Abstract 9963: The A2B Adenosine Receptor Antagonist (GS-6201) Improves Cardiac Remodeling and Dysfunction after Myocardial Infarction (MI) in Rat
Activation of A2B adenosine receptors in cardiac cells stimulates the release of inflammatory cytokines and fibrotic mediators. Adenosine concentration is elevated and A2B receptor expression is increased in hypoxic /ischemic myocardium. In the present study, the effect of GS-6201 (GS), a selective and potent A2B adenosine receptor antagonist (Ki 8.3 nM), alone or in combination with enalapril (ENL), was evaluated in a rat model of MI-induced cardiac remodeling and dysfunction (25-min myocardial ischemia followed by 5-wk reperfusion). Starting one week after MI, animals (n=8-13/group) were treated with GS (30 mg/kg), ENL (6 mg/kg), GS+ ENL or placebo via oral gavage once daily for 4 weeks. Serial echocardiographic assessments of LV geometry and function were conducted at baseline, 1, 3 and 5 weeks after MI. Significant cardiac dysfunction, hypertrophy and fibrosis developed in placebo treated animals. Compared to the placebo, GS, ENL and GS+ENL significantly improved LV ejection fraction (EF) and fractional shortening (FS), reduced LV end-systolic volume and decreased myocardial fibrosis at 5 week post MI. GS, ENL and GS+ ENL also significantly ameliorated plasma biomarkers including IL-6, TGF-β1 and BNP. Data were shown in Table 1. In summary, A2B adenosine receptor antagonist GS-6201 effectively reduced MI-induced LV remodeling and dysfunction in a rat model, possibly mediated through anti-inflammatory and anti-fibrotic mechanisms. The effects of GS-6201 and ENL were comparable, while the combination of GS-6201 with ENL provided an additional benefit.
- © 2012 by American Heart Association, Inc.