In vitro and in vivo assessment of the cardiovascular effects of the cardiotonic drug MDL 19205.

: Various in vitro and in vivo techniques were used to evaluate the cardiovascular actions of MDL 19205, a new cardiotonic agent. In the anesthetized dog, intravenous administration of MDL 19205 (0.1-1 mg/kg) produced marked increases in cardiac contractile force which were accompanied by small increases in heart rate and minor decreases in blood pressure. These effects were not altered by alpha- or beta-adrenergic receptor blockade, reserpine pretreatment, or bilateral carotid sinus denervation. In isolated cat cardiac tissues, MDL 19205 (10(-5)-10(-3) M) produced a selective inotropic effect relative to isoproterenol and, unlike isoproterenol, was nonarrhythmogenic. Adrenergic beta-receptor or histamine H1-receptor blockade did not modify the inotropic effects of MDL 19205 in guinea pig atria. The vasodilatory effect of MDL 19205 in the canine isolated pump-perfused hindlimb preparation was not significantly attenuated by surgical sympathectomy, alpha- or beta-adrenergic receptor blockade, cholinergic or histaminergic receptor blockade, or indomethacin pretreatment, indicating that MDL 19205 produced direct relaxation of vascular smooth muscle. MDL 19205 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. The pharmacological profile revealed by these and other studies suggests that MDL 19205 should be useful in the clinical treatment of congestive heart failure.