In particulate preparations from guinea pig ventricle, histamine caused a three to five-fold stimulation of basal adenylate cyclase activity. The H2 antagonist, cimetidine, displaced the dose-response curve of histamine to the right in a parallel fashion suggesting competitive antagonism. Schild plots were linear with slopes near one, consistent with a competitive inhibition mechanism. The affinity of cimetidine was independent of whether histamine or the pure H2 agonist dimaprit was used to activate the enzyme. A series of ten H2 antagonists related to cimetidine were examined for inhibition of histamine-stimulated cyclase activity. An excellent correlation was found between the affinities of these compounds for the H2 linked cyclase system and for physiological H2 receptors. Although several H1 antagonists also appeared to be competitive inhibitors of the histamine-activated cyclase, their affinities did not correlate with data for H1 receptors in the guinea pig ileum. The affinities of the antagonists, both H2 and H1, on the cardiac adenylate cyclase were virtually identical to their affinities for a histamine-stimulated cyclase from brain. The results suggest that the histamine-sensitive adenylate cyclase in ventricular muscle quantitatively retains the properties of an H2 receptor system as defined physiologically and that the histamine receptors in ventricle and brain are not distinguishable. This study provides further strong evidence that histamine's inotropic and chronotropic effects on the intact heart are mediated by cAMP through H2 receptor activation.
ACKNOWLEDGMENT The authors extend their sincere appreciation to Dr. C. R. Ganellin (Smith Kline and French Laboratories, England) for his generous gift of the H2 antagonists used in this study and to Drs. Kanof and Greengard for sending us their manuscripts prior to publication.
- Copyright © 1979 by Academic Press, Inc.