Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination

Abstract

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 determined 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·kg−1·day−1), DIP (6 mg·kg−1·day−1), or ATV + DIP. In addition, rats received 3-days of the following: aminophylline (Ami; 10 mg·kg−1·day−1) or Ami + ATV + 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 ± 2.8% of the area at risk. ATV (33.1 ± 2.1%) and DIP (30.5 ± 1.5%) did not affect IS, whereas ATV + DIP reduced IS (12.2 ± 0.5%; P < 0.001 vs. each of the other groups). There was no difference in IS between the Ami alone (48.1 ± 0.8%) and the Ami + ATV + DIP (45.8 ± 2.9%) group ( P = 0.422), suggesting that Ami completely blocked the protective effect. Myocardial adenosine level in the controls was 30.6 ± 3.6 pg/μl. ATV (51.0 ± 4.9 pg/μl) and DIP (51.5 ± 6.8 pg/μl) caused a small increase in adenosine levels, whereas ATV + DIP caused a greater increase in adenosine levels (66.4 ± 3.1 pg/μl). ATV and DIP alone did not affect myocardial Ser473 phosphorylated-Akt and Ser1177 phosphorylated-eNOS levels, whereas ATV + 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.