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

Yumei Ye, Yu Lin, Regino Perez-Polo, Ming He Huang, Michael G. Hughes, David J. McAdoo, Saraswathy Manickavasagam, Barry F. Uretsky, Yochai Birnbaum

Research output: Contribution to journalArticle

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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/μ-l. ATV (51.0 ± 4.9 pg/μ-l) 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/μ-l). 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number1
DOIs
StatePublished - Jul 2007

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Dipyridamole
Reperfusion Injury
Adenosine
Nitric Oxide Synthase Type III
Atorvastatin Calcium
Myocardial Infarction
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Aminophylline
5'-Nucleotidase
Immunoblotting
Reperfusion
Myocardial Ischemia

Keywords

  • Adenosine
  • Akt
  • Infarct size
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Physiology

Cite this

Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination. / Ye, Yumei; Lin, Yu; Perez-Polo, Regino; Huang, Ming He; Hughes, Michael G.; McAdoo, David J.; Manickavasagam, Saraswathy; Uretsky, Barry F.; Birnbaum, Yochai.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 293, No. 1, 07.2007.

Research output: Contribution to journalArticle

Ye, Yumei ; Lin, Yu ; Perez-Polo, Regino ; Huang, Ming He ; Hughes, Michael G. ; McAdoo, David J. ; Manickavasagam, Saraswathy ; Uretsky, Barry F. ; Birnbaum, Yochai. / Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination. In: American Journal of Physiology - Heart and Circulatory Physiology. 2007 ; Vol. 293, No. 1.
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AU - Perez-Polo, Regino

AU - Huang, Ming He

AU - Hughes, Michael G.

AU - McAdoo, David J.

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N2 - 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/μ-l. ATV (51.0 ± 4.9 pg/μ-l) 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/μ-l). 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.

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KW - Adenosine

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