Carvedilol in heart mitochondria - Protonophore or opener of the mitochondrial K-ATP channels?

Carvedilol (({1-[carbazolyl-(4)-oxy]-3-[2-methoxyphenoxyethyl) amino]-propa nol-(2)}) has been shown to protect cardiac mitochondria from oxidative str ess. In this work we examined the mechanisms responsible for an observed de pressive effect in the mitochondrial transmembrane potential (Delta Psi). T wo possible mechanisms were considered: a protonophoretic activity and the opening of mitochondrial ATP-sensitive potassium channels. We show that car vedilol increases mitochondrial inner membrane permeability to protons, but not to potassium, causing an increase in state IV respiration in the prese nce and absence of oligomycin. By contrast, a K-ATP-channel inhibitor, 5-hy droxydecanoic acid, did not affect carvedilol-induced depolarizations. Henc e, our results suggest that carvedilol depresses mitochondrial Delta Psi by a weak protonophoretic mechanism. (C) 2001 Elsevier Science Inc. All right s reserved.