Protective effect of Na+ /H+ exchange inhibitor, SM-20550, on impaired mitochondrial respiratory function and mitochondrial Ca2+ overload in ischemic/reperfused rat hearts.
The aim of this study was to investigate whether a selective Na+/H+ exchange inhibitor, SM-20550, can modulate the mitochondrial respiratory function and mitochondrial Ca2+ content in isolated rat hearts subjected to 40 min of ischemia and 20 min of reperfusion. SM-20550 (10, 100 nM) was administered for 5 min prior to ischemia and for 20 min during the reperfusion period. At 20 min after reperfusion, treatment with SM-20550 (10, 100 nM) improved the recovery of left ventricular developed pressure and suppressed the rise in left ventricular end-diastolic pressure. Mitochondrial function, assessed by the state 3 oxygen respiration rate, respiratory control index, and oxidative phosphorylation rate, was significantly impaired after ischemia/reperfusion. Administration with SM-20550 (10, 100 nM) attenuated the impaired mitochondrial function, improving the state 3 respiration rate, respiratory control index, and oxidative phosphorylation rate. The mitochondrial Ca2+ content was significantly increased after ischemia/reperfusion but was suppressed by treatment with SM-20550 (10, 100 nM). A significant linear correlation was observed between the respiratory control index and mitochondrial Ca2+ content in the ischemic/reperfused hearts. In conclusion, SM-20550 improved the postischemic recovery of left ventricular function and concurrently protected mitochondrial function mediated by preventing mitochondrial Ca2+ overload.
Yamamoto
Setsuko
S
Research Center, Sumitomo Pharmaceuticals Co., Ltd., 1-98 Kasugadenaka 3-Chome, Konohana-ku, Osaka 554-0022, Japan. setukoy@sumitomopharm.co.jp
Matsui
Kazuki
K
Ohashi
Naohito
N
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D016277:Ventricular Function, Left / Q000187:drug effects
D000578:Amidines; D007211:Indoles; C121094:SM 20550; D017923:Sodium-Hydrogen Exchangers; D002118:Calcium