Dipyridamole with low-dose aspirin augments the infarct size-limiting effects of simvastatin.
OBJECTIVE
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.
Ye
Yumei
Y
Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
Long
Bo
B
Qian
Jinqiao
J
Perez-Polo
Jose R
JR
Birnbaum
Yochai
Y
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D004176:Dipyridamole; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001241:Aspirin