The present experiments were designed to examine the reflex cardiovascular effects of intracoronary administration of acetylstrophanthidin in the conscious dog. Administration of 4 micrograms/kg of this agent into the left circumflex coronary artery increased left ventricular dP/dtmax but had no effect on mean arterial pressure, heart rate, renal resistance, or iliac resistance. The positive inotropic effects of acetylstrophanthidin were less under control conditions (+599 mmHg/s) than during bilateral cervical vagal cold block (+850 mmHg/s, P less than 0.05); however, interruption of vagal efferent influences (atropine) alone did not alter the contractile effects of acetylstrophanthidin. Interruption of sympathetic efferent influences on the heart with either the nicotinic ganglionic receptor antagonist, hexamethonium, or the beta 1-adrenergic receptor antagonist, metoprolol, also augmented the inotropic effects of acetylstrophanthidin to a degree similar to that observed with vagal cold block. In contrast to the effects observed with acetylstrophanthidin, the inotropic effects of intracoronary administration of calcium gluconate were not altered by vagal cold block or any other conditions examined in this study. We conclude that interruption of vagal afferents results in an augmentation of the positive inotropic actions of acetylstrophanthidin and that this augmented inotropic effect can be accounted for by interruption of cardiac vagal afferent-mediated restraint on sympathetic outflow to the heart.