To investigate whether addition of vasodilator drugs can increase the beneficial effects on the ischemic myocardium of diastolic synchronized retroperfusion (DSR), low doses of verapamil (2 micrograms/kg/min) or nitroglycerin (0.7 microgram/kg/min) were infused through DSR in open-chest dogs undergoing 180 minutes of proximal left anterior descending coronary artery occlusion. Verapamil-DSR (n = 6), nitroglycerin-DSR (n = 6) or DSR alone (n = 8, controls) were started 10 minutes after the onset of occlusion and maintained for 170 minutes. Regional myocardial blood flow (MBF) (microspheres) and left ventricular function (endocardial ultrasonic crystals) were simultaneously assessed in nonischemic and ischemic zones in the 3 groups, before and after 10 and 180 minutes of coronary occlusion. DSR alone significantly increased ischemic regional MBF, endocardial/epicardial flow ratio and endocardial segmental length shortening. Verapamil DSR increased both nonischemic and ischemic regional MBF but reduced the endocardial/epicardial flow ratio and worsened ischemic contractile function. Nitroglycerin DSR did not modify ischemic transmural flow compared with DSR alone, but abolished the beneficial endocardial/epicardial blood flow redistribution, resulting in no additional improvement of contractile function. Thus, ischemic MBF and function are not improved by addition of small amounts of verapamil or nitroglycerin to the arterial retroperfusate in this model of acute myocardial ischemia.