Objective-In a phase III clinical trial (PLATelet inhibition and patient Outcomes, PLATO), ticagrelor provided better clinical outcomes than clopidogrel in patients with acute coronary syndromes. In addition to P2Y 12 -receptor antagonism, ticagrelor prevents cell uptake of adenosine and has proven able to augment adenosine effects. Adenosine protects the heart against ischemia-reperfusion injury. We compared the effects of clopidogrel and ticagrelor on myocardial infarct size (IS). Approach and Results-Rats received oral ticagrelor (0, 75, 150, or 300 mg/kg/d) or clopidogrel (30 or 90 mg/kg/d) for 7 days and underwent 30-minute coronary artery ligation and 24-hour reperfusion. Area at risk was assessed by blue dye and IS by 2,3,5-triphenyl-tetrazolium-chloride. Cyclooxygenase-2 (COX2) enzyme activity was assessed by ELISA and expression by real-time polymerase chain reaction. Mechanism responsible was explored using adenosine-receptor antagonist (CGS15943, an A 2A /A 1 antagonist) or cyclooxygenase inhibition by either aspirin (5, 10, or 25 mg/kg) or specific cyclooxygenase-1 (SC560) or COX2 (SC5815) inhibitors. Ticagrelor, dose-dependently, reduced IS, whereas clopidogrel had no effect. Adenosine-receptor antagonism blocked the ticagrelor effect and COX2 inhibition by SC5815, or high-dose aspirin attenuated the IS-limiting effect of ticagrelor, whereas cyclooxygenase-1 inhibition or low-dose aspirin had no effect. Ticagrelor, but not clopidogrel, upregulated COX2 expression and activity. Also this effect was blocked by adenosine-receptor antagonism. Ticagrelor, but not clopidogrel, increased Akt and endothelial nitric oxide synthase phosphorylation.
Conclusions-Ticagrelor
Nanhwan et al Ticagrelor Limits Infarct Size 2079and that higher doses of aspirin may attenuate COX2 activity 1 and thereby part of the beneficial effects mediated by ticagrelor.In this study, we evaluated whether pretreatment with ticagrelor or clopidogrel limits myocardial IS, using an experimental model of transient mechanical coronary artery occlusion that is independent of intraluminal thrombus formation. Next, we studied the signaling pathways mediating this protective effect with special emphasis on the role of adenosine-receptor activation and COX2 activity.
Materials and MethodsMaterials and Methods are available in the online-only Supplement.
Results
Ticagrelor Limits Myocardial ISA total of 8 rats died during surgery (2 in the control, 1 in the ticagrelor 75 mg/kg/d, 1 in the ticagrelor 150 mg/kg/d, 2 in the clopidogrel 30 mg/kg/d, and 2 in the clopidogrel 90 mg/kg/d group). Body weight, left ventricular (LV) weight, and the size of the area at risk (AR) were comparable among groups (Table 1). IS, expressed as percentage of the LV (Table 1) or percentage of the AR ( Figure 1A), was significantly and dose-dependently reduced in the ticagrelor-treated animals, whereas clopidogrel at 30 and 90 mg/kg/d had no effect. Hemodynamic data are presented in Figure IA and IB in the online-only Data Supplement.Plasma levels of ticagrelor 16 ho...
