Calcium channel blockers, which induce vasodilation by relaxing vascular smooth muscle cells, have proven effective in the treatment of angina pectoris. To study mechanisms of calcium blockade in ischemic heart disease, conscious chronically instrumented dogs with a single coronary artery ameroid constrictor were studied during steady-state treadmill runs which induced regional myocardial ischemia. During exercise-induced ischemia, regional systolic wall thickening and subendocardial blood flow were both significantly reduced in the ischemic zone. Calcium channel blockade with verapamil, diltiazem, or nifedipine enhanced regional systolic wall thickening. Regional subendocardial blood flow in the ischemic region, measured during diltiazem and nifedipine experiments, improved during exercise. Reduced coronary artery resistance in the native vessels and/or recruitment of collaterals appears to largely explain the increased total myocardial blood supply in the jeopardized area and the increased function. However, after diltiazem, reduced exercise heart rates as well as reduced left ventricular end-diastolic pressure also contributed to the improvement in the oxygen-supply imbalance in the ischemic myocardium. These data provide a basis for understanding the efficacy of calcium channel blocker treatment in patients with coronary artery disease.