F 15845, a new persistent sodium current blocker inhibits rat femoral artery ischaemia

Dr. Bocquet, Arnaud , Sablayrolles, Sylvie , Dr. Vacher, Bernard , Dr. Le Grand, Bruno. Institut de Recherche Pierre Fabre CV2, 17 Avenue Jean Moulin, 81106 Castrres, France.

Background and purpose: Persistent sodium current is implicated in myocardial ischaemia and is prevented by the newly described 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino3,4-dihydro-2H-1,5benzoxathiepine bromhydrate (F 15845), a selective persistent sodium current blocker. Herein, anti-ischaemic properties of F 15845 were assessed against femoral artery ischaemia in two in vitro models of vascular reactivity.

Experimental approach: Isometric tension measurement on rat femoral arteries was used to characterize the protective effect of F 15845 against veratrine (100 µg.ml-1) or hypoxia induced ischaemia that produced a strong and rapid contraction of the vessels.

Key results: Immunofluoresence demonstrated that rat femoral arteries expressed the Nav1.5 channel. When exposed to veratrine (100 µg.ml-1), a potent persistent sodium current activator, vessels developed a rapid and strong contraction abolished by both absence of Na+ or pre- and post-treatment with F 15845. With a preventive treatment, anti-ischaemic effect potency depends of the extracellular K+ concentration (IC50 11 µmol.L-1 and 0.77 µmol.L-1 for 5 mmol.L-1 KCl and 20 mmol.L-1 KCl, respectively) whereas a curative treatment was not affected by extracellular K+ concentration. Finally, F 15845 concentration- dependently prevents rat femoral arteries contraction induced by hypoxic ischaemia.

Conclusion and implication: F 15845, a selective blocker of persistent sodium current prevents vascular ischaemia injuries.