Reperfusion-induced Ins(1,4,5)P(3) generation and arrhythmogenesis require activation of the Na(+)/Ca(2+) exchanger.
Reperfusion of globally ischemic rat hearts causes rapid generation of inositol(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 phosphate response in reperfusion depends on the activation of the Na(+)/H(+) exchanger, which might reflect a central role for increased Ca(2+)following reverse mode activation of the Na(+)/Ca(2+) 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 [(3)H]inositol labeling. 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 of arrhythmias. Inhibition of NCX either by reperfusion at low Ca(2+) (1133+/-173 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01 relative to reperfusion control) or by adding 10 microm KB-R7943, an inhibitor of reverse mode Na(+)/Ca(2+) exchange, 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 development of ventricular fibrillation. Lower concentrations of KB-R7943 were less effective. Reverse mode activation of NCX is therefore required for the 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.
Woodcock
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Cellular Biochemistry Laboratory, Baker Medical Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, 8008, Victoria, Australia. liz.woodcock@baker.edu.au
Arthur
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Harrison
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Gao
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Du
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D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000502:physiology; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D019831:Sodium-Calcium Exchanger; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D019831:Sodium-Calcium Exchanger; D015544:Inositol 1,4,5-Trisphosphate; D018021:Lithium Chloride; D013890:Thiourea; D002118:Calcium; D009638:Norepinephrine