F 15845, a new blocker of the persistent sodium current prevents consequences of hypoxia in rat femoral artery.
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.
Bocquet
A
A
Centre de Recherche Pierre Fabre, Castres cedex, France.
Sablayrolles
S
S
Vacher
B
B
Le Grand
B
B
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
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