Figure 1.

(A) Typical recordings of veratridine-induced persistent sodium current mediated by human embryonic kidney (HEK 293) cells transfected with hNa_v1.5 (elicited at −30 mV from a holding potential of −110 mV) in presence and absence of 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5 benzoxathiepine bromhydrate (F 15845) (10⁻⁵ mol·L⁻¹). (B) Veratridine-induced persistent sodium current steady-state inactivation in absence or presence of F 15845 (10⁻⁵ mol·L⁻¹) in HEK 293 cells transfected with hNa_v1.5. Steady-state inactivation is shifted to hyperpolarized potentials by F 15845 with mean V_0.5 values of −80.5 ± 2.3 mV and −84.9 ± 2.5 mV (n = 7, P < 0.05) in vehicle and in presence of F 15845 respectively. Data are means ± SEM. n = 7; *P < 0.05 compared with corresponding vehicle. (C) Voltage-dependent sodium channel blocking effects of F 15845 from 10⁻⁷–3.2 × 10⁻⁵ mol·L⁻¹ on persistent sodium current. As the holding potential (HP) depolarizes from −110 to −90 mV, the inhibition of persistent sodium current by F 15845 increases significantly. This unique property of sodium channel blockade renders F 15845 selective for depolarized (i.e. ischaemic) cardiac tissue. Data are means ± SEM. n = 5–10. (D) Typical recordings of peak (rapid) sodium current mediated by HEK 293 cells transfected with hNa_v1.5 in presence and absence of F 15845 (10 µmol). Note a very weak inhibition on peak current elicited at −30 mV from a holding potential of −110 mV. (E) Peak sodium current activation and inactivation curves in absence or presence of F 15845 (10 µmol) in HEK 293 cells transfected with hNa_v1.5. Note shift of steady-state inactivation to hyperpolarized potentials by F 15845 without significantly affecting peak current activation parameters. Data are expressed as mean ± SEM. n = 4–5.