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(Circulation. 2004;109:2773-2779.)
© 2004 American Heart Association, Inc.

Basic Science Reports

ß-Adrenoceptor Blocker Carvedilol Provides Cardioprotection via an Adenosine-Dependent Mechanism in Ischemic Canine Hearts

Hiroshi Asanuma, MD, PhD; Tetsuo Minamino, MD, PhD; Shoji Sanada, MD, PhD; Seiji Takashima, MD, PhD; Hisakazu Ogita, MD, PhD; Akiko Ogai, BS; Masanori Asakura, MD, PhD; Yulin Liao, MD; Yoshihiro Asano, MD, PhD; Yasunori Shintani, MD; Jiyoong Kim, MD; Yoshiro Shinozaki, BS; Hidezo Mori, MD, PhD; Koichi Node, MD, PhD; Soichiro Kitamura, MD, PhD; Hitonobu Tomoike, MD, PhD; Masatsugu Hori, MD, PhD; Masafumi Kitakaze, MD, PhD

From the Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita (H.A., T.M., S.S., S.T., H.O., M.A., Y.L., Y.A., Y. Shintani, K.N., M.H.); the Cardiovascular Division, National Cardiovascular Center, Suita (A.O., J.K., H.M., S.K., H.T., M.K.); and the Physiology Department, Tokai University School of Medicine, Isehara (Y. Shinozaki), Japan.

Correspondence to Masafumi Kitakaze, MD, Cardiovascular Division, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita City, Osaka Pref. 565-8565, Japan. E-mail kitakaze{at}zf6.so-net.ne.jp

Received July 23, 2003; de novo received December 18, 2003; revision received February 18, 2004; accepted February 25, 2004.

Background— Carvedilol is a ß-adrenoceptor blocker with a vasodilatory action that is more effective for the treatment of congestive heart failure than other ß-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.

Methods and 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 · 100 g^–1 · 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.

Key Words: adenosine • stress • ischemia • reperfusion • infarction

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