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 understood, phenomenon in mitochondrial bioenergetics. It has been recognised that this phenomenon is related to the opening of a protein pore in the inner mitochondrial membrane, and that opening of this pore is the cause of some forms of mitochondrial dysfunction. In this work, we propose that carvedilol, a multi-role cardioprotective compound, may act as an inhibitor of the high-conductance state of the mitochondrial permeability transition pore, a conclusion supported by the finding that carvedilol provides differential protection against mitochondrial swelling in sucrose and KCl-based media, and that it is unable to protect against calcium-induced depolarisation of the mitochondrial membrane. We also show that carvedilol inhibits the oxidation of mitochondrial thiol groups and that, beyond causing a slight depression of the membrane potential, it has no inhibitory effect on mitochondrial calcium uptake.A decrease in the number of oxidised protein thiol groups may be the main mechanism responsible for this selective inhibition of the permeability transition pore in heart mitochondria. These effects may be important for the role of carvedilol in some cardiac pathologies.
Oliveira
P J
PJ
Centro de Neurociências e Biologia Celular de Coimbra, Dep. Zoologia, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3049-517, Coimbra, Portugal.
Coxito
P M
PM
Rolo
A P
AP
Santos
D L
DL
Palmeira
C M
CM
Moreno
A J
AJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects; D010539:Permeability; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019802:Succinic Acid / Q000378:metabolism
D000975:Antioxidants; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D019802:Succinic Acid; D002118:Calcium