Actions of veratridine on tetrodotoxin-sensitive voltage-gated Na currents, Na1.6, in murine vas deferens myocytes.
OBJECTIVE
The effects of veratridine, an alkaloid found in Liliaceae plants, on tetrodotoxin (TTX)-sensitive voltage-gated Na(+) channels were investigated in mouse vas deferens.


METHODS
Effects of veratridine on TTX-sensitive Na(+) currents (I(Na)) in vas deferens myocytes dispersed from BALB/c mice, homozygous mice with a null allele of Na(V)1.6 (Na(V)1.6(-/-)) and wild-type mice (Na(V)1.6(+/+)) were studied using patch-clamp techniques. Tension measurements were also performed to compare the effects of veratridine on phasic contractions in intact tissues.


RESULTS
In whole-cell configuration, veratridine had a concentration-dependent dual action on the peak amplitude of I(Na): I(Na) was enhanced by veratridine (1-10 microM), while higher concentrations (> or =30 microM) inhibited I(Na). Additionally, two membrane current components were evoked by veratridine, namely a sustained inward current during the duration of the depolarizing rectangular pulse and a tail current at the repolarization. Although veratridine caused little shift of the voltage dependence of the steady-state inactivation curve and the activation curve for I(Na), veratridine enhanced a non-inactivating component of I(Na). Veratridine caused no detectable contractions in vas deferens from Na(V)1.6(-/-) mice, although in tissues from Na(V)1.6(+/+) mice, veratridine (> or =3 microM) induced TTX-sensitive contractions. Similarly, no detectable inward currents were evoked by veratridine in Na(V)1.6(-/-) vas deferens myocytes, while veratridine elicited both the sustained and tail currents in cells taken from Na(V)1.6(+/+) mice.


CONCLUSIONS
These results suggest that veratridine possesses a dual action on I(Na) and that the veratridine-induced activation of contraction is induced by the activation of Na(V)1.6 channels.
Zhu
Hai-Lei
HL
Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Wassall
Richard D
RD
Takai
Maki
M
Morinaga
Hidetaka
H
Nomura
Masatoshi
M
Cunnane
Thomas C
TC
Teramoto
Noriyoshi
N
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000502:physiology; D018408:Patch-Clamp Techniques; D062687:Sodium Channel Agonists; D015222:Sodium Channels / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects* / Q000502:physiology; D014701:Veratridine / Q000494:pharmacology*
D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C491046:Scn8a protein, mouse; D062687:Sodium Channel Agonists; D015222:Sodium Channels; D013779:Tetrodotoxin; D014701:Veratridine