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 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/microl. ATV (51.0 +/- 4.9 pg/microl) and DIP (51.5 +/- 6.8 pg/microl) caused a small increase in adenosine levels, whereas ATV + DIP caused a greater increase in adenosine levels (66.4 +/- 3.1 pg/microl). 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.
Ye
Yumei
Y
Division of Cardiology, University of Texas Medical Branch, 5.106 John Sealy Annex, 301 University Blvd., Galveston, TX 77555-0553, USA.
Lin
Yu
Y
Perez-Polo
Regino
R
Huang
Ming-He
MH
Hughes
Michael G
MG
McAdoo
David J
DJ
Manickavasagam
Saraswathy
S
Uretsky
Barry F
BF
Birnbaum
Yochai
Y
D000241:Adenosine / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000069059:Atorvastatin; D002316:Cardiotonic Agents / Q000008:administration & dosage; D004176:Dipyridamole / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D006538:Heptanoic Acids / Q000008:administration & dosage*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000378:metabolism* / Q000517:prevention & control*; D011758:Pyrroles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D002316:Cardiotonic Agents; D004338:Drug Combinations; D006538:Heptanoic Acids; D011758:Pyrroles; D004176:Dipyridamole; D000069059:Atorvastatin; D000241:Adenosine