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KMID : 0043320100330081241
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Archives of Pharmacal Research
2010 Volume.33 No. 8 p.1241 ~ p.1251
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Cardioprotective effects of the novel Na+/H+ exchanger-1 inhibitor KR-32560 in a perfused rat heart model of global ischemia and reperfusion: Involvement of the Akt-GSK-3β cell survival pathway and antioxidant enzyme
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Jung In-Sang
Lee Sung-Hun
Yang Min-Kyu
Park Jung-Woo
Yi Kyu-Yang
Yoo Sung-Eun
Kwon Suk-Hyung
Chung Hun-Jong
Choi Wahn-Soo
Shin Hwa-Sup
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Abstract
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To investigate the cardioprotective effects and mechanism of action of KR-32560 {[5-(2-methoxy-5-fluorophenyl)furan-2-ylcarbonyl]guanidine}, a newly synthesized NHE-1 inhibitor, we evaluated the effects of KR-32560 on cardiac function in a rat model of ischemia/reperfusion (I/R)-induced heart injury as well as the role antioxidant enzymes and pro-survival proteins play these observed effects. In isolated rat hearts subjected to 25 min of global ischemia followed by 30 min of reperfusion, KR-32560 (3 and 10 μM) significantly reversed the I/Rinduced decrease in left ventricular developed pressure and increase in left ventricular enddiastolic pressure. In rat hearts reperfused for 30 min, KR-32560 (10 μM) significantly decreased the malondialdehyde content while increasing the activities of both glutathione peroxidase and catalase, two important antioxidant enzymes. Western blotting analysis of left ventricles subjected to I/R showed that KR-32560 significantly increased phosphorylation of both Akt and GSK-3β in a dose-dependent manner, with no effect on the phosphorylation of eNOS. These results suggest that KR-32560 exerts potent cardioprotective effects against I/Rinduced rat heart injury and that its mechanism involves antioxidant enzymes and the Akt-GSK-3β cell survival pathway.
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KEYWORD
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KR-32560, Cardioprotection, Na+/H+ exchanger, Akt GSK-3β Reperfusion
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