Molecular Pharmacology, Vol 16, 417-428, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Studies on Histamine H₂ Receptors Coupled to Cardiac Adenylate Cyclase

Blockade by H₂ and H₁ Receptor Antagonists

¹ Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, Ohio 45267
² Department of Pharmacology, Mount Sinai School of Medicine of the City University of New York, New York 10029

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.

Note:
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.

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