Reperfusion-induced Ins(1,4,5)P-3 generation and arrhythmogenesis require activation of the Na+/Ca2+ exchanger

Reperfusion of globally ischemic rat hearts causes rapid generation or inos itol(1,4,5)trisphosphate [Ins(1,4,5)P-3] and the development of arrhythmias , following stimulation of alpha (1)-adrenergic receptors by norepinephrine released from the cardiac sympathetic nerves. The heightened inositol phos phate response in reperfusion depends on the activation of the Na+/H+ excha nger, which might reflect a central role for increased Ca2+ following rever se mode activation of the Na+/Ca2+ exchanger (NCX). Isolated. perfused rat hearts were subjected to 20 min ischemia followed by 2 min reperfusion and the content of Ins(1,4,5)P-3 measured by mass analysis or by anion-exchange high performance liquid chromatography (HPLC) following [H-3]inositol labe ling. Reperfusion caused generation of Ins(1.4.5)P-3 (1266 +/- 401 to 3387 +/- 256 cpm/g tissue, mean +/- S.E.M.. n = 6, P<0.01) and the development o f arrhythmias. Inhibition of NCX either by reperfusion at low Ca2+ (1133 +/ - 173 cpm/g tissue, mean +/- S.E.M., n=6, P<0.01 relative to reperfusion co ntrol) or by adding 10 muM KB-R7943, an inhibitor of reverse mode Na+/Ca2exchange, prevented the Ins(1,4.5)P-3 response (1151 +/- 243 cpm/g tissue, mean +/- S.E.M., n = 6, P<0.01 relative to reperfusion control) and the dev elopment of ventricular fibrillation. Lower concentrations of KB-R7943 were less effective. Reverse mode activation of NCX is therefore required for t he enhanced Ins(1,4,5)P-3 response in early reperfusion, and inhibitors of this transporter may be useful in the prevention of arrhythmias under such conditions. (C) 2001 Academic Press.