| Budget Amount *help |
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2002: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
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| Research Abstract |
Accumulating evidence suggets that mitochondrial adenosine triphoshate-senstive potassium (mito-K_<ATP>) channel may have an important role in the protection of myocardium during ischemia. In the present study, we examine the effects of propofol, lidocaine and mexiletine on mito-K_<ATP> channel activities and the role of mito-K_<ATP> channels on the carioprotective effects of ischemia-induced preconditioning (IPC) in isolated rat ventricular myocytes.
Flavoprotein fluorescence was measured evaluate mitochondrial oxidation mediated by mito- K_<ATP> channels. The change of flourescence was normalized to baseline flavoprotein fluorescence obtained after exposure to 5uM 2, 4-dinitrophenol (DNP), a protonophore that uncouples respiration from ATP synthesis and collapses the mitochontrial potential, at the end of the experiments.
Diazoxide (25uM), a selective mmito-K_<ATP> channel opener, caused reversible mitochondrial oxidation to 63 ^^+__- 19% of DNP values (n=7). 5-hydroxydecanoic acid (10
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0uM), a selective mito-K_<ATP> channel blocker, attenuated the oxidative effects of diazoxide to 2 ^+_- 5% of the DNA value. Propofol, lidocaine and Mexiletine inhibited diazoxide (100uM) -induced flavoprotein fluorescence in a concentration-dependent manner. The EC_<50> values of propofol, lidocaine and mexiletine were 14.6ug/ml (n=9) 98^^+__-63uM (n-7) and 107^^+__-42uM (n=7), respecitively. These results suggest that propofol, lidocaine and mexiletine may attenuate cardioprotective effects of mito-K__<ATP> channels.
Next, we evaluated the effects of mito-K__<ATP> channel activities on IPC. Non-preconditioned group (control group) received a continuos 15 minutes ischemia, whereas preconditioned group (IPC group) subjected to 5 minutes ischemia, 10 minutes reperfusion, and finally 15 minutes ischemia. To simulate ischemia, we used 5uM DNP. Flavoprotein fluorescence of the IPC group was significantly increased compared to that of the control group. These results indicate that cardioprotective effects of IPC are due to increased activities of mito-K_<ATP> channels by ischemic stimulation. Less
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