Role of nitric oxide and free radicals in cardioprotection by blocking Na+/H+ and Na+/Ca2+ exchange in rat heart.
Inhibition of Na(+)/H(+) (NHE) and Na(+)/Ca(2+) (NCE) exchangers prevents myocardial ischemia/reperfusion injury by preventing cardiomyocyte Ca(2+) overload. We hypothesized that it may influence ischemic/reperfused myocardium also indirectly by preventing endothelial Ca(2+) accumulation, and thereby by attenuating reperfusion-induced formation of nitric oxide (NO) and/or oxygen free radicals. Langendorff-perfused rat hearts were subjected to 30-min ischemia and 30-min reperfusion. Myocardial outflow of NO (nitrite+nitrate) and hydroxyl radical (*OH, salicylate method), and functional recoveries were followed during reperfusion. In all groups, there was a transient rise in NO and *OH outflow upon reperfusion. An inhibitor of NHE, cariporide (10 microM) [(4-Isopropyl-3-methylsulfonyl-benzoyl)-quanidine methanesulfonate], and an inhibitor of the reverse mode of NCE, KB-R7943 (5 microM) (2-[4-(4-Nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate), decreased NO and *OH formation, reduced contracture, and improved the recovery of mechanical function during reperfusion, compared to the untreated hearts. The formation of NO was reduced by 40% by 100 microM N(G)-methyl-L-arginine acetate salt (L-NMMA, NO synthase inhibitor), and not affected by 50 microM L-NMMA. *OH formation, contracture, and the functional recoveries were affected neither by 50 nor by 100 microM L-NMMA. Also, the effects of cariporide and KB-R7943 were unaffected by 100 microM L-NMMA. This study shows for the first time that the inhibition of NHE and NCE attenuates post-ischemic myocardial formation of NO and *OH, suggesting that prevention of Ca(2+) overload is cardioprotective via these mechanisms. The results indicate, however, that NO synthase pathway did not interfere with the protection afforded by NHE or NCE in our model.
Maczewski
Michał
M
Department of Clinical Physiology, Medical Center of Postgraduate Education, Marymoncka 99, 01-813 Warsaw, Poland.
Beresewicz
Andrzej
A
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D017665:Hydroxyl Radical / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D004791:Enzyme Inhibitors; D005609:Free Radicals; D006146:Guanidines; D009566:Nitrates; D009573:Nitrites; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D017665:Hydroxyl Radical; C093373:cariporide; D019001:Nitric Oxide Synthase; D013890:Thiourea