SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts. Basic Res Cardiol 2007 Jul;102(4):350-8
Date
05/01/2007Pubmed ID
17468933Pubmed Central ID
PMC3942648DOI
10.1007/s00395-007-0653-4Scopus ID
2-s2.0-34250342563 (requires institutional sign-in at Scopus site) 96 CitationsAbstract
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.
Author List
Strande JL, Hsu A, Su J, Fu X, Gross GJ, Baker JEAuthor
John E. Baker PhD Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AndrostadienesAnimals
Cardiotonic Agents
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors
Glyburide
Hirudins
Male
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardium
Nitric Oxide
Nitric Oxide Synthase
Oligopeptides
Phosphatidylinositol 3-Kinases
Platelet Aggregation Inhibitors
Potassium Channel Blockers
Potassium Channels
Proto-Oncogene Proteins c-akt
Pyrroles
Quinazolines
RNA, Messenger
Rats
Rats, Sprague-Dawley
Receptor, PAR-1
Recombinant Proteins
Research Design
Signal Transduction
Thrombin
Time Factors
Ventricular Function, Left
omega-N-Methylarginine
