Isolated working rat hearts, receiving no drug treatment, recovered low values of contractile function after 33 min of zero-flow global ischemia and 30-min reperfusion, had lower ATP and creatine phosphate (CrP) values in the subendocardium than in the subepicardium after reperfusion (subendocardial/subepicardial ratio ATP = 0.44, CrP = 0.45), and had a subendocardial reperfusion defect including 15.9% of ventricular cross-sectional area. Contracture pressure increased during the later part of ischemia to 25.4 mm Hg. Addition of nisoldipine (1 nM) 10 min before ischemia did not depress preischemic contractile function and did not delay or reduce contracture or the breakdown of high-energy phosphate compounds during ischemia. On reperfusion, nisoldipine-treated hearts showed a dramatic improvement in recovery of contractile function, increased subendocardial energy levels yielding a more uniform transmural energy distribution (subendocardial/subepicardial ratio ATP = 0.79, CrP = 0.94), and enhanced reflow to the subendocardium (area of no reflow = 1.0%). In contrast, addition of vehicle or a low concentration of verapamil (1 nM) before ischemia or nisoldipine during reperfusion did not improve recovery of contractile function. The beneficial effects do not appear to be induced by direct myocardial actions of nisoldipine but may reflect improved vascular function which is associated with the vascular selectivity of this calcium antagonist.