Carvedilol: relation between antioxidant activity and inhibition of the mitochondrial permeability transition.
OBJECTIVE
The mitochondrial permeability transition (MPT) is an event related to severe oxidative stress (for example, during myocardial ischemia and reperfusion) and excessive mitochondrial calcium accumulation, also being implicated in cell death. In this study, we compared the effect of carvedilol on the cardiac MPT induced by calcium and phosphate (Ca/Pi) and calcium/carboxyatractyloside (Ca/Catr). Oxidative stress plays a major role in MPT induction by Ca/Pi, leading to the oxidation of protein thiol groups, in contrast with Ca/Catr, where such oxidation is secondary to MPT induction and is not caused by oxidative stress.


METHODS
Mitochondria were isolated from rat hearts and parameters related to MPT induction were evaluated (n = 5 for each inducer): mitochondrial swelling and oxidation of protein thiol groups (both measured by spectrophotometry).


RESULTS
Using Ca/Pi, carvedilol protected mitochondria from MPT induction, particularly in its high conductance form. Its effect was demonstrated by analyzing the decrease in mitochondrial swelling amplitude. Simultaneously, we observed inhibition of protein thiol group oxidation (p < 0.001). By contrast, carvedilol did not show any protective effect with Ca/Catr.


CONCLUSIONS
Carvedilol was only effective against the MPT when the oxidation of protein thiol groups was the cause and not the consequence of the MPT phenomenon. The results clearly show that during myocardial aggressions (ischemia and reperfusion, for example), the protective effect of carvedilol is primarily due to an antioxidant mechanism, inhibiting the production and effects of reactive oxygen species.
Oliveira
Paulo J
PJ
Centro de Neurociências e Biologia Celular de Coimbra, Unidade de Investigação Básica em Cardiologia, Universidade de Coimbra, Coimbra, Portugal.
Esteves
Telma
T
Rolo
Anabela P
AP
Monteiro
Pedro
P
Gonçalves
Lino
L
Palmeira
Carlos M
CM
Moreno
António J
AJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001278:Atractyloside / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D007425:Intracellular Membranes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D010710:Phosphates / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors
D000975:Antioxidants; D002227:Carbazoles; D010710:Phosphates; D011412:Propanolamines; D017382:Reactive Oxygen Species; D000077261:Carvedilol; D001278:Atractyloside; C003853:carboxyatractyloside; D002118:Calcium