The effect of an Na+/H+ exchange inhibitor, SM-20550, on ischemia/reperfusion-induced endothelial dysfunction in isolated perfused rat hearts.
The aim of this study was to test the protective effect of an Na+/H+ exchange (NHE) inhibitor, SM-20550, on ischemia/reperfusion-induced endothelial dysfunction. Isolated rat hearts were subjected to 30 min of global ischemia followed by 20 min of reperfusion and their responses to the endothelial-dependent vasodilator, acetylcholine, and the endothelial-independent vasodilator, nitroglycerin, before and after ischemia were examined. Acetylcholine-induced relaxation was impaired after ischemia/reperfusion while nitroglycerin induced relaxation was not. Administration of 1-10 nmol/l SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid] before and after ischemia prevented impairment of acetylcholine-induced relaxation. To further understand the mechanism of SM-20550 in protecting endothelial function, we measured the inhibitory activity of SM-20550 on NHE in cultured endothelial cells. SM-20550 (1-100 nmol/l) inhibited recovery from acidosis induced by an NH4Cl prepulse in a concentration-dependent manner. Oxygen radicals from endothelial cells and leukocytes are one of the major sources of endothelial cell injury during ischemia and reperfusion. Consequently, we tested the effect of SM-20550 on H2O2-induced endothelial cell injury. SM-20550 (100-1,000 nmol/l) prevented H2O2-induced cell injury measured by lactate dehydrogenase assay. In conclusion, SM-20550 inhibited NHE in endothelial cells, protected ischemia/reperfusion-induced endothelial dysfunction and prevented H2O2-induced endothelial cell injury at higher concentrations.
Yamamoto
S
S
Research Center, Sumitomo Pharmaceuticals Co. Ltd., 1-98, Kasugadenaka 3-Chome, Konohana-ku, Osaka 554-0022, Japan. setukoy@sumitomopharm.co.jp
Matsui
K
K
Itoh
N
N
Ohashi
N
N
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion / Q000009:adverse effects*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*
D000578:Amidines; D007211:Indoles; C121094:SM 20550; D017923:Sodium-Hydrogen Exchangers; D006861:Hydrogen Peroxide