Abstract
Background: Clopidogrel (C) and Ticagrelor (T) are P2Y12 ADP receptor antagonists. In addition, ticagrelor inhibits adenosine cell uptake. In PLATO trial T reduced the incidence of the primary composite endpoint myocardial infarction, stroke or cardiovascular death over C in patients with acute coronary syndromes. Previous data show that 7d pretreatment with T limits infarct size (IS) in rats. We compared the effects of C and T, administered just before reperfusion on IS. We also assessed the effect of T and C, administered just before reperfusion and/or 6w oral treatment on cardiac remodeling. Methods: Rats underwent 30min coronary artery ligation. 1) At 25min of ischemia rats received intraperitoneal (IP) vehicle, T (10 or 30mg/kg), or C (12.5mg/kg). Area at risk (AR) was assessed by blue dye and IS by TTC staining 24h after reperfusion. 2) Rats received vehicle without (sham) or with (control) coronary ischemia, T (30mg/kg) IP (TIP), T (300mg/kg/d) oral for 6w, started a day after reperfusion (TPO), TIP+PO (TIPPO), or C (12.5mg/kg IP +62.5mg/kg/d PO for 6w). LV dimensions and function was assessed by echo at 6w. Results: 1) AR was comparable among groups. IS was 45.3±1.7% of the AR in the control group. T10 (31.5±1.8%; p=0.001) and T30 (21.4±2.6% p<0.001) significantly reduced IS, whereas C (42.4±2.6%) had no effect. Platelet aggregation in the controls was 64.7±1.3% and was comparable in T30 (24.9±1.8%) and C (23.2±1.8%) at 2h post reperfusion. T30 increased Akt, eNOS and ER1/2 phosphorylation 4h after reperfusion, whereas C had no effect. 2) Platelet aggregation at 1w oral treatment was 59.7±3.2% in the control group and was comparable in TIPPO (18.1±1.3%) and C (17.4±0.7%). Left ventricular ejection fraction was 77.6±0.9%*, 44.8±3.5%, 69.5±1.6%*, 69.2±1.0%*, 76.3±1.2%*, and 37.4±3.7% in the sham, vehicle, TIP, TPO, TIPPO and C treated group, respectively (*p<0.001 vs. vehicle). Left ventricular diameters at diastole and systole showed the same pattern. Conclusions: T, but not C, administered just before reperfusion protects against reperfusion injury. Oral T (in combination or not with acute treatment just before reperfusion) treatment for 6w improves heart function. C, despite achieving similar degree of platelet inhibition had no effect on remodeling.
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