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.
MeSH terms
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Androstadienes / pharmacology
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Animals
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Cardiotonic Agents / pharmacology*
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Cardiotonic Agents / therapeutic use
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Glyburide / pharmacology
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Hirudins / pharmacology
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Male
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Myocardial Infarction / genetics
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Myocardial Infarction / metabolism
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Myocardial Infarction / pathology
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Myocardial Infarction / physiopathology
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Myocardial Infarction / prevention & control*
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Myocardial Reperfusion Injury / genetics
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Myocardial Reperfusion Injury / metabolism
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Myocardial Reperfusion Injury / pathology
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Myocardial Reperfusion Injury / physiopathology
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Myocardial Reperfusion Injury / prevention & control*
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Myocardium / metabolism
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Myocardium / pathology
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Nitric Oxide / metabolism
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / metabolism
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Oligopeptides / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Potassium Channel Blockers / pharmacology
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Potassium Channels / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrroles / pharmacology*
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Pyrroles / therapeutic use
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Quinazolines / pharmacology*
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Quinazolines / therapeutic use
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptor, PAR-1 / antagonists & inhibitors*
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Receptor, PAR-1 / genetics
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Receptor, PAR-1 / metabolism
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Recombinant Proteins / pharmacology
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Research Design
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Signal Transduction / drug effects*
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Thrombin / antagonists & inhibitors
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Thrombin / metabolism*
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Time Factors
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Ventricular Function, Left / drug effects
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Wortmannin
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omega-N-Methylarginine / pharmacology
Substances
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Androstadienes
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Cardiotonic Agents
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Enzyme Inhibitors
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Hirudins
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N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine
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Oligopeptides
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PAR-1-activating peptide
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Phosphoinositide-3 Kinase Inhibitors
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Potassium Channel Blockers
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Potassium Channels
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Pyrroles
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Quinazolines
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RNA, Messenger
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Receptor, PAR-1
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Recombinant Proteins
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omega-N-Methylarginine
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Nitric Oxide
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Nitric Oxide Synthase
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Proto-Oncogene Proteins c-akt
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Thrombin
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Glyburide
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Wortmannin
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lepirudin