Cardiovascular pharmacology of 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a novel and potent cardiotonic agent with vasodilator properties.

Abstract

The cardiovascular profile of 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (MCI-154), a novel cardiotonic agent structurally different from cardiac glycosides and beta-adrenoceptor agonists, was investigated in vivo. In anesthetized, open-chest dogs, MCI-154 (0.3-100 micrograms/kg i.v., bolus injection) produced dose-dependent increases in dP/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance with a relatively small increase in heart rate. The positive inotropic effect of MCI-154 was more potent than those of amrinone and milrinone. In anesthetized, intact-chest dogs, infusion of MCI-154 (0.3-3 micrograms/kg/min i.v.) also exerted a positive inotropic effect. P.o. administrations of MCI-154 (10-300 micrograms/kg) increased dP/dtmax in conscious beagle dogs. The cardiotonic effect of MCI-154 was not attenuated by blockade of autonomic receptors, catecholamine depletion and prostaglandin synthesis inhibition. MCI-154 (0.3-30 micrograms i.a.) produced a direct vasodilator effect in the canine hind-limb. MCI-154 (3 and 30 micrograms/kg i.v.) was effective in heart failure models induced with high doses of propranolol or verapamil. The potent cardiotonic and vasodilator activities of MCI-154 revealed by the present study suggest that this agent would be an effective remedy for the treatment of heart failure.