title: F 15845, a new blocker of the persistent sodium current prevents consequences of hypoxia in rat femoral artery.
abstract: OBJECTIVE
  The persistent sodium current is involved in myocardial ischaemia and is selectively inhibited by the newly described 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate (F 15845). Here, we describe the pharmacological profile of F 15845 against the effects of hypoxia in femoral arteries in vitro.
  
  
  METHODS
  Isometric tension measurement of rat isolated femoral arteries was used to characterize the protective effect of F 15845 against contraction of the vessels induced by veratrine (100 microg.mL(-1)) or hypoxia.
  
  
  RESULTS
  Rat femoral artery expressed the Na(v)1.5 channel isoform. When exposed to veratrine (100 microg.mL(-1)), vessels developed a rapid and strong contraction that was abolished by both absence of sodium and blockade of the Na(+)/Ca(++) exchanger by KB-R7943 (10 and 32 micromol.L(-1)) or treatment with F 15845. When used before veratrine exposure, the potency of F 15845 depended on the extracellular K(+) concentration (IC(50)= 11 and 0.77 micromol.L(-1) for 5 and 20 mmol.L(-1) KCl, respectively), whereas its potency was unaffected by extracellular K(+) concentration when given after veratrine. F 15845 did not affect either KCl (80 mmol.L(-1)) or phenylephrine-induced femoral artery contraction. Moreover, endothelium disruption did not affect the protective effect of F 15845 against veratrine-induced femoral artery contraction, suggesting a mechanism of action dependent on smooth muscle cells. Finally, F 15845 prevented in a concentration-dependent manner rat femoral artery contraction induced by hypoxia.
  
  
  CONCLUSIONS
  F 15845, a selective blocker of the persistent sodium current prevented vascular contraction induced by hypoxic conditions.
authors.affiliation: Centre de Recherche Pierre Fabre, Castres cedex, France.
authors.forename: A
authors.initials: A
authors.lastname: Bocquet
authors.forename: S
authors.initials: S
authors.lastname: Sablayrolles
authors.forename: B
authors.initials: B
authors.lastname: Vacher
authors.forename: B
authors.initials: B
authors.lastname: Le Grand
mesh_terms: D000818:Animals; D001582:Benzothiepins / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005263:Femoral Artery / Q000187:drug effects* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D062554:NAV1.5 Voltage-Gated Sodium Channel; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000096:biosynthesis*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D014702:Veratrine / Q000494:pharmacology
chemical_list: C541955:3-(3-(2-methoxyphenylthio)-2-methylpropyl)amino-3,4-dihydro-2H-1,5-benzoxathiepine; D001582:Benzothiepins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568322:Scn5a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D014702:Veratrine