We have investigated the cardiovascular actions of vanadate, a naturally occurring Na+-K+-ATPase inhibitor, in six series of pentobarbitalized dogs. In three of the series, isomotic sodium vanadate was infused intravenously at progressively faster rates while arterial pressure and other parameters were measured. In two other series, the solution was infused directly into the coronary artery with coronary flow held constant during measurement of perfusion pressure, left ventricular contractile force (LVCF), and dP/dt. In one series, the agent was infused into the brachial artery with brachial artery flow held constant, and small and large vessel resistances in skin and muscle were calculated. Intravenous infusion increased arterial pressure and reduced cardiac output, the latter resulting from both decreased heart rate and stroke volume. LVCF fell. Total peripheral, pulmonary, coronary, and renal resistances rose. Coronary and renal flows fell, and the latter was associated with reduced urine flow. Intracoronary infusion raised coronary resistance, but had little effect on heart rate, LVCF, and dP/dt. Intrabrachial infusion raisedthe resistance to flow through all components of the forelimb vascular bed. Thus, in the dog, vanadate activates vascular smooth muscle, but has little effect on cardiac muscle. In the latter respect, its action differs from that of ouabain.