The effect of prostaglandin A1 (PGA1) on myocardial contractile force (MCF) was compared in the open-chest dog with that of two widely used potent antihypertensive agents, nitroprusside and diazoxide. In one group of animals a strain gage arch was sutured onto the right ventricular wall. The three agents were given intravenously as bolus injections before and during ganglion and beta-adrenergic blockade. Before blockade PGA1 markedly increased MCF, nitroprusside did so to a lesser degree, and the effect of diazoxide was variable. During blockade PGA1 still increased MCF, whereas diazoxide markedly reduced MCF and nitroprusside had no effect. To eliminate the effect of changes in preload or afterload on MCF, a second group of animals was studied using a left ventricular bypass technique and ganglion blockade. The strain gage arch was sutured onto the left ventricle. Again, PGA1 increased, diazoxide decreased, and nitroprusside had no effect on MCF. PGA1 appears to have a direct positive inotropic effect, diazoxide a direct negative inotropic effect, and nitroprusside no direct effect on myocardial contractility. The present study further dictates added caution in the use of diazoxide in patients taking sympatholytic medication. PGA1, on the other hand, may represent an additional effective agent in the treatment of hypertensive emergencies. The combination of cardiovascular effects of PGA1, namely, vasodilation, positive inotropism, and natriuresis, make it a potentially useful adjunct in the treatment of severe nonhypertensive congestive heart failure.