In this study, calcium overload during reperfusion and the severity of morphologically evident ischemic myocardial injury were compared in hypertrophied and normal hearts. Hypertrophied hearts isolated from rats where a clip had been placed on the proximal thoracic aorta for 6 weeks were compared to those from sham-operated rats in an isolated state perfused with Krebs-Henseleit buffer containing 3% albumin, 1.2 mM palmitate and 11 mM glucose. The isolated hearts were exposed to global, no-flow, normothermic ischemia following potassium arrest and were reperfused. Following ischemia and reperfusion, left ventricular end diastolic pressure was increased (39 +/- 7 v 13 +/- 2 mmHg, P < 0.05), and percentage recovery of left ventricular systolic function was decreased (34.4 +/- 8.9 v 77.1 +/- 6.3% P < 0.05), in hypertrophied hearts compared to control hearts. Calcium overload during reperfusion was two and one-half times greater in the hypertrophied hearts than in the control hearts and showed significant relationships with recovery of left ventricular systolic function (r = -0.86, P < 0.001) and left ventricular end diastolic pressure (r = 0.78, P < 0.005). Myocardial energy charge did not differ between the two groups at the end of reperfusion. Ischemic myocardial injury was quantitated morphologically by point counting techniques in a comparable series of control and hypertrophied hearts. After ischemia, hearts were either exposed to a monoclonal antimyosin antibody to identify and measure irreversibly injured myocardium by light microscopy or fixed by perfusion with 2.5% glutaraldehyde to quantitate the morphologic changes ultrastructurally. Control and hypertrophied hearts were not significantly different in severity of myocardial injury due to ischemia as assessed morphologically. Thus, the data suggest that calcium overload during reperfusion plays a significant role in post-ischemic left ventricular dysfunction of the hypertrophied heart. The accelerated calcium overload that occurs in the hypertrophied rat heart during reperfusion cannot be explained by differences in severity of myocardial injury during ischemia which indicates that other mechanisms are responsible.