Inhibitory effect of carvedilol in the high-conductance state of the mitochondrial permeability transition pore

The mitochondrial permeability transition is a widely studied, but poorly u nderstood, phenomenon in mitochondrial bioenergetics. It has been recognise d that this phenomenon is related to the opening of a protein pore in the i nner mitochondrial membrane, and that opening of this pore is the cause of some forms of mitochondrial dysfunction. In this work, we propose that carv edilol, a multi-role cardioprotective compound, may act as an inhibitor of the high-conductance state of the mitochondrial permeability transition por e, a conclusion supported by the finding that carvedilol provides different ial protection against mitochondrial swelling in sucrose and KCl-based medi a, and that it is unable to protect against calcium-induced depolarisation of the mitochondrial membrane. We also show that carvedilol inhibits the ox idation of mitochondrial thiol groups and that, beyond causing a slight dep ression of the membrane potential, it has no inhibitory effect on mitochond rial calcium uptake. A decrease in the number of oxidised protein thiol groups may be the main m echanism responsible for this selective inhibition of the permeability tran sition pore in heart mitochondria. These effects may be important for the r ole of carvedilol in some cardiac pathologies. (C) 2001 Elsevier Science B. V. All rights reserved.