Characterization of the cardiovascular activities of a new cardiotonic agent, MDL 17043 (1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazole-2-one)

Abstract

The cardiovascular actions of 1,3-dihydro-4-methyl-5[4-(methylthio)-benzoyl]-2H-imidazol-2-one (MDL 17043), a new noncatecholamine, nonglycoside cardiotonic agent, were examined in vivo in anesthetized dogs and in vitro in isolated cat atrial and papillary muscle preparations and guinea pig atria. In the anesthetized dog, intravenous administration of MDL 17043 (0.1--1 mg/kg) produced marked increases in cardiac contractile force which were accompanied by minor increases in heart rate and small decreases in blood pressure. These effects were not altered by alpha- or beta-adrenergic receptor blockade, catecholamine depletion produced by reserpine, bilateral vagotomy, or by bilateral carotid sinus denervation. MDL 17043 (10(-5)--10(-3) M) produced positive inotropic effects in isolated papillary muscle and left atrial strips of the cat that were much greater than the positive chronotropic effects seen in the spontaneously beating right atrium of the cat. The in vitro inotropic effects of MDL 17043 in guinea pig electrically driven left atrial strips were not modified by adrenergic beta-receptor or histamine H1-receptor blockade. The vasodilatory effect of MDL 17043 in the canine isolated pump-perfused hindlimb preparation was not attenuated by surgical sympathectomy, alpha- or beta-adrenergic receptor blockade, cholinergic or histaminergic receptor blockade, or by prostaglandin synthesis inhibition, indicating that MDL 17043 produces direct relaxation of vascular smooth muscle. MDL 17043 was found to be safe and effective when administered acutely in combination with ouabain, hydralazine, nitroglycerin, or furosemide, agents commonly used in the treatment of congestive heart failure.