title: Identification of a cardiac sodium channel insensitive to synthetic modulators.
abstract: BACKGROUND
  DPI 201-106 (DPI) was the first synthetic compound showing cardioselective modulation of voltage-gated sodium channels (VGSCs) resulting in a positive inotropic effect. Currently, the exact mode of action for this class of compounds is not known.
  
  
  METHODS
  Effects of different natural and synthetic sodium channel modulators were investigated in cardiac tissue of several species with conventional electrophysiologic methods.
  
  
  RESULTS
  In electrically driven cardiac tissues, all compounds investigated increased force of contraction (FC) and action potential duration (APD) with increasing concentrations except for DPI in cattle trabecular muscle, which demonstrated no effect. Interestingly, calculation of EC50 levels at 30% repolarization demonstrates that natural VGSC-ligands were highly potent in prolonging the APD in cattle whereas no positive trends could be obtained for DPI and SDZ 211-939 (SDZ) in cattle.
  
  
  CONCLUSIONS
  These results demonstrate that the binding site for DPI and SDZ is distinct from sites 2 or 3 of the VGSC alpha-subunit. Moreover, this is the first time that these compounds show no effect or even shortening of APD. This finding will enable the characterization of the mode of action and probably the binding site for synthetic VGSC-modulators.
authors.affiliation: Institute of Veterinary-Pharmacology, University of Berne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Mevissen
authors.forename: H
authors.initials: H
authors.lastname: Denac
authors.forename: A
authors.initials: A
authors.lastname: Schaad
authors.forename: C J
authors.initials: CJ
authors.lastname: Portier
authors.forename: G
authors.initials: G
authors.lastname: Scholtysik
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006041:Goats; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006736:Horses; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D012756:Sheep; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D013997:Time Factors; D014701:Veratridine / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D010879:Piperazines; D015222:Sodium Channels; D014701:Veratridine; C046261:DPI 201-106