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(Circulation Research. 2003;93:759.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Activation of Adenosine A₁ Receptor Attenuates Cardiac Hypertrophy and Prevents Heart Failure in Murine Left Ventricular Pressure-Overload Model

Yulin Liao^*, Seiji Takashima^*, Yoshihiro Asano^*, Masanori Asakura, Akiko Ogai, Yasunori Shintani, Tetsuo Minamino, Hiroshi Asanuma, Shoji Sanada, Jiyoong Kim, Hisakazu Ogita, Hitonobu Tomoike, Masatsugu Hori, Masafumi Kitakaze

From the Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine (Y.L., S.T., Y.A., M.A., Y.S., T.M., H.A., S.S., H.O., M.H.) and Cardiovascular Division of Internal Medicine, National Cardiovascular Center (A.O., J.K., H.T., M.K.), Osaka, Japan.

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

Sympathomimetic stimulation, angiotensin II, or endothelin-1 is considered to be an essential stimulus mediating ventricular hypertrophy. Adenosine is known to protect the heart from excessive catecholamine exposure, reduce production of endothelin-1, and attenuate the activation of the renin-angiotensin system. These findings suggest that adenosine may also attenuate myocardial hypertrophy. To verify this hypothesis, we examined whether activation of adenosine receptors can attenuate cardiac hypertrophy and reduce the risk of heart failure. Our in vitro study of neonatal rat cardiomyocytes showed that 2-chloroadenosine (CADO), a stable adenosine analogue, inhibits protein synthesis of cardiomyocytes induced by phenylephrine, endothelin-1, angiotensin II, or isoproterenol, which were mimicked by the stimulation of adenosine A₁ receptors. For our in vivo study, cardiac hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6 male mice. Four weeks after TAC, both heart to body weight ratio (6.80±0.18 versus 8.34±0.33 mg/g, P<0.0001) as well as lung to body weight ratio (6.23±0.27 versus 10.03±0.85 mg/g, P<0.0001) became significantly lower in CADO-treated mice than in the TAC group. Left ventricular fractional shortening and left ventricular dP/dt_max were improved significantly by CADO treatment. Similar results were obtained using the selective adenosine A₁ agonist N⁶-cyclopentyladenosine (CPA). A nonselective adenosine antagonist, 8-(p-sulfophenyl)-theophylline, and a selective adenosine A₁ antagonist, 8-cyclopentyl-1,3-dipropylxanthine, eliminated the antihypertrophic effect of CADO and CPA, respectively. The plasma norepinephrine level was decreased and myocardial expression of regulator of G protein signaling 4 was upregulated in CADO-treated mice. These results indicate that the stimulation of adenosine receptors attenuates both the cardiac hypertrophy and myocardial dysfunction via adenosine A₁ receptor–mediated mechanisms.

Key Words: adenosine • cardiomyopathy • echocardiography • heart failure • myocytes

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