FREE-RADICALS ENHANCE NA+ CA2+ EXCHANGE IN VENTRICULAR MYOCYTES/

Oxygen-derived free radicals (OFR) have been implicated in the pathoge nesis of intracellular Ca2+ overload and the arrhythmias that characte rize cardiac reperfusion. These arrhythmias may in large part be due t o activation of the pathological transient inward current (I-TI) Howev er, the identity of the I-TI generated by OFR is uncertain. We previou sly found that H2O2, an OFR-generating compound, markedly stimulated t he I-TI elicited by brief caffeine pulses in patch-clamped guinea pig ventricular myocytes. In the present study, using patch-clamped rabbit ventricular myocytes loaded with the Ca2+-sensitive indicator fura 2, we have further characterized this I-TI and have identified its major component to be Na+/Ca2+ exchange, based on its dependence on extrace llular Na+ and sarcoplasmic reticulum Ca2+ release, its sensitivity to Ni2+, and the effects of its inhibition on relaxation. The effect on I-TI was not unique to H2O2, because another free radical-generating s ystem, xanthine + xanthine oxidase, produced a similar response. We hy pothesize that enhancement of Na+/Ca2+ exchange by OFR during reperfus ion, when intracellular Na+ is elevated, may promote intracellular Ca2 + overload and triggered arrhythmias.