Impact of carvedilol on the mitochondrial damage induced by hypoxanthine and xantine oxidase--what role in myocardial ischemia and reperfusion?
OBJECTIVE
The cardioprotective effects of carvedilol (CV) may be explained in part by interactions with heart mitochondria. The objective of this work was to study the protection afforded by CV against oxidative stress induced in isolated heart mitochondria by hypoxanthine and xanthine oxidase (HX/XO), a well-known source of reactive oxygen species (ROS) in the cardiovascular system.


METHODS
Mitochondria were isolated from Wistar rat hearts (n = 8) and incubated with HX/XO in the presence and in the absence of calcium. Several methods were used to assess the protection afforded by CV: evaluation of mitochondrial volume changes (by measuring changes in the optical density of the mitochondrial suspension), calcium uptake and release (with a fluorescent probe, Calcium Green 5-N) and mitochondrial respiration (with a Clark-type oxygen electrode).


RESULTS
CV decreased mitochondrial damage associated with ROS production by HX and XO, as verified by the reduction of mitochondrial swelling and increase in mitochondrial calcium uptake. In the presence of HX and XO, CV also ameliorated mitochondrial respiration in the active phosphorylation state and prevented decrease in the respiratory control ratio (p < 0.05) and in mitochondrial phosphorylative efficiency (p < 0.001).


CONCLUSIONS
The data indicate that CV partly protected heart mitochondria from oxidative damage induced by HX and XO, which may be useful during myocardial ischemia and reperfusion. It is also suggested that mitochondria may be a priority target for the protective action of some compounds.
Oliveira
Paulo J
PJ
Centro de Neurociências e Biologia Celular de Coimbra, Unidade de Investigação Básica em Cardiologia, Universidade de Coimbra, Coimbra, Portugal.
Rolo
Anabela P
AP
Monteiro
Pedro
P
Gonçalves
Lino
L
Palmeira
Carlos M
CM
Moreno
António J
AJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D019271:Hypoxanthine / Q000378:metabolism*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000628:therapy; D015425:Myocardial Reperfusion; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014969:Xanthine Oxidase / Q000378:metabolism*
D000975:Antioxidants; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D019271:Hypoxanthine; D014969:Xanthine Oxidase