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Vol. 53, Issue 4, 670-675, April 1998

(-)-CGP 12177 Causes Cardiostimulation and Binds to Cardiac Putative beta 4-Adrenoceptors in Both Wild-Type and beta 3-Adrenoceptor Knockout Mice

Alberto J. Kaumann, Frédéric Preitner, Doreen Sarsero, Peter Molenaar, Jean-Pierre Revelli, and Jean Paul Giacobino

The Babraham Institute, Cambridge CB2 4AT, UK (A.K.), Département de Biochimie Médicale, Centre Médical Universitaire, CH-1211 Genève 4, Switzerland (F.P., J.P.R., J.P.G.), and Department of Pharmacology, The University of Melbourne, Victoria 3052, Australia (D.S., P.M.)

Some blockers of beta 1- and beta 2-adrenoceptors cause cardiostimulant effects through an atypical beta -adrenoceptor (putative beta 4-adrenoceptor) that resembles the beta 3-adrenoceptor. It is likely but not proven that the putative beta 4-adrenoceptor is genetically distinct from the beta 3-adrenoceptor. We therefore investigated whether or not the cardiac atypical beta -adrenoceptor could mediate agonist effects in mice lacking a functional beta 3-adrenoceptor gene (beta 3KO). (-)-CGP 12177, a beta 1- and beta 2-adrenoceptor blocker that causes agonist effects through both beta 3-adrenoceptors and cardiac putative beta 4-adrenoceptors, caused cardiostimulant effects that were not different in atria from wild-type (WT) mice and beta 3KO mice. The effects of (-)-CGP 12177 were resistant to blockade by (-)-propranolol (200 nM) but were blocked by (-)-bupranolol (1 µM) with an equilibrium dissociation constant of 15 nM in WT and 17 nM in beta 3KO. (-)-[3H]CGP 12177 labeled a similar density of the putative beta 4-adrenoceptor in ventricular membranes from the hearts of both WT (Bmax = 52 fmol/mg protein) and beta 3KO (Bmax = 53 fmol/mg protein) mice. The affinity of (-)-[3H]CGP 12177 for the cardiac putative beta 4-adrenoceptor was not different between WT (Kd = 46 nM) and beta 3KO (Kd= 40 nM). These results provide definitive evidence that the cardiac putative beta 4-adrenoceptor is distinct from the beta 3-adrenoceptor.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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