Document Detail

First Report on an Inotropic Peptide Activating TTX-Sensitive, "Neuronal" Sodium Currents in the Heart.
MedLine Citation:
PMID:  25424392     Owner:  NLM     Status:  Publisher    
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" TTX-sensitive sodium channels.
METHODS AND 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 (200nM) 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 TTX-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.
Paulus Kirchhof; Tzachy Tal; Larissa Fabritz; Jan Klimas; Nir Nesher; Jan S Schulte; Petra Ehling; Tatayana Kanyshkova; Thomas Budde; Sigrid Nikol; Lisa Fortmueller; Birgit Stallmeyer; Frank U Müller; Eric Schulze-Bahr; Wilhelm Schmitz; Eliahu Zlotkin; Uwe Kirchhefer
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-25
Journal Detail:
Title:  Circulation. Heart failure     Volume:  -     ISSN:  1941-3297     ISO Abbreviation:  Circ Heart Fail     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-26     Completed Date:  -     Revised Date:  2014-11-27    
Medline Journal Info:
Nlm Unique ID:  101479941     Medline TA:  Circ Heart Fail     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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