Minoxidil opens mitochondrial K ATP channels and confers cardioprotection

ATP‐sensitive potassium channel in the mitochondrial inner membrane (mitoK ATP channel) rather than in the sarcolemma (sarcK ATP channel) appears to play an important role in cardioprotection. We examined the effect of minoxidil, a potent antihypertensive agent and hair growth stimulator, on sarcK ATP and mitoK ATP channels in guinea‐pig ventricular myocytes. Minoxidil activated a glybenclamide‐sensitive sarcK ATP channel current in the whole‐cell recording mode with an EC 50 of 182.6 μ M . Minoxidil reversibly increased the flavoprotein oxidation, an index of mitoK ATP channel activity, in a concentration‐dependent manner. The EC 50 for mitoK ATP channel activation was estimated to be 7.3 μ M ; this value was notably ∼25‐fold lower than that for sarcK ATP channel activation. Minoxidil (10 μ M ) significantly attenuated the ouabain‐induced increase of mitochondrial Ca 2+ concentration, which was measured by loading cells with rhod‐2 fluorescence. Furthermore, pretreatment with minoxidil (10 μ M ) before 20‐min no‐flow ischaemia significantly improved the recovery of developed tension measured after 60 min of reperfusion in coronary perfused guinea‐pig ventricular muscles. These cardioprotective effects of minoxidil were completely abolished by the mitoK ATP channel blocker 5‐hydroxydecanoate (500 μ M ). Our results indicate that minoxidil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by the selective activation of mitoK ATP channels.British Journal of Pharmacology (2004) 141 , 360–366. doi: 10.1038/sj.bjp.0705613