Cardioprotection of SM-15681, an Na+/H+ exchange inhibitor in ischemic and hypoxic isolated perfused rat hearts.
We investigated the effects of SM-15681 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide monohydrochloride) on Na+/H+ exchange activity in the myocardium and in ischemic and hypoxic injury in isolated perfused rat hearts. These effects were compared with those of ethylisopropyl amiloride (EIPA). Na+/H+ exchange activity was studied with a NH4Cl prepulse technique under HCO3(-)-free conditions. SM-15681 (10(-8)-10(-7) M) inhibited pH recovery of acidosis in the rat myocardium in a concentration-dependent manner and the IC50 value of SM-15681 (80 nM) was similar to that of EIPA. In perfused rat hearts, SM-15681 (10(-6) M) and EIPA (10(-6) M) significantly improved cardiac functions and prevented enzyme release and abnormal elevation of tissue Ca2+ content during 20 min of reperfusion after 40 min of ischemia and 20 min of reoxygenation after 30 min of hypoxia. We conclude that an Na+/H+ exchange inhibitor, SM-15681, shows cardioprotective effects on ischemia/reperfusion and hypoxia/reoxygenation injury. Our results also support the hypothesis that Na+/H+ exchange contributes to the pathophysiology of cardiac ischemic reperfusion injury.
Toda
H
H
Research Center, Sumitomo Pharmaceutical Co. Ltd., Osaka, Japan.
Noguchi
T
T
Miyagishi
A
A
Ito
N
N
Umekawa
K
K
Sato
Y
Y
Kitano
M
M
Ohashi
N
N
D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006859:Hydrogen / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D017136:Ion Transport / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*
D000577:Amides; D000889:Anti-Arrhythmia Agents; D007211:Indoles; D018696:Neuroprotective Agents; C401341:SM 20220; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D006859:Hydrogen; D012964:Sodium; C039614:ethylisopropylamiloride