title: GS-6201, a selective blocker of the A2B adenosine receptor, attenuates cardiac remodeling after acute myocardial infarction in the mouse.
abstract: Adenosine (Ado) is released in response to tissue injury, promotes hyperemia, and modulates inflammation. The proinflammatory effects of Ado, which are mediated by the A(2B) Ado receptor (AdoR), may exacerbate tissue damage. We hypothesized that selective blockade of the A(2B) 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 A(2B) 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 < 0.001) and significantly limited the increase in left ventricular (LV) end-diastolic diameter by 40% (P < 0.001), the decrease in LV ejection fraction by 18% (P < 0.01) and the changes in the myocardial performance index by 88% (P < 0.001) at 28 days after AMI. Selective blockade of A(2B) AdoR with GS-6201 reduces caspase-1 activity in the heart and leads to a more favorable cardiac remodeling after AMI in the mouse.
authors.affiliation: Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhong
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Van Tassell
authors.forename: Harsha
authors.initials: H
authors.lastname: Kannan
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004452:Echocardiography; D004789:Enzyme Activation; D006439:Hemodynamics / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011687:Purines; D011720:Pyrazoles; D043704:Receptor, Adenosine A2B; C518643:3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione; D020170:Caspase 1