Published Online
on October 16, 2006

A more recent version of this article appeared on October 31, 2006

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Submitted on March 30, 2006
Revised on August 22, 2006
Accepted on August 28, 2006

Long-Term Stimulation of Adenosine A2b Receptors Begun After Myocardial Infarction Prevents Cardiac Remodeling in Rats

Masakatsu Wakeno MD, Tetsuo Minamino MD, PhD, Osamu Seguchi MD, Hidetoshi Okazaki MD, Osamu Tsukamoto MD, PhD, Ken-ichiro Okada MD, PhD, Akio Hirata MD, PhD, Masashi Fujita MD, PhD, Hiroshi Asanuma MD, PhD, Jiyoong Kim MD, Kazuo Komamura MD, PhD, Seiji Takashima MD, PhD, Naoki Mochizuki MD, PhD, and Masafumi Kitakaze MD, PhD^*

From the Departments of Bioregulatory Medicine (M.W., O.S., H.O., N.M.) and Cardiovascular Medicine (T.M., O.T., K.-i.O., A.H., M.F., S.T.), Osaka University Graduate School of Medicine, and Divisions of Cardiovascular Medicine (M.W., O.S., H.O., H.A., K.K., J.K., M.K.) and Structural Analysis (M.W., O.S., H.O., N.M.), National Cardiovascular Center, Suita, Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: kitakaze{at}zf6.so-net.ne.jp.

Background--Adenosine inhibits proliferation of cardiac fibroblasts and hypertrophy of cardiomyocytes, both of which may play crucial roles in cardiac remodeling. In the present study, we investigated whether chronic stimulation of adenosine receptors begun after myocardial infarction (MI) prevents cardiac remodeling.

Methods and Results--MI was produced in Wistar rats by permanent ligation of the left anterior descending coronary artery. One week after the onset of MI, animals were randomized into 8 groups: vehicle, dipyridamole (DIP; the adenosine uptake inhibitor, 50 mg/kg), 2-chroloadenosine (CADO; the stable analogue of adenosine, 2 mg/kg), and CADO in the presence of the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (8-SPT) or the selective antagonist for adenosine A1, A2a, A2b, or A3 receptor. Three weeks after treatment, hemodynamic and echocardiographic parameters in the DIP and CADO groups were significantly improved compared with the vehicle group. These hemodynamic and echocardiographic improvements were blunted by either 8-SPT or the selective adenosine A2b antagonist MRS1754 but not by the selective antagonists for other subtypes of adenosine receptors. The collagen volume fraction was smaller, and gene expression of the molecules associated with cardiac remodeling such as matrix metalloproteinase in noninfarcted areas was reduced in the DIP and CADO groups compared with the vehicle group, both of which were attenuated by either 8-SPT or MRS1754.

Conclusions--Long-term stimulation of adenosine A2b receptors begun after MI attenuates cardiac fibrosis in the noninfarcted myocardium and improves cardiac function. Drugs that stimulate adenosine A2b receptors or increase adenosine levels are new candidates for preventing cardiac remodeling after MI.

Key words: adenosine • heart failure • myocardial infarction • remodeling

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