Beta-adrenoceptor blocker carvedilol provides cardioprotection via an adenosine-dependent mechanism in ischemic canine hearts.
BACKGROUND
Carvedilol is a beta-adrenoceptor blocker with a vasodilatory action that is more effective for the treatment of congestive heart failure than other beta-blockers. Recently, carvedilol has been reported to reduce oxidative stress, which may consequently reduce the deactivation of adenosine-producing enzymes and increase cardiac adenosine levels. Therefore, carvedilol may also have a protective effect on ischemia and reperfusion injury, because adenosine mediates cardioprotection in ischemic hearts.


RESULTS
In anesthetized dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours. Carvedilol reduced the infarct size (15.0+/-2.8% versus 40.9+/-4.2% in controls), and this effect was completely reversed by the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (45.2+/-5.4%) or by an inhibitor of ecto-5'-nucleotidase (44.4+/-3.6%). There were no differences of either area at risk or collateral flow among the various groups. When the coronary perfusion pressure was reduced in other dogs so that coronary blood flow was decreased to 50% of the nonischemic level, carvedilol increased coronary blood flow (49.4+/-5.6 to 73.5+/-7.5 mL x 100 g(-1) x min(-1); P<0.05) and adenosine release (112.3+/-22.2 to 240.6+/-57.1 nmol/L; P<0.05) during coronary hypoperfusion. This increase of coronary blood flow was attenuated by either 8-sulfophenyltheophylline or superoxide dismutase. In human umbilical vein endothelial cells cultured with or without xanthine and xanthine oxidase, carvedilol caused an increase of ecto-5'-nucleotidase activity.


CONCLUSIONS
Carvedilol shows a cardioprotective effect against ischemia and/or reperfusion injury via adenosine-dependent mechanisms.
Asanuma
Hiroshi
H
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
Minamino
Tetsuo
T
Sanada
Shoji
S
Takashima
Seiji
S
Ogita
Hisakazu
H
Ogai
Akiko
A
Asakura
Masanori
M
Liao
Yulin
Y
Asano
Yoshihiro
Y
Shintani
Yasunori
Y
Kim
Jiyoong
J
Shinozaki
Yoshiro
Y
Mori
Hidezo
H
Node
Koichi
K
Kitamura
Soichiro
S
Tomoike
Hitonobu
H
Hori
Masatsugu
M
Kitakaze
Masafumi
M
D015720:5'-Nucleotidase / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism / Q000502:physiology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077261:Carvedilol; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects*; D004285:Dogs; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011412:Propanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D011433:Propranolol / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D011433:Propranolol; D015720:5'-Nucleotidase; D000241:Adenosine