Dipyridamole with Low-Dose Aspirin Augments the Infarct Size-Limiting Effects of Simvastatin

Abstract

PurposeStatins 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).MethodsRats 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).ResultsSIM 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.ConclusionsDuring 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.

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…Blockade of COX-2 can abolish the cardioprotective phenomena, most importantly delayed or second window preconditioning (Przyklenk and Heusch, 2003;Huhn et al, 2009a;Guo et al, 2012). High-dose aspirin, which blocks both COX-1 and COX-2, interferes with endogenous cardioprotection (Ye et al, 2010b). Nevertheless, many patients with an acute MI receive high-dose aspirin (.300 mg) orally or intravenously.…”

Time to Give Up on Cardioprotection?

“…Only high-dose aspirin that blocks both cyclo-oxygenase 1 and 2 seems to interfere with cardioprotection. 215,216 While a patient with coronary artery disease who suffers an AMI or undergoes a cardiovascular intervention will likely have one or more of the above drugs on board, nitrates, opioids, and purinergic receptor 2Y 12 (P2Y 12 ) antagonists would be administered acutely to induce coronary vasodilation and control blood pressure, to reduce pain, and to inhibit platelet aggregation. Although chronic nitrate use and nitrate tolerance abrogate protection by conditioning interventions, 217,218 the acute use of nitrates during surgical coronary revascularization does not interfere with protection by remote ischemia preconditioning.…”

Chronic Treatment With Ticagrelor Limits Myocardial Infarct Size

“…18,27,28 We found that the IS-limiting effect of ticagrelor was abrogated with CGS15943, an adenosine-receptor antagonist, whereas CGS15943 alone or in combination with clopidogrel had no effect (Figure 2). Moreover, CGS15943 abolished ticagrelorinduced upregulation of cNOS, cPLA 2 , and COX2 activities (Figure 3), upregulation of Akt and eNOS phosphorylation, …”

“…16,17 For instance, statins activate ecto-5′ nucleotidase that converts AMP into adenosine 18 , and the IS-limiting effect of statins is dependent on adenosine-receptor activation. 18,27,28 We found that the IS-limiting effect of ticagrelor was abrogated with CGS15943, an adenosine-receptor antagonist, whereas CGS15943 alone or in combination with clopidogrel had no effect (Figure 2). Moreover, CGS15943 abolished ticagrelorinduced upregulation of cNOS, cPLA 2 , and COX2 activities (Figure 3), upregulation of Akt and eNOS phosphorylation, and upregulation of COX2 mRNA levels ( Figure 4).…”