Carvedilol in heart mitochondria: protonophore or opener of the mitochondrial K(ATP) channels?
Carvedilol ([1-[carbazolyl-(4)-oxy]-3-[2-methoxyphenoxyethyl) amino]-propanol-(2)]) has been shown to protect cardiac mitochondria from oxidative stress. In this work we examined the mechanisms responsible for an observed depressive effect in the mitochondrial transmembrane potential (delta psi). Two possible mechanisms were considered: a protonophoretic activity and the opening of mitochondrial ATP-sensitive potassium channels. We show that carvedilol increases mitochondrial inner membrane permeability to protons, but not to potassium, causing an increase in state IV respiration in the presence and absence of oligomycin. By contrast, a K(ATP)-channel inhibitor, 5-hydroxydecanoic acid, did not affect carvedilol-induced depolarizations. Hence, our results suggest that carvedilol depresses mitochondrial delta psi by a weak protonophoretic mechanism.
Oliveira
P J
PJ
Centro de Neurociências de Coimbra. Dep. Zoologia, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, Portugal.
Rolo
A P
AP
Sardão
V A
VA
Coxito
P M
PM
Palmeira
C M
CM
Moreno
A J
AJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D000077261:Carvedilol; D004305:Dose-Response Relationship, Drug; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D011522:Protons; D051381:Rats; D017208:Rats, Wistar; D014634:Valinomycin / Q000494:pharmacology
D000975:Antioxidants; D002227:Carbazoles; D007476:Ionophores; D015221:Potassium Channels; D011412:Propanolamines; D011522:Protons; D000077261:Carvedilol; D014634:Valinomycin; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D011188:Potassium