Ye Y, Lin Y, Perez-Polo R, Huang MH, Hughes MG, McAdoo DJ, Manickavasagam S, Uretsky BF, Birnbaum Y. Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination. Atorvastatin (ATV) limits infarct size (IS) by activating Akt and ecto-5-nucleotidase, which generates adenosine. Activated Akt and adenosine activate endothelial nitric oxide synthase (eNOS). When given orally, high doses (10 mg/kg) are needed to achieve full protection. We

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... termined whether dipyridamole (DIP), by preventing the reuptake of adenosine, has a synergistic effect with ATV in reducing myocardial IS. In this study, rats received 3-days of the following: water, ATV (2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), DIP (6 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), or ATV ϩ DIP. In addition, rats received 3-days of the following: aminophylline (Ami; 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) or Ami ϩ ATV ϩ DIP. Rats underwent 30 min of myocardial ischemia followed by 4 h of reperfusion (IS protocol), or hearts were explanted for immunoblotting. As a result, IS in the controls was 34.0 Ϯ 2.8% of the area at risk. ATV (33.1 Ϯ 2.1%) and DIP (30.5 Ϯ 1.5%) did not affect IS, whereas ATV ϩ DIP reduced IS (12.2 Ϯ 0.5%; P Ͻ 0.001 vs. each of the other groups). There was no difference in IS between the Ami alone (48.1 Ϯ 0.8%) and the Ami ϩ ATV ϩ DIP (45.8 Ϯ 2.9%) group (P ϭ 0.422), suggesting that Ami completely blocked the protective effect. Myocardial adenosine level in the controls was 30.6 Ϯ 3.6 pg/l. ATV (51.0 Ϯ 4.9 pg/l) and DIP (51.5 Ϯ 6.8 pg/l) caused a small increase in adenosine levels, whereas ATV ϩ DIP caused a greater increase in adenosine levels (66.4 Ϯ 3.1 pg/l). ATV and DIP alone did not affect myocardial Ser473 phosphorylated-Akt and Ser1177 phosphorylated-eNOS levels, whereas ATV ϩ DIP significantly increased them. In conclusion, low-dose ATV and DIP had synergistic effects in reducing myocardial IS and activation of Akt and eNOS. This combination may have a potential benefit in augmenting the eNOS-mediated pleiotropic effects of statins. adenosine; Akt; infarct size; nitric oxide synthase Address for reprint requests and other correspondence: Y. Birnbaum,