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.
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.
Kohi
M
M
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Norota
I
I
Takanashi
M
M
Endoh
M
M
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002046:Bupranolol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D004285:Dogs; D004347:Drug Interactions; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism / Q000494:pharmacology; D011412:Propanolamines / Q000378:metabolism; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011412:Propanolamines; D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; D002046:Bupranolol; C033394:CGP 12177; D002118:Calcium; C037293:denopamine; D011224:Prazosin