PT - JOURNAL ARTICLE AU - Toldo, Stefano AU - Zhong, Hongyan AU - Mezzaroma, Eleonora AU - Van Tassell, Benjamin W. AU - Kannan, Harsha AU - Zeng, Dewan AU - Belardinelli, Luiz AU - Voelkel, Norbert F. AU - Abbate, Antonio TI - GS-6201, a Selective Blocker of the A<sub>2B</sub> Adenosine Receptor, Attenuates Cardiac Remodeling after Acute Myocardial Infarction in the Mouse AID - 10.1124/jpet.111.191288 DP - 2012 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 587--595 VI - 343 IP - 3 4099 - http://jpet.aspetjournals.org/content/343/3/587.short 4100 - http://jpet.aspetjournals.org/content/343/3/587.full SO - J Pharmacol Exp Ther2012 Dec 01; 343 AB - Adenosine (Ado) is released in response to tissue injury, promotes hyperemia, and modulates inflammation. The proinflammatory effects of Ado, which are mediated by the A2B Ado receptor (AdoR), may exacerbate tissue damage. We hypothesized that selective blockade of the A2B AdoR with 3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione (GS-6201) during acute myocardial infarction (AMI) would reduce adverse cardiac remodeling. Male ICR mice underwent coronary artery ligation or sham surgery (n = 10–12 per group). The selective A2B AdoR antagonist GS-6201 (4 mg/kg) was given intraperitoneally twice daily starting immediately after surgery and continuing for 14 days. Transthoracic echocardiography was performed before surgery and after 7, 14, and 28 days. A subgroup of mice was killed 72 h after surgery, and the activity of caspase-1, a key proinflammatory mediator, was measured in the cardiac tissue. All sham-operated mice were alive at 4 weeks, whereas 50% of vehicle-treated mice and 75% of GS-6201-treated mice were alive at 4 weeks after surgery. Compared with vehicle, treatment with GS-6201 prevented caspase-1 activation in the heart at 72 h after AMI (P &lt; 0.001) and significantly limited the increase in left ventricular (LV) end-diastolic diameter by 40% (P &lt; 0.001), the decrease in LV ejection fraction by 18% (P &lt; 0.01) and the changes in the myocardial performance index by 88% (P &lt; 0.001) at 28 days after AMI. Selective blockade of A2B AdoR with GS-6201 reduces caspase-1 activity in the heart and leads to a more favorable cardiac remodeling after AMI in the mouse.