Actions of veratridine on tetrodotoxin‐sensitive voltage‐gated Na + currents, Na V 1.6, in murine vas deferens myocytes

Background and purpose:  The effects of veratridine, an alkaloid found in Liliaceae plants, on tetrodotoxin (TTX)‐sensitive voltage‐gated Na + channels were investigated in mouse vas deferens. Experimental approach:  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. Key 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 µM), while higher concentrations (≥30 µM) 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 (≥3 µM) 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 and implications:  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.