The rapid i.v. administration of digitalis has recently been shown to cause a substantial increase in coronary vascular resistance in the normal heart. This neurogenically mediated decrease in coronary blood flow would be potentially detrimental if it occurred during ischemia. The present study evaluates the effects of i.v. acetylstrophanthidin and digoxin on coronary vascular resistance during acute global ischemia in 29 dogs anesthetized with chloralose and urethane. Under these conditions, 0.5 mg of i.v. acetylstrophanthidin in 15 dogs resulted in erratic increases in coronary vascular resistance. The peak rise was 12+/-5% above control (P less than 0.01). In 7 of the 15 dogs, the initial erratic rise in coronary vascular resistance culminated in a steep rise associated with acute elevation in left ventricular end-diastolic pressure, which in four dogs terminated in ventricular fibrillation. During the nonischemic control periods, the peak rise in coronary vascular resistance with acetylstrophanthidin was 16+/-1% above control (P less than 0.01). In five dogs, prior alpha adrenergic receptor blockade with phenoxybenzamine prevented the rise in coronary vascular resistance with acetylstrophanthidin during ischemia. Similar erratic increases in coronary vascular resistance were observed with i.v. digoxin (1 mg) during ischemia in three dogs. In two of these dogs, there was a progressive rise in coronary vascular resistance associated with elevation of left ventricular end-diastolic pressure and ventricular fibrillation. The increase in coronary vascular resistance with digoxin during ischemia was abolished with phenoxybenzamine in two additional dogs. Thus, i.v. digitalis in the ischemic heart results in potentially detrimental increases in coronary vascular resistance mediated through alpha adrenergic receptor stimulation.