EVALUATION OF THE ALPHA-ADRENOCEPTOR-MEDIATED AND BETA-ADRENOCEPTOR-MEDIATED ACTIVITIES OF THE NOVEL, ORALLY ACTIVE INOTROPIC AGENT, IBOPAMINE, IN THE CARDIOVASCULAR-SYSTEM OF THE PITHED RAT - COMPARISON WITH EPININE AND DOPAMINE

  • 1 August 1987
    • journal article
    • research article
    • Vol. 242  (2) , 455-463
Abstract
The alpha and beta adrenoceptor-mediated effects of the novel, orally active inotropic prodrug, ibopamine, have been studied in the pithed rat and compared with those effects mediated by dopamine and the active form of ibopamine, epinine. All three agents produced alpha adrenoceptor-mediated pressor responses in pithed rats, and the vasopressor effects of ibopamine and epinine, but not dopamine, were potentiated by beta adrenoceptor blockade with propranolol (3 mg/kg i.v.). Cathecholamine depletion with reserpine (5 mg/kg i.p.) did not affect the vasoconstrictor response elicited by any of these agents, indicating a direct effect in the vasculature. Epinine was 10 times more potent than ibopamine or dopamine. The pressor response to all three agents was antagonized by the alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.) and the alpha-2 adrenoceptor antagonist, rauwolscine (0.5 mg/kg i.v.) suggesting the involvement of both alpha adrenoceptor subtypes in the vasopressor responses elicited by these compounds. After complete blockade of alpha adrenoceptors using a combination of phenoxybenzamine (3 mg/kg i.v.), prazosin (0.1 mg/kg i.v.) and rauwolscine (1 mg/kg i.v.), higher doses of ibopamine, epinine and dopamine produced a propranolol-sensitive, beta-1 adrenoceptor-mediated positive chronotropic response that was significantly reduced in reserpine-pretreated rats, indicating a significant indirect component in the activity of these compounds at the level of the myocardium. Epinine and dopamine were equipotent and were 10 times more potent than ibopamine as directly acting beta-1 adrenoceptor agonists. In addition, after elevation of diastolic blood pressure by i.v. infusion of angiotensin II in alpha adrenoceptor-blocked animals, all three compounds produced beta-2 adrenoceptor-mediated vasodepressor responses that were sensitive to inhibition by propranolol. Dopamine was equipotent at beta-1 and beta-2 adrenoceptors, but epinine and ibopamine were both significantly more potent at beta-2 adrenoceptors relative to beta-1 adrenoceptors. These alpha and beta adrenoceptor-mediated activities of epinine and dopamine may contribute to the intropic selectivity and peripheral hemodynamic actions produced by oral administration of ibopamine and i.v. administration of dopamine in patients with congestive heart failure.

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