1. Academic Validation
  2. SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts

SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts

  • Basic Res Cardiol. 2007 Jul;102(4):350-8. doi: 10.1007/s00395-007-0653-4.
Jennifer L Strande 1 Anna Hsu Jidong Su Xiangping Fu Garrett J Gross John E Baker
Affiliations

Affiliation

  • 1 Division of Cardiovascular Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA. jstrande@mcw.edu
Abstract

Myocardial ischemia/reperfusion (I/R) injury is partly mediated by Thrombin. In support, the functional inhibition of Thrombin has been shown to decrease infarct size after I/R. Several cellular responses to Thrombin are mediated by a G-protein coupled Protease-activated Receptor 1 (PAR1).However, the role of PAR1 in myocardial I/R injury has not been well characterized. Therefore, we hypothesized that PAR1 inhibition will reduce the amount of myocardial I/R injury. After we detected the presence of PAR1 mRNA and protein in the rat heart by RT-PCR and immunoblot analysis,we assessed the potential protective role of SCH 79797, a selective PAR1 Antagonist, in two rat models of myocardial I/R injury. SCH 79797 treatment immediately before or during ischemia reduced myocardial necrosis following I/R in the intact rat heart. This response was dose-dependent with the optimal dose being 25 microg/kg IV. Likewise, SCH 79797 treatment before ischemia in the isolated heart model reduced infarct size and increased ventricular recovery following I/R in the isolated heart model with an optimal concentration of 1 microM. This reduction was abolished by a PAR1 selective agonist. 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 K(ATP) channel blocker. PAR1 activating peptide,wortmannin, L-NMA and glibenclamide alone had no effect on functional recovery or infarct size. A single treatment of SCH 79797 administered prior to or during ischemia confers immediate cardioprotection suggesting a potential therapeutic role of PAR1 Antagonist in the treatment of injury resulting from myocardial ischemia and reperfusion.

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