We compared the systemic and coronary hemodynamic effects of four successive doses of pinacidil, a new experimental antihypertensive agent, with hydralazine in awake normal dogs. The two agents produced comparable dose-dependent decreases in total peripheral vascular resistance, but, compared to hydralazine, pinacidil has only a minor inotropic effect, as evidenced by the changes in cardiac output, left ventricular dP/dt and dP/dt/P. Unlike hydralazine, pinacidil produced the changes only after aortic pressure had decreased significantly. The inotropic effects of pinacidil were abolished by propranolol pretreatment, suggesting that these effects are mediated by beta adrenergic receptors, probably secondary to sympathetic activation of the baroreceptor reflex. In addition, although myocardial oxygen consumption and coronary blood flow were increased by both hydralazine and pinacidil, left ventricular work increased only after hydralazine administration. Coronary sinus oxygen saturation increased to a much greater degree after pinacidil (from 20 +/- 2 to 70 +/- 4%) than after hydralazine and the fall in myocardial oxygen extraction was greater with pinacidil, suggesting that pinacidil has a greater coronary vasodilator effect. Finally, the systemic and coronary vasodilator effects of pinacidil probably are not mediated via prostaglandins, beta receptor stimulation or adenosine because indomethacin, propranolol or aminophylline treatment had no effect upon its vascular effects. Thus, it appears that pinacidil differs from hydralazine in its mode of action and probably exerts its vasodilator effect by a direct action on vascular smooth muscle.