were as follows: impromidine > dimaprit > histamine > 4-methylhistamine > 2-methylhistamine > 2-thiazolylethylamine > 2-pyridylethylamine > telemethylhistamine. The relative efficacy (i.e., maximal response) on cyclic AMP generation were histamine = dimaprit > 4-methylhistamine > 2-methylhistamine > 2-thiazolylethylamine > 2-pyridylethylamine > impromidine > nordimaprit > telemethylhistamine. Although the potency of some agonists for cyclic AMP generation did not agree with that for inhibition of [³H]histamine binding, at sufficiently high concentrations all agonists abolished binding of [³H]histamine. These results confirmed earlier reports that the actions of these agonists reflect their interaction with histamine H₂ receptors to activate a common catalytic moiety of adenylate cyclase located on the parietal cells. Impromidine, a specific and highly selective H₂ agonist, was a partial agonist and its potency as an agonist was equal to its potency as an inhibitor of the action of histamine on cyclic AMP, suggesting that impromidine and histamine interact with the same class of receptors. We compared the ability of the agonists to inhibit [³H]histamine binding and to increase cyclic AMP. We found that with histamine, 4-methylhistamine, 2-methylhistamine, 2-thiazolylethylamine, and 2-pyridylethylamine there was a linear relationship between their ability to inhibit [³H]histamine binding and their ability to stimulate cyclic AMP synthesis, and the slope of the line describing this relationship was approximately 1. In contrast, with impromidine, dimaprit, and nordimaprit the line describing this relationship was nonlinear. Higher concentrations of impromidine or dimaprit were required for half-maximal inhibition of binding than for half-maximal stimulation of cyclic AMP, whereas the inverse was the case with nordimaprit. Performing a direct comparison by plotting the log (potency) for inhibition of [³H]histamine binding against the log (potency) for cyclic AMP stimulation resulted in two significantly different regression lines. We concluded that these two lines reflect the presence of two distinct classes of binding sites for [³H]histamine that may have different affinities for the various agonists. Occupation of one site (i.e., the H₂ receptor) is sufficient to stimulate the generation of cyclic AMP.