title: GsMTx4-D is a cardioprotectant against myocardial infarction during ischemia and reperfusion.
abstract: GsMTx4 is a selective inhibitor of cationic mechanosensitive ion channels (MSCs) and has helped establish the role of MSCs in cardiac physiology. Inhomogeneous local mechanical stresses due to hypercontracture and swelling during ischemic reperfusion injury (IRI) likely induce elevated MSC activity that can contribute to cation imbalance. The aim of this study was to determine if the D enantiomer of GsMTx4 can act as a cardioprotectant in a mouse IRI model. Ischemia and reperfusion involved ligating a coronary artery followed by release of the ligature. GsMTx4-D was tested by either acute intravenous injection during the ischemic event or by two day pretreatment by intraperitoneal injection, both methods achieving similar results. Based on pharmacokinetic studies, GsMTx4-D dosage was set to achieve expected plasma concentrations between 50 and 5000nM and heart tissue concentrations between 1 and 200nM by intravenous injection. Relative to vehicle injected animals, GsMTx4-D reduced infarct area by ~40% for acute and pretreated animals for both 20 and 45min ischemic challenges. Many indicators of cardiac output were indistinguishable from sham-treated control hearts after GsMTx4-D treatment showing improvement at both 4 and 48h post ischemia, and premature ventricular beats immediately following reperfusion were also significantly reduced. To determine if GsMTx4-D cardioprotection could act directly at the level of cardiomyocytes, we tested its effects in vitro on indicators of IRI damage like cation influx and activation of inflammatory kinases in isolated myocytes cultured under hypoxic conditions. Hypoxia challenged cardiomyocytes treated with 10μM GsMTx4-D showed improved contractility and near normal contraction-related Ca(2+) influx. GsMTx4-D inhibited indicators of ischemic damage such as the apoptotic signaling system JNK/c-Jun, but also inhibited the energy response signaling system Akt kinase. We conclude that GsMTx4-D is a potent cardioprotectant in vivo that may act directly on cardiomyocytes and potentially be useful in multidrug strategies to treat IRI.
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, United States.
authors.forename: Jinli
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, United States.
authors.forename: Yina
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, United States.
authors.forename: Frederick
authors.initials: F
authors.lastname: Sachs
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, United States.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, United States. Electronic address: suchyna@buffalo.edu.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Suchyna
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013111:Spider Venoms / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D036341:Intercellular Signaling Peptides and Proteins; C411249:MTx4 protein, Grammostola spatulata; D010455:Peptides; D013111:Spider Venoms; D002118:Calcium
keywords: Arrhythmia; Cardiac output; GsMTx4; Mechanosensitive ion channels; Myocardial infarction; Pharmacokinetics; Reperfusion injury