Cardiovascular pharmacology of 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a novel and potent cardiotonic agent with vasodilator properties.
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.
D000758:Anesthesia; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006333:Heart Failure / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006614:Hindlimb / Q000098:blood supply; D008297:Male; D011433:Propranolol / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D002316:Cardiotonic Agents; D011724:Pyridazines; D014665:Vasodilator Agents; C052228:MCI 154; D011433:Propranolol; D014700:Verapamil