Interaction of histamine with gastric mucosal cells. Effect of histamine agonists on binding and biological response
Batzri, S.; Harmon, J.W.; Thompson, W.F.
Molecular Pharmacology 22(1): 33-40
1982
ISSN/ISBN: 0026-895X PMID: 6289074 Document Number: 185012
In dispersed cells from guinea pig fundic mucosa, histamine and each of 8 chemically related analogs inhibited binding of [3H]histamine and caused a 2- to 18-fold increase in cellular cAMP. 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 cAMP generation was histamine = dimaprit > 4-methylhistamine > 2-methylhistamine > 2-thiazolylethylamine > 2-pyridylethylamine > imipromidine > nordimaprit > telemethylhistamine. Although the potency of some agonists for cAMP generation did not agree with that for inhibition of [3H]histamine binding, at sufficiently high concentrations all agonists abolished binding of [3H]histamine. The actions of these agonists may 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 cAMP, suggesting that impromidine and histamine interact with the same class of receptors. The ability of the agonists to inhibit [3H]histamine binding and to increase cAMP was compared. 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 cAMP synthesis and the slope of the line describing this relationship was .apprx. 1. 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 cAMP, while 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 cAMP stimulation resulted in 2 significantly different regression lines. These 2 lines may reflect the presence of 2 distinct classes of binding sites for [3H]histamine that may have different affinities for the various agonists. Occupation of 1 site (i.e., the H2 receptor) is apparently sufficient to stimulate the generation of cAMP.