Role of the reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte injury

Objective: We have recently shown that spontaneous Ca2+ oscillations elicit irreversible hypercontracture of cardiomyocytes during reoxygenation. The aim of this study was to investigate whether influx of exterior Ca2+ throug h the reverse mode of the Na+/Ca2+ exchanger (NCE) contributes to the devel opment of these oscillations and, therefore, to reoxygenation-induced hyper contracture. Methods: Isolated cardiomyocytes and hearts from rats were use d as models. Cardiomyocytes were exposed to 60 min simulated ischemia (pH(o ) 6.4) and 10 min reoxygenation (pH(o) 7.4). During reoxygenation cardiomyo cytes were superfused with medium containing I mmol/l Ca2+ (control), with nominally Ca2+-free medium or with medium containing 10 mu mol/l KB-R 7943 (KB), a selective inhibitor of the reverse mode of the NCE. Results: In reo xygenated cardiomyocytes rapid Ca2+ oscillations occurred which were reduce d under Ca2+-free conditions or in presence of KB. Hypercontracture was als o significantly reduced under Ca2+-free conditions or in presence of KB. Af ter 30 min of normoxic perfusion isolated rat hearts were subjected to 60 m in global ischemia and reperfusion. KB (10 mu mol/1) was present during the first 10 min of reperfusion. LVEDP, LVdevP and lactate dehydrogenase (LDH) release were measured. Presence of KB reduced post-ischemic LVEDP and impr oved left ventricular function (LVdevP). In KB treated hearts the reperfusi on induced release of LDH was markedly reduced from 81.1 +/- 9.9 (control) to 49.3 +/- 8.8 U/60 min/g dry weight. Conclusion: Our study shows that inh ibition of the reverse mode of the NCE, during reperfusion only, protects c ardiomyocytes and whole hearts against reperfusion injury. (C) 2001 Elsevie r Science BY All rights reserved.