Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, VA, USA.
J Pharmacol Exp Ther. 2012 Dec;343(3):587-95. doi: 10.1124/jpet.111.191288. Epub 2012 Aug 24.
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.
腺苷（Ado）在组织损伤时释放，促进充血，并调节炎症。Ado 的促炎作用是通过 A（2B）Ado 受体（AdoR）介导的，可能会加重组织损伤。我们假设，在急性心肌梗死（AMI）期间，用 3-乙基-1-丙基-8-（1-（3-三氟甲基苯甲基）-1H-吡唑-4-基）-3,7-二氢嘌呤-2,6-二酮（GS-6201）选择性阻断 A（2B）AdoR，可减少不良的心脏重塑。雄性 ICR 小鼠接受冠状动脉结扎或假手术（每组 10-12 只）。选择性 A（2B）AdoR 拮抗剂 GS-6201（4mg/kg）在手术后立即腹膜内给药，每天两次，持续 14 天。在手术前和手术后 7、14 和 28 天进行经胸超声心动图检查。手术后 72 小时，处死一小部分小鼠，测量心脏组织中关键促炎介质半胱氨酸蛋白酶-1 的活性。所有假手术组的小鼠在 4 周时均存活，而在手术后 4 周时，50%的载体治疗组和 75%的 GS-6201 治疗组的小鼠存活。与载体相比，GS-6201 治疗可在 AMI 后 72 小时防止心脏中半胱氨酸蛋白酶-1 的激活（P<0.001），并显著限制左心室（LV）舒张末期直径增加 40%（P<0.001），LV 射血分数降低 18%（P<0.01），心肌性能指数变化 88%（P<0.001）。在 AMI 后 28 天，选择性阻断 A（2B）AdoR 用 GS-6201 可降低心脏中的半胱氨酸蛋白酶-1 活性，并导致 AMI 后心脏重塑更加有利。
