期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 35, 期 9, 页码 1035-1042出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/S0022-2828(03)00151-2
关键词
glibenclamide; 5-hydroxydecanoate; myocardial infarction; P1075 pre conditioning
资金
- NHLBI NIH HHS [HL-20648, HL-50688, HL-67842] Funding Source: Medline
We have recently proposed that opening of mitochondrial K-ATP channels (mitoK(ATP)) acts as a trigger for preconditioning (PC) by causing mitochondria to produce reactive oxygen species (ROS). Controversy exists as to whether the putative sarcolemma-selective K-ATP channel opener P1075 also opens mitoK(ATP) channels and may be cardioprotective. We purified mitoK(ATP) channels from either rabbit heart, rat heart or rat brain and reconstituted the proteins into liposomes. mitoK(ATP) channels from each of these tissues were opened by P1075 with EC50 values of 60-90 nM. We next tested whether P1075 causes rabbit cardiomyocytes to produce ROS in a K-ATP-dependent fashion. Mitochondrial ROS production was monitored by the appearance of fluorescence as reduced MitoTracker(TM) Red was oxidized. P 1075 (100 PM) led to a 44 +/- 9% increase in ROS generation (P < 0.001 vs. untreated cells), which was similar to the increase seen with 50 muM diazoxide, a selective mitoK(ATP) channel opener (49 +/- 9%, P < 0.001 vs. untreated cells). The effect of P1075 was equally potent at a concentration of 150 nM. The P1075-induced increase in ROS production was blocked by 50 muM glibenclamide (GLI), a non-selective K-ATP blocker, and by 5-hydroxydecanoate (1 mM), a highly selective mitoK(ATP) blocker (-6 +/-14% and +4 +/- 12%, respectively; P = n.s). In isolated rabbit hearts, P1075 (150 nM) markedly reduced infarct size compared to control animals (10.6 +/- 8.1 % of the area at risk vs. 31.5 +/- 5.6%, P < 0.05). GLI (5 muM) as well as 5-hydroxydecanoate (200 muM) completely blocked P1075's anti-infarct effect (31.7 +/- 9.5% and 27.7 +/- 4.6% infarction, respectively; P = n.s. vs. untreated hearts). These data provide strong evidence that P1075 does open mitoKAT, channels and protects the ischemic rabbit heart in a mitoK(ATP)-dependent manner. (C) 2003 Elsevier Science Ltd. All rights reserved.
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