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F 15845, a new blocker of the persistent sodium current prevents consequences of hypoxia in rat femoral artery
Author(s) -
Bocquet A,
Sablayrolles S,
Vacher B,
Le Grand B
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00912.x
Subject(s) - femoral artery , contraction (grammar) , phenylephrine , hypoxia (environmental) , extracellular , sodium , artery , endocrinology , potency , medicine , isometric exercise , chemistry , pharmacology , in vitro , biochemistry , oxygen , blood pressure , organic chemistry
BACKGROUND AND PURPOSE 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 . EXPERIMENTAL APPROACH 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 µg·mL −1 ) or hypoxia. KEY RESULTS Rat femoral artery expressed the Na v 1.5 channel isoform. When exposed to veratrine (100 µg·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 µmol·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 µmol·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. CONCLUSION AND IMPLICATIONS F 15845, a selective blocker of the persistent sodium current prevented vascular contraction induced by hypoxic conditions.