Abstract 1288: The Selective PAR-1 Antagonist, SCH 79797, Limits Myocardial ischemia-Reperfusion Injury in Rat Hearts through PAR-1 by Activation of PI3 Kinase, NOS and KATP Channels
Objective: Myocardial ischemia-reperfusion (I/R) injury is partly induced by the pro-coagulant and pro-inflammatory properties of thrombin. In support, the functional inhibition of thrombin has been shown to decrease infarct size after I/R injury by reducing inflammation. Several cellular responses to thrombin are mediated by the G-protein coupled protease-activated receptor-1 (PAR-1). Therefore, we hypothesized that inhibition of PAR-1 will reduce myocardial I/R injury
Methods/Results: We detected the presence of PAR-1 mRNA and protein in the rat heart by RT-PCR and immunoblot analysis. We then assessed the potential protective role of SCH 79797, a PAR-1 antagonist, in two rat models of myocardial I/R injury. For in vivo studies, rat hearts (n=6/group) underwent 30 minutes of regional no-flow ischemia followed by 3 hours of reperfusion. SCH 79797 treatment immediately before ischemia reduced infarct size from 62±3% to 43±5% area at risk. For in vitro studies, isolated rat hearts (n=8/group) were subjected to 30 minutes of regional ischemia and 3 hours of reperfusion. SCH 79797 treatment immediately before ischemia reduced infarct size from 51±3% to 30±5% of the left ventricle. SCH 79797 treatment also promoted the recovery of myocardial function by increasing left ventricular developed pressure from 59±5% to 67±4% of pre-ischemic levels. These effects of SCH 79797 occur in a concentration-dependent manner with an optimal concentration of 25 μg/kg IV in vivo and 1.0 μM in vitro and were abolished by a PAR-1 activating peptide. We then determined the role of PI3 kinase, NOS and ATP-dependent potassium (KATP) channels in mediating SCH 79797-induced cardioprotection. SCH 79797-induced resistance to myocardial ischemia was abolished by wortmannin, an inhibitor of PI3 kinase, L-NMA, a NOS inhibitor and glibenclamide, a nonselective KATP channel blocker. PAR-1 activating peptide, wortmannin, L-NMA and glibenclamide alone had no effect on cardioprotection.
Conclusion: A single treatment of SCH 79797 administered prior to ischemia confers immediate cardioprotection by the PAR-1 pathway. This suggests a potential therapeutic role of SCH 79797 in the treatment of injury resulting from myocardial ischemia and reperfusion.