title: F 15845 inhibits persistent sodium current in the heart and prevents angina in animal models.
abstract: OBJECTIVE
  Activation of the persistent sodium current in ischaemic myocardium results in calcium overload which is toxic for the cardiomyocyte. Thus, the activity of 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5 benzoxathiepine bromhydrate (F 15845), a new selective persistent sodium current blocker, in protecting against the effects of cardiac ischaemia was examined, in both in vitro and in vivo models.
  
  
  METHODS
  Electrophysiological studies using patch-clamp and conventional microlelectrode techniques, isolated perfused hearts and models of angina in anaesthetized animals were used to assess the protection afforded by F 15845 against ischaemia-induced changes.
  
  
  RESULTS
  F 15845 reduced the persistent sodium current activated by veratridine (IC(50) 1.58 x 10(-6) mol.L(-1)). F 15845 blocked voltage-gated human cardiac sodium channels in a novel, voltage-dependent manner, selectively affecting steady-state inactivation. F 15845 did not affect action potential shape and basal function of guinea pig isolated perfused hearts but did reduce ischaemia-induced diastolic contracture in this model (IC(50) 0.64 x 10(-6) mol.L(-1)). In rabbits, F 15845 given i.v. (ED(50) 0.05 mg.kg(-1)) or orally (ED(50) 0.13 mg.kg(-1)) dose-dependently and powerfully inhibited regional myocardial ischaemia-induced ST segment elevation in the absence of haemodynamic effects, implying direct cardiac activity. In dogs, F 15845 dose-dependently inhibited epicardial ST segment changes (70 +/- 8% at 0.63 mg.kg(-1)) in an experimental angina model of demand ischaemia, again without haemodynamic effects, confirming a direct anti-anginal activity.
  
  
  CONCLUSIONS
  F 15845 is a selective, potent blocker of the persistent sodium current, generated by the human Na(v)1.5 channel isoforms, and prevents cardiac angina in animal models.
authors.affiliation: Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, Castres Cedex, France.
authors.forename: B
authors.initials: B
authors.lastname: Vacher
authors.forename: C
authors.initials: C
authors.lastname: Pignier
authors.forename: R
authors.initials: R
authors.lastname: Létienne
authors.forename: Y
authors.initials: Y
authors.lastname: Verscheure
authors.forename: B
authors.initials: B
authors.lastname: Le Grand
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000787:Angina Pectoris / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001582:Benzothiepins / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D017202:Myocardial Ischemia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D015222:Sodium Channels / Q000502:physiology*; D014701:Veratridine
chemical_list: C541955:3-(3-(2-methoxyphenylthio)-2-methylpropyl)amino-3,4-dihydro-2H-1,5-benzoxathiepine; D001582:Benzothiepins; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014701:Veratridine