TICAGRELOR LIMITS MYOCARDIAL INFARCT SIZE- AN ADENOSINE AND COX2 DEPENDENT EFFECT
Yochai Birnbaum, M.D., Baylor College of Medicine, Texas, USA
Background: In a phase III clinical trial (PLATO) Ticagrelor (TIC) showed better clinical outcomes than Clopidogrel (CLOP) in patients with acute coronary syndromes. In addition to P2Y12 receptor antagonism, TIC prevents cell uptake of adenosine and thus, may augment adenosine effects. Adenosine protects the heart against ischemia-reperfusion injury. We compared the effects of CLOP and TIC on myocardial infarct size (IS).
Methods: Rats received oral TIC (0, 75, 150 or 300 mg/kg/d) or CLOP (30 or 90 mg/kg/d) for 7d and underwent 30min coronary artery ligation and 24h reperfusion. Area at risk (AR) was assessed by blue dye and IS by TTC. We assessed whether adenosine receptor inhibition (CGS15943, an A2A/A1 antagonist) or COX inhibition by either aspirin (5, 10, or 25 mg/kg) or specific COX1 (SC560) or COX2 (SC5815) inhibitors could reduce the IS-limiting effects of TIC. COX2 enzyme activity was assessed by ELISA and expression by rt-PCR.
Results: TIC, dose-dependently, reduced IS (IS in the control group was 53.2±2.4% of the AR and 42.2±1.6%, 34.7±1.3% and 22.3±1.3% in the TIC 75, 150 and 300 mg/kg/d, respectively), whereas CLOP had no effect (50.2±1.1% and 50.5±2.0%, respectively). Adenosine receptor antagonism blocked the TIC effect. COX2 inhibition by SC5815 or high-dose (10 and 25 mg/kg/d) aspirin attenuated the IS-limiting effect of TIC, whereas COX1 inhibition or low-dose aspirin (5 mg/kg/d) had no effect. TIC, but not CLOP, upregulated COX2 expression and activity. This effect was blocked by adenosine receptor antagonism. TIC, but not CLOP increased Akt and eNOS phosphorylation.
Conclusions: TIC, but not CLP reduces myocardial IS. The protective effect of TIC was dependent on adenosine receptor activation with downstream upregulation of eNOS and COX2 activity. Blocking COX2 with either specific COX2 inhibitor or high-dose of aspirin abrogated the IS-limiting effects of TIC.