{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T19:51:20Z","timestamp":1760730680107,"version":"3.40.5"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2015,1]]},"abstract":"<jats:sec><jats:title>Background\u2014<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results\u2014<\/jats:title><jats:p>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 Nav<jats:sub>1.5<\/jats:sub>, but selectively activated the brain-type sodium channels Nav<jats:sub>1.6<\/jats:sub>or Nav<jats:sub>1.3<\/jats:sub>in cellular electrophysiological recordings obtained from rodent thalamic slices. Nav<jats:sub>1.3<\/jats:sub>(SCN3A) mRNA was detected in human and mouse heart tissue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions\u2014<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1161\/circheartfailure.113.001066","type":"journal-article","created":{"date-parts":[[2014,11,26]],"date-time":"2014-11-26T05:53:04Z","timestamp":1416981184000},"page":"79-88","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["First Report on an Inotropic Peptide Activating Tetrodotoxin-Sensitive, \u201cNeuronal\u201d Sodium Currents in the Heart"],"prefix":"10.1161","volume":"8","author":[{"given":"Paulus","family":"Kirchhof","sequence":"first","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzachy","family":"Tal","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larissa","family":"Fabritz","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Klimas","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nir","family":"Nesher","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan S.","family":"Schulte","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Ehling","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatayana","family":"Kanyshkova","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Budde","sequence":"additional","affiliation":[{"name":"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; 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