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In this study, we evaluated levosimendan, a new drug developed for the treatment of acute and decompensated heart failure, as a potential activator of ATP-sensitive potassium flux to the matrix of cardiac mitochondria. We estimated the KATP channel openers-induced increase in mitochondrial inner membrane permeability for potassium by registering changes in membrane potential of heart mitochondria, oxidizing endogenous substrates. We compared the effect of levosimendan with the effects of the known KATP channel openers diazoxide and pinacidil. Levosimendan (1 μM) accelerated potassium-specific ΔΨ decrease by 0.15%/s, whereas 50 μM diazoxide by 0.10%/s, and 50 μM pinacidil by 0.08%/s, respectively. These results were confirmed by swelling experiments of non-respiring mitochondria in potassium nitrate medium. We found that levosimendan with an EC50 of 0.83 ± 0.24 μM activates potassium flux to the mitochondrial matrix. This effect is discussed as a possible explanation of the anti-ischemic action of levosimendan.