Abstract
The voltage- and frequency-dependent interactions of pentobarbital with voltage-gated sodium channels were examined in whole-cell patch-clamp recordings. Using rat brain IIA and rat muscle rSkM1 sodium channels expressed in stably transfected Chinese hamster ovary cell lines, it was found that pentobarbital reduced peak inward sodium currents with IC50 values of 1.2 mM (brain) and 1.0 mM (muscle). Analysis of steady state channel availability curves revealed two distinct effects of pentobarbital on both channel isoforms, i.e., a voltage-independent current reduction and an additional hyperpolarizing shift in the voltage dependence of channel availability. The latter effect leads to a voltage dependence of pentobarbital potency. Pentobarbital was also found to slow channel recovery after depolarization, yielding an additional use-dependent component of current suppression. Use-dependent block was enhanced by higher stimulation frequencies, longer pulse durations, and more depolarized holding and pulse potentials. All effects were identical for both channels. These findings can be explained in terms of the modulated receptor hypothesis and are consistent with a preferential interaction of pentobarbital with the inactivated channel state. As a consequence, actual pentobarbital potency would depend largely on experimental conditions or, in vivo, on the physiological parameters of a particular cell.
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