Subendocardial flow is selectively impaired during coronary hypoperfusion. Systolic compression of intramyocardial vessels not only stops capillary flow but empties vessels as well, leading to reversed flow in the arteries that penetrate the myocardium. The tone of these vessels influences the magnitude of flow oscillation during the cardiac cycle, but whether vessel tone is an independent determinant of subendocardial perfusion during coronary hypoperfusion has not been determined. The discovery of endothelin (ET-1) has made it possible to counteract metabolic vasodilation and increase vessel tone during hypoperfusion. A shunt from a carotid artery to the left anterior descending coronary artery was installed in open-chest pigs anesthetized with halothane. Arterial pressure and heart rate were held constant, and coronary pressure was reduced in stages by restricting shunt flow during intracoronary infusion of ET-1 (n = 7) or adenosine (n = 5). Microspheres were injected at each stage to determine layer flow. Coronary resistance was two- to three-fold higher and subendocardial flow was lower at similar coronary pressures in the animals receiving ET-1 than in those receiving adenosine. In contrast, flow distribution across the left ventricular wall was more homogeneous with ET-1 than with adenosine, even at coronary pressures low enough to cause lactate production and regional hypokinesis. These results demonstrate that vessel tone has an independent effect on absolute subendocardial flow as well as transmural flow distribution during coronary hypoperfusion.