The purpose of this study was to test the hypothesis that moderately severe exercise-induced regional myocardial ischemia can be prevented by combined pharmacologic intervention. Eight chronically instrumented dogs were studied using an ameroid constrictor to produce critical stenosis of the left circumflex coronary artery. The dogs were studied during steady state treadmill exercise that induced regional myocardial dysfunction (reduced systolic wall thickening; sonomicrometers) and ischemia (reduced subendocardial blood flow; microspheres). During a control exercise run, wall thickening in the ischemic posterior wall decreased from 21.4 to 13.3% whereas subendocardial blood flow failed to increase normally (36% of that in the normal zone). In the control anterior wall, both wall thickening and subendocardial blood flow increased significantly during the control run. Wall thickness-left ventricular pressure loop areas were calculated as an index of regional work; this index increased abruptly with the onset of exercise in both regions but became significantly depressed in the ischemic region during the steady state exercise. Therapy with a combination of atenolol (0.3 mg/kg body weight orally), diltiazem (0.3 mg/kg intravenously) and isosorbide dinitrate (2.0 mg/kg orally) effectively prevented regional myocardial ischemia and regional dysfunction. After drug therapy, wall thickening in the posterior wall increased from 17.3% at rest to 18.8% during exercise, and the regional transmural blood flow pattern was markedly improved. The initial overshoot of the regional work index during exercise was blunted by the drug therapy, and at steady state no differences between the ischemic and control regions were detected. Thus, combined drug therapy can eliminate exercise-induced regional myocardial ischemic dysfunction and appears to normalize the oxygen supply-demand imbalance.