Cardiovascular Pharmacology of the Vasodilator-Cardiotonic Agent, 349U85

349U85 is a chemically novel, nonglycoside, noncatecholamine cardiotonic-vasodilator agent with a unique cardiovascular profile in vitro and in vivo. 349U85 and milrinone, 10(-6) to 3 x 10(-5) M each, produce concentration-dependent increases in tension development of 33-60% and 37-60%, respectively, with corresponding 5-18% and 17-55% increases in contractile rate, respectively, in guinea pig spontaneously beating isolated paired atria. In anesthetized dogs, 349U85 at 0.03-1.0 mg/kg i.v. produces dose-dependent increases in left ventricular contractility (dP/dt) of 12-159%, decreases in total peripheral resistance of 11-38%, and increases in heart rate of 3-26%. Milrinone, Cl-914, and enoximone produce comparable increases in dP/dt and decreases in peripheral resistance yet increase the heart rate a maximum of 71, 49, and 41%, respectively. Intra-arterial injection of 349U85 into the vascularly isolated hindlimb of anesthetized dogs produces dose-dependent direct vasodilation. The inotropic effect of 349U85, following a single intravenous dose, is sustained in excess of 4 h while comparable initial inotropic effects of milrinone and enoximone are sustained less than 1 and 2.5 h, respectively. 349U85 effectively reverses acute cardiac depression in anesthetized dogs with a duration exceeding that of milrinone. In conscious dogs, 349U85, at 0.1-1.0 mg/kg p.o., produces a dose-dependent positive inotropic effect (15-73%) with no significant effect on heart rate. Following a single oral dose of 349U85, the inotropic effect is sustained in excess of 6 h. Results of these studies indicate that 349U85 is a potent, long-lasting positive inotropic and vasodilator agent with minimal heart rate effect in vitro and in vivo and is different from a number of reference inodilators.