Inhibition of Na(+)/H(+) exchange at the beginning of reperfusion is cardioprotective in isolated, beating adult cardiomyocytes.
Stimulation of Na(+)/H(+)exchange during ischemia-reperfusion results in cardiac damage. However, it is unclear whether the Na(+)/H(+)exchanger is active during the ischemic period or during reperfusion. Adult beating cardiomyocytes were exposed to an ischemia mimetic solution for 90 min and then reperfused with a normal solution for 30 min. 5-(N,N-dimethyl)-amiloride (DMA), a blocker of the Na(+)/H(+)exchanger, was administered during ischemia and the first 3 min of reperfusion or only during the first 3 min of reperfusion. Administration of DMA only upon reperfusion resulted in increased cell survival (81+/-1%, P<0.05) compared to using the drug during ischemia and reperfusion (63+/-3%) and in the absence of drug (60+/-1%). During ischemia, pH(i)was lower when DMA was present in the ischemic solution. The inhibition of the Na(+)/H(+)exchanger retarded the recovery of pH during reperfusion. The highest recovery of active cell shortening was observed when DMA was used at the beginning of reperfusion. The use of DMA also reduced the level of passive cell shortening during reperfusion, and when used at the beginning of reperfusion significantly increased the recovery of Ca(2+)transients. Our results demonstrate that the exchanger is primarily active during reperfusion and that inhibition of the exchanger solely at this time has a strong cardioprotective effect.
Hurtado
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Cell Biology Laboratory, St Boniface General Hospital Research Centre, Winnipeg, Canada.
Pierce
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D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006863:Hydrogen-Ion Concentration; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013050:Spectrometry, Fluorescence; D013997:Time Factors
D017923:Sodium-Hydrogen Exchangers; C039465:5-dimethylamiloride; D000584:Amiloride