Carvedilol inhibits mitochondrial oxygen consumption and superoxide production during calcium overload in isolated heart mitochondria.
BACKGROUND
The COMET study suggested the better effect of carvedilol to metoprolol in treating heart failure. However, its underlying mechanisms of action remain unclear. As a result, evaluation of the distinct effects of both drugs on the mitochondrial function and reactive oxygen species (ROS) production during Ca(2+) overload was investigated.


RESULTS
The mitochondrial oxygen consumption (mVO(2)) and the mitochondrial ROS production in isolated rat heart mitochondria was measured. Ca(2+) overload from 10 to 100 micromol/L augmented mVO(2) was from 527+/-139 to 671 +/-138 nmol/mg (p<0.05), and this was then completely suppressed by carvedilol (1 micromol/L), but not by metoprolol (100 micromol/L). Ca(2+) overload augmented the ROS production upon complex I injury (9.7+/-1.2 to 11.4+/-1.4 nmol/mg, p<0.05). Carvedilol dose-dependently suppressed this ROS production, whereas metoprolol did not.


CONCLUSIONS
Carvedilol, but not metoprolol, was thus found to inhibit the calcium-dependent augmentation of mVO(2) and ROS production upon complex I injury. This new effect of carvedilol might partly explain the beneficial effect of carvedilol for the treatment of heart failure.
Kametani
Ryosuke
R
The Department of Cardiovascular Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Miura
Toshiro
T
Harada
Nozomu
N
Shibuya
Masaki
M
Wang
Ruijuan
R
Tan
Hong
H
Fukagawa
Yasuhiro
Y
Kawamura
Shuji
S
Matsuzaki
Masunori
M
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077261:Carvedilol; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology; D011412:Propanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D017382:Reactive Oxygen Species; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D013481:Superoxides; D008790:Metoprolol; D002118:Calcium