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CARDIOVASCULAR

Bepridil, an Antiarrhythmic Drug, Opens Mitochondrial K_ATP Channels, Blocks Sarcolemmal K_ATP Channels, and Confers Cardioprotection

Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan (T.Sat., T.Sai., T.O., H.N.); Department of Biology, Portland State University, Portland, Oregon (A.D.T.C., K.D.G.); and Department of Physiology, Tokai University School of Medicine, Isehara, Japan (H.I.)

Bepridil, which is clinically useful in the treatment of arrhythmias, has been reported to inhibit sarcolemmal ATP-sensitive K⁺ (sarcK_ATP) channels. However, the effect of bepridil on mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channels remains unclear. The objective of the present study was to determine whether bepridil activates mitoK_ATP channels and confers cardioprotection. SarcK_ATP channels composed of Kir6.2+SUR2A in human embryonic kidney (HEK) 293 cells were examined using the patch-clamp technique. Flavoprotein fluorescence in guinea pig ventricular cells and matrix volume in isolated rat heart mitochondria were measured to assay mitoK_ATP channel activity. Mitochondrial Ca²⁺ concentration ([Ca²⁺]_m) was measured by loading cells with rhod-2 fluorescence. Coronary-perfused guinea pig ventricular muscles were subjected to 35-min no-flow ischemia followed by 60-min reperfusion. Bepridil (10 µM) completely inhibited the pinacidil-induced Kir6.2+SUR2A channel current expressed in HEK 293 cells. Bepridil reversibly oxidized the flavoprotein and increased mitochondrial matrix volume in a concentration-dependent manner. Furthermore, bepridil significantly attenuated the ouabain-induced increase of [Ca²⁺]_m. Pretreatment with bepridil for 5 min before ischemia improved the recovery of developed tension measured after 60 min of reperfusion. These effects of bepridil were abolished by the mitoK_ATP channel blocker 5-hydroxydecanoate (500 µM) and by the nonselective K_ATP channel blocker glisoxepide (10 µM). Our results indicate that bepridil is an opener of mitoK_ATP channels but an inhibitor of sarcK_ATP channels and exerts a direct cardioprotective effect on native cardiac myocytes. This is the first report of a unique modulator of K_ATP channels; bepridil would be expected to mitigate ischemic injury while blunting arrhythmias.

Address correspondence to: Dr. Toshiaki Sato, Department of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: tsato{at}faculty.chiba-u.jp

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