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KMID : 0043320070300050634
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Archives of Pharmacal Research
2007 Volume.30 No. 5 p.634 ~ p.640
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Cardioprotective Effects of BMS-180448, a Prototype mitoKATP Channel Opener, and the Role of Salvage Kinases, in the Rat Model of Global Ischemia and Reperfusion Heart Injury
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Lee Ju-Han
Jung In-Sang
Lee Sung-Hun
Yang Min-Kyu
Hwang Ji-Hye
Lee Hak-Dong
Cho Yu-Sun
Song Min-Jin
Yi Kyu-Yang
You Sung-Eun
Kwon Suk-Hyung
Kim Bo-Kyung
Lee Chang-Soo
Shin Hwa-Sup
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Abstract
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To investigate the involvement of reperfusion-induced salvage kinases (RISK) as possible signaling molecules for the cardioprotective effects of BMS-180448, a prototype mitochondrial ATP-sensitive K+ (mitoKATP) channel opener, we measured its cardioprotective effects in a rat model of ischemia/reperfusion (I/R) heart injury, together with western blotting analysis of five different signaling proteins. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, BMS-180448 (1, 3 and 10 킡) significantly increased reperfusion left ventricular developed pressure (LVDP) and 30-min reperfusion double product (heart rate x LVDP) in a concentration-dependent manner, while decreasing left ventricular end-diastolic pressure (LVEDP) throughout reperfusion period in a concentration-dependent manner. SDSPAGE/ western blotting analysis of left ventricle reperfused for 30 min revealed that BMS- 180448 significantly decreased phospho-GSK3?at high concentration, whereas it tended to increase slightly phospho-eNOS and phospho-p70S6K with concentration. However, BMS- 180448 had no effect on phospho-Akt and phospho-Bad. These results suggest that the cardioprotective effects of BMS-180448 against I/R heart injury may result from direct activation of mitoKATP channel in cardiomyocytes, with the minimal role of RISK pathway in the activation of this channel and the cardioprotective effects of BMS-180448.
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KEYWORD
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BMS-180448, Cardioprotection, mitoKATP, ischemia, Reperfusion, Rat heart
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