Details of Mode and Mechanism of Action of Denopamine, a New Orally Active Cardiotonic Agent with Affinity for β1-Receptors

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Abstract
We investigated the detailed mode and mechanism of action of denopamine in canine right ventricular muscle. When administered in single doses, denopamine produced a positive inotropic effect (PIE) and increased cyclic AMP levels. Concentration-response curves for both variables were sigmoid. The maximum PIE of denopamine was almost the same as that produced by isoproterenol. However, the maximum increase in cyclic AMP caused by denopamine was .apprx. 65% of that attained with isoproterenol. When administered cumulatively, concentration-PIE curves for denopamine were bell-shaped, ascending at 10-7 to 10-6 M, reaching a maximum at .apprx. .times. 10-6 M which was .apprx. 75% of that attained with single administrations, and descending at higher concentrations. The bell-shaped curve, which was computer-fitted, suggested that denopamine behaves as an agonist with pD2 of 6.12 and as an antagonist with pD2 of 4.50. The PIE of denopamine was antagonized by atenolol (pA2 = 7.66) but not by ICI 118,551 (< 10-7 M), indicating that denopamine is a selective .beta.1-receptor agonist. The PIE of denopamine was augmented by 3-isobutyl-1-methylxanthine. The PIE and increase in cyclic AMP level caused by 3 .times. 10-6 M denopamine were abolished by 10-6 M atenolol or 3 .times. 10-6 M carbachol. From these results we concluded that the PIE of denopamine is derived from the mechanism of action as a selective .beta.1-receptor partial agonist. We suggested the close coupling of the .beta.1-receptor-adenylate cyclase-cyclic AMP system to positive inotropy.