title: First report on an inotropic peptide activating tetrodotoxin-sensitive, "neuronal" sodium currents in the heart.
abstract: BACKGROUND
  New therapeutic approaches to improve cardiac contractility without severe risk would improve the management of acute heart failure. Increasing systolic sodium influx can increase cardiac contractility, but most sodium channel activators have proarrhythmic effects that limit their clinical use. Here, we report the cardiac effects of a novel positive inotropic peptide isolated from the toxin of the Black Judean scorpion that activates neuronal tetrodotoxin-sensitive sodium channels.
  
  
  RESULTS
  All venoms and peptides were isolated from Black Judean Scorpions (Buthotus Hottentotta) caught in the Judean Desert. The full scorpion venom increased left ventricular function in sedated mice in vivo, prolonged ventricular repolarization, and provoked ventricular arrhythmias. An inotropic peptide (BjIP) isolated from the full venom by chromatography increased cardiac contractility but did neither provoke ventricular arrhythmias nor prolong cardiac repolarization. BjIP increased intracellular calcium in ventricular cardiomyocytes and prolonged inactivation of the cardiac sodium current. Low concentrations of tetrodotoxin (200 nmol/L) abolished the effect of BjIP on calcium transients and sodium current. BjIP did not alter the function of Nav1.5, but selectively activated the brain-type sodium channels Nav1.6 or Nav1.3 in cellular electrophysiological recordings obtained from rodent thalamic slices. Nav1.3 (SCN3A) mRNA was detected in human and mouse heart tissue.
  
  
  CONCLUSIONS
  Our pilot experiments suggest that selective activation of tetrodotoxin-sensitive neuronal sodium channels can safely increase cardiac contractility. As such, the peptide described here may become a lead compound for a new class of positive inotropic agents.
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.). p.kirchhof@bham.ac.uk.
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Tzachy
authors.initials: T
authors.lastname: Tal
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Jan
authors.initials: J
authors.lastname: Klimas
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Nir
authors.initials: N
authors.lastname: Nesher
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Jan S
authors.initials: JS
authors.lastname: Schulte
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Petra
authors.initials: P
authors.lastname: Ehling
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Tatayana
authors.initials: T
authors.lastname: Kanyshkova
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Budde
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Sigrid
authors.initials: S
authors.lastname: Nikol
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Lisa
authors.initials: L
authors.lastname: Fortmueller
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Birgit
authors.initials: B
authors.lastname: Stallmeyer
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Frank U
authors.initials: FU
authors.lastname: Müller
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schmitz
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Eliahu
authors.initials: E
authors.lastname: Zlotkin
authors.affiliation: From the Department of Cardiovascular Medicine (P.K., L.F., S.N., L.F.), Department of Pharmacology and Toxicology (J.K., J.S.S., F.U.M., W.S., U.K.), and Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH) (B.S., E.S.-B.), Hospital of the University of Muenster, Muenster, Germany; Center for Cardiovascular Sciences, School of Clinical and Experimental Medicine, and SWBH NHS Trust, University of Birmingham, Birmingham, United Kingdom (P.K., L.F.); Technion Israel Institute of Technology, Haifa, Israel (T.T.); Department of Animal and Cell Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (T.T., N.N., E.Z.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic (J.K.); Department of Neurology, and Division of Neuropathophysiology, Institute of Physiology I (P.E.) and Institute of Physiology I (T.K., T.B.), University of Muenster, Muenster, Germany; and Department of Clinical and Interventional Angiology, Asklepios Clinic St. Georg, Hamburg, Germany (S.N.).
authors.forename: Uwe
authors.initials: U
authors.lastname: Kirchhefer
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010865:Pilot Projects; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium
keywords: acute heart failure; arrhythmias, cardiac; drug therapy; inotropic agents, positive cardiac; sodium channels