Dipyridamole with low-dose aspirin augments the infarct size-limiting effects of simvastatin

Yumei Ye, Bo Long, Jinqiao Qian, Jose R. Perez-Polo, Yochai Birnbaum

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Purpose: Statins protect against ischemia-reperfusion injury and limit myocardial infarct size (IS). This effect is dependent on increased generation of adenosine by ecto-5′ nucleotidase and downstream activation of cyclooxygenase-2 (COX2). Dipyridamole (DIP) augments the IS-limiting effects of statins by blocking the cellular reuptake of adenosine; whereas aspirin (ASA) attenuates the effect by inhibiting COX2. We studied the effect of acute administration of DIP, ASA and their combination on the IS-limiting effect of simvastatin (SIM). Methods: Rats received oral SIM (10 mg/kg/d) or vehicle for 3 days. Rats underwent 30 min of coronary artery occlusion and 4 h reperfusion. After 5 min of ischemia rats received i.v. DIP (5 mg/kg), ASA (20 mg/kg or 2 mg/kg) or DIP+ASA (2 mg/kg) or vehicle alone. Ischemia area at risk (AR) was assessed by blue dye and IS by TTC. Myocardial samples were analyzed for the activation of Akt, ERK 1/2, endothelial nitric oxide synthase (eNOS), and cyclic-AMP-response-element-binding-protein (CREB). Results: SIM limited IS. High- or low-dose ASA alone had no effect on IS. DIP alone or with low-dose ASA significantly reduced IS. Low-dose ASA did not attenuate the SIM effect, whereas high-dose ASA completely blocked the effect. The combination of DIP+low-dose ASA+SIM resulted in the smallest IS. Both SIM and DIP+low-dose ASA augmented Akt phosphorylation and their effect was additive. Both SIM and DIP+low-dose ASA augmented eNOS, ERK 1/2 and CREB phosphorylation. Conclusions: During acute myocardial ischemia, DIP alone or with low-dose ASA limits IS and does not attenuate the IS-limiting effect of SIM as high-dose ASA.

Original languageEnglish (US)
Pages (from-to)391-399
Number of pages9
JournalCardiovascular Drugs and Therapy
Volume24
Issue number5-6
DOIs
StatePublished - Dec 2010

Fingerprint

Simvastatin
Dipyridamole
Aspirin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Cyclic AMP Response Element-Binding Protein
Nitric Oxide Synthase Type III
Cyclooxygenase 2
Adenosine
Ischemia
Phosphorylation
5'-Nucleotidase
Coronary Occlusion
Reperfusion Injury
Reperfusion
Myocardial Ischemia
Coronary Vessels
Coloring Agents
Myocardial Infarction

Keywords

  • Adenosine
  • Aspirin
  • Dipyridamole
  • Reperfusion injury
  • Statins

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Dipyridamole with low-dose aspirin augments the infarct size-limiting effects of simvastatin. / Ye, Yumei; Long, Bo; Qian, Jinqiao; Perez-Polo, Jose R.; Birnbaum, Yochai.

In: Cardiovascular Drugs and Therapy, Vol. 24, No. 5-6, 12.2010, p. 391-399.

Research output: Contribution to journalArticle

Ye, Yumei ; Long, Bo ; Qian, Jinqiao ; Perez-Polo, Jose R. ; Birnbaum, Yochai. / Dipyridamole with low-dose aspirin augments the infarct size-limiting effects of simvastatin. In: Cardiovascular Drugs and Therapy. 2010 ; Vol. 24, No. 5-6. pp. 391-399.
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T1 - Dipyridamole with low-dose aspirin augments the infarct size-limiting effects of simvastatin

AU - Ye, Yumei

AU - Long, Bo

AU - Qian, Jinqiao

AU - Perez-Polo, Jose R.

AU - Birnbaum, Yochai

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N2 - Purpose: Statins protect against ischemia-reperfusion injury and limit myocardial infarct size (IS). This effect is dependent on increased generation of adenosine by ecto-5′ nucleotidase and downstream activation of cyclooxygenase-2 (COX2). Dipyridamole (DIP) augments the IS-limiting effects of statins by blocking the cellular reuptake of adenosine; whereas aspirin (ASA) attenuates the effect by inhibiting COX2. We studied the effect of acute administration of DIP, ASA and their combination on the IS-limiting effect of simvastatin (SIM). Methods: Rats received oral SIM (10 mg/kg/d) or vehicle for 3 days. Rats underwent 30 min of coronary artery occlusion and 4 h reperfusion. After 5 min of ischemia rats received i.v. DIP (5 mg/kg), ASA (20 mg/kg or 2 mg/kg) or DIP+ASA (2 mg/kg) or vehicle alone. Ischemia area at risk (AR) was assessed by blue dye and IS by TTC. Myocardial samples were analyzed for the activation of Akt, ERK 1/2, endothelial nitric oxide synthase (eNOS), and cyclic-AMP-response-element-binding-protein (CREB). Results: SIM limited IS. High- or low-dose ASA alone had no effect on IS. DIP alone or with low-dose ASA significantly reduced IS. Low-dose ASA did not attenuate the SIM effect, whereas high-dose ASA completely blocked the effect. The combination of DIP+low-dose ASA+SIM resulted in the smallest IS. Both SIM and DIP+low-dose ASA augmented Akt phosphorylation and their effect was additive. Both SIM and DIP+low-dose ASA augmented eNOS, ERK 1/2 and CREB phosphorylation. Conclusions: During acute myocardial ischemia, DIP alone or with low-dose ASA limits IS and does not attenuate the IS-limiting effect of SIM as high-dose ASA.

AB - Purpose: Statins protect against ischemia-reperfusion injury and limit myocardial infarct size (IS). This effect is dependent on increased generation of adenosine by ecto-5′ nucleotidase and downstream activation of cyclooxygenase-2 (COX2). Dipyridamole (DIP) augments the IS-limiting effects of statins by blocking the cellular reuptake of adenosine; whereas aspirin (ASA) attenuates the effect by inhibiting COX2. We studied the effect of acute administration of DIP, ASA and their combination on the IS-limiting effect of simvastatin (SIM). Methods: Rats received oral SIM (10 mg/kg/d) or vehicle for 3 days. Rats underwent 30 min of coronary artery occlusion and 4 h reperfusion. After 5 min of ischemia rats received i.v. DIP (5 mg/kg), ASA (20 mg/kg or 2 mg/kg) or DIP+ASA (2 mg/kg) or vehicle alone. Ischemia area at risk (AR) was assessed by blue dye and IS by TTC. Myocardial samples were analyzed for the activation of Akt, ERK 1/2, endothelial nitric oxide synthase (eNOS), and cyclic-AMP-response-element-binding-protein (CREB). Results: SIM limited IS. High- or low-dose ASA alone had no effect on IS. DIP alone or with low-dose ASA significantly reduced IS. Low-dose ASA did not attenuate the SIM effect, whereas high-dose ASA completely blocked the effect. The combination of DIP+low-dose ASA+SIM resulted in the smallest IS. Both SIM and DIP+low-dose ASA augmented Akt phosphorylation and their effect was additive. Both SIM and DIP+low-dose ASA augmented eNOS, ERK 1/2 and CREB phosphorylation. Conclusions: During acute myocardial ischemia, DIP alone or with low-dose ASA limits IS and does not attenuate the IS-limiting effect of SIM as high-dose ASA.

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