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

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.

• Authors: Jennifer L Strande, Anna Hsu, Jidong Su, Xiangping Fu, Garrett J Gross, John E Baker
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 102 Issue 4 Pg. 350-8 (Jul 2007) ISSN: 0300-8428 [Print] Germany
• PMID: 17468933 (Publication Type: Journal Article)

Chemical References

• Androstadienes
• Cardiotonic Agents
• Enzyme Inhibitors
• Hirudins
• N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine
• Oligopeptides
• PAR-1-activating peptide
• Phosphoinositide-3 Kinase Inhibitors
• Potassium Channel Blockers
• Potassium Channels
• Pyrroles
• Quinazolines
• RNA, Messenger
• Receptor, PAR-1
• Recombinant Proteins
• omega-N-Methylarginine
• Nitric Oxide
• Nitric Oxide Synthase
• Proto-Oncogene Proteins c-akt
• Thrombin
• Glyburide
• Wortmannin
• lepirudin

Topics

• Androstadienes (pharmacology)
• Animals
• Cardiotonic Agents (pharmacology, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Glyburide (pharmacology)
• Hirudins (pharmacology)
• Male
• Myocardial Infarction (genetics, metabolism, pathology, physiopathology, prevention & control)
• Myocardial Reperfusion Injury (genetics, metabolism, pathology, physiopathology, prevention & control)
• Myocardium (metabolism, pathology)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Oligopeptides (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Potassium Channel Blockers (pharmacology)
• Potassium Channels (metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Pyrroles (pharmacology, therapeutic use)
• Quinazolines (pharmacology, therapeutic use)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor, PAR-1 (antagonists & inhibitors, genetics, metabolism)
• Recombinant Proteins (pharmacology)
• Research Design
• Signal Transduction (drug effects)
• Thrombin (antagonists & inhibitors, metabolism)
• Time Factors
• Ventricular Function, Left (drug effects)
• Wortmannin
• omega-N-Methylarginine (pharmacology)