HYDROGEN-PEROXIDE INDUCED IMPAIRMENT OF POSTISCHEMIC VENTRICULAR-FUNCTION IS PREVENTED BY THE SODIUM-HYDROGEN EXCHANGE INHIBITOR HOE-642 (CARIPORIDE)

Objective: Sodium-hydrogen exchange (NHE) activation is a major mechan ism of cardiac injury produced by ischemia and reperfusion. In additio n, NHE may mediate the direct effects of hydrogen peroxide (H2O2) in n ormally perfused hearts. The present study was done to determine wheth er H2O2 at low concentrations producing mild myocardial depression aff ects post-ischemic recovery of function and to determine the ability o f the NHE inhibitor HOE 642 to modulate this effect, Methods: Isolated Langendorff-perfused rat hearts with a left ventricular balloon infla ted to an initial end-diastolic pressure of 5 mmHg were subjected to 9 0 min of global zero-flow ischemia followed by 60 min reperfusion. In Study 1, hearts were randomized for perfusion with or without H2O2 (20 mu M) for 15 min before ischemia and throughout reperfusion. In Study 2, identical experiments were done except that the hearts were pretre ated with the NHE inhibitor HOE 642 (5 mu M). Function was assessed by determining intraventricular pressures. Results: Recovery of develope d 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 c ontrol and H2O2-treated hearts, respectively (P<0.05). Recovery of rat es of pressure development (+dP/dt) and relaxation (-dP/dt) paralleled the effects seen with developed pressure. Moreover, these effects wer e associated with significantly elevated end-diastolic pressure during the last 20 min of reperfusion. In Study 2, HOE 642 completely preven ted the deleterious effect of H2O2, both with respect to ventricular r ecovery and to the elevation in end-diastolic pressure during reperfus ion. Conclusions: Our results show that very low concentrations of H2O 2 significantly impair recovery of function in this rat model of myoca rdial ischemia-reperfusion. Moreover, our results suggest that this ef fect is likely dependent on NHE activity and can be prevented by treat ment with the NHE inhibitor HOE 642. (C) 1998 Elsevier Science B.V. Al l rights reserved.