PT  - JOURNAL ARTICLE
AU  - Kohi, M
AU  - Norota, I
AU  - Takanashi, M
AU  - Endoh, M
TI  - 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.
DP  - 1993 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1292--1300
VI  - 265
IP  - 3
4099  - http://jpet.aspetjournals.org/content/265/3/1292.short
4100  - http://jpet.aspetjournals.org/content/265/3/1292.full
SO  - J Pharmacol Exp Ther1993 Jun 01; 265
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.