Basic Research in Cardiology

, Volume 102, Issue 4, pp 350–358

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

Authors

    • Division of Cardiovascular MedicineMedical College of Wisconsin
  • A. Hsu
    • Dept. of Pharmacology and ToxicologyMedical College of Wisconsin
  • J. Su
    • Division of Cardiothoracic SurgeryMedical College of Wisconsin
  • X. Fu
    • Division of Cardiothoracic SurgeryMedical College of Wisconsin
  • G. J. Gross
    • Dept. of Pharmacology and ToxicologyMedical College of Wisconsin
  • J. E. Baker
    • Dept. of Pharmacology and ToxicologyMedical College of Wisconsin
    • Division of Cardiothoracic SurgeryMedical College of Wisconsin
    • Children's Research InstituteChildren's Hospital of Wisconsin
ORIGINAL CONTRIBUTION

DOI: 10.1007/s00395-007-0653-4

Cite this article as:
Strande, J.L., Hsu, A., Su, J. et al. Basic Res Cardiol (2007) 102: 350. doi:10.1007/s00395-007-0653-4

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 μg/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 μM. 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 KATP 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.

Key words

myocardial ischemic reperfusion injuryprotease-activated receptorsthrombin receptor antagonist

Copyright information

© Steinkopff-Verlag 2007