RT Journal Article SR Electronic T1 On the mechanism of action of the beta-1 partial agonist denopamine in regulation of myocardial contractility: effects on myocardial alpha adrenoceptors and intracellular Ca++ transients. JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1292 OP 1300 VO 265 IS 3 A1 M Kohi A1 I Norota A1 M Takanashi A1 M Endoh YR 1993 UL http://jpet.aspetjournals.org/content/265/3/1292.abstract AB Experiments were carried out to study the effects of denopamine on myocardial alpha-1 adrenoceptors in the rabbit and on intracellular Ca++ transients in the dog ventricular muscle. Denopamine displaced the specific binding of the alpha-1 receptor antagonist [3H]prazosin with high and low affinities in the membrane fraction derived from the rabbit ventricle. The positive inotropic effect (PIE) of denopamine, however, was not affected by prazosin. A beta receptor antagonist bupranolol antagonized the PIE of denopamine in a concentration-dependent manner. In the rabbit denopamine acted as a beta receptor partial agonist with an intrinsic activity of 0.8 and shifted the concentration-response curve for isoproterenol to the right (Kp = 1.5 microM). In addition, denopamine attenuated the maximal inotropic response to phenylephrine mediated by alpha-1 receptors, but did not affect the pD2 value for phenylephrine. In isolated dog right ventricular muscle, the bell-shaped concentration-response relationship for the inotropic effect of denopamine was associated with coinciding increase and decrease in the amplitude of aequorin light transients. The relationship between the increase in peak Ca++ transients and developed tension in response to denopamine was the same as the relation during administration of isoproterenol. The present results indicate that denopamine binds myocardial alpha-1 adrenoceptors with high affinity and may thereby inhibit the maximal response of phenylephrine mediated by alpha-1 receptors. The PIE of denopamine is mediated exclusively by beta receptors. The change in Ca++ sensitivity caused by denopamine may not be different from that induced by a beta receptor full agonist isoproterenol.