OBJECTIVE Sodium-hydrogen exchange (NHE) activation is a major mechanism of cardiac injury produced by ischemia and reperfusion. In addition, NHE may mediate the direct effects of hydrogen peroxide (H2O2) in normally perfused hearts. The present study was done to determine whether H2O2 at low concentrations producing mild myocardial depression affects post-ischemic recovery of function and to determine the ability of the NHE inhibitor HOE 642 to modulate this effect. METHODS Isolated Langendorff-perfused rat hearts with a left ventricular balloon inflated to an initial end-diastolic pressure of 5 mmHg were subjected to 90 min of global zero-flow ischemia followed by 60 min reperfusion. In Study 1, hearts were randomized for perfusion with or without H2O2 (20 microM) for 15 min before ischemia and throughout reperfusion. In Study 2, identical experiments were done except that the hearts were pretreated with the NHE inhibitor HOE 642 (5 microM). Function was assessed by determining intraventricular pressures. RESULTS Recovery of developed pressure in Study 1 after 10 min reperfusion was 60.3 +/- 8% of pre-ischemic values in control hearts whereas this was reduced to 29.9 +/- 10% in hearts treated with H2O2 (P < 0.05). After 60 min of reperfusion recovery of developed pressure was 80.3 +/- 5.2% and 60.7 +/- 7% in control and H2O2-treated hearts, respectively (P < 0.05). Recovery of rates of pressure development (+dP/dt) and relaxation (-dP/dt) paralleled the effects seen with developed pressure. Moreover, these effects were associated with significantly elevated end-diastolic pressure during the last 20 min of reperfusion. In Study 2, HOE 642 completely prevented the deleterious effect of H2O2, both with respect to ventricular recovery and to the elevation in end-diastolic pressure during reperfusion. CONCLUSIONS Our results show that very low concentrations of H2O2 significantly impair recovery of function in this rat model of myocardial ischemia-reperfusion. Moreover, our results suggest that this effect is likely dependent on NHE activity and can be prevented by treatment with the NHE inhibitor HOE 642.