VOLTAGE-DEPENDENT AND FREQUENCY-DEPENDENT PENTOBARBITAL SUPPRESSION OF BRAIN AND MUSCLE SODIUM-CHANNELS EXPRESSED IN A MAMMALIAN-CELL LINE

The voltage- and frequency-dependent interactions of pentobarbital wit h voltage-gated sodium channels were examined in whole-cell patch-clam p recordings. Using rat brain IIA and rat muscle rSdM1 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 pen tobarbital on both channel isoforms, i.e., a voltage-independent curre nt reduction and an additional hyperpolarizing shift in the voltage de pendence 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 e nhanced by higher stimulation frequencies, longer pulse durations, and more depolarized holding and pulse potentials. All effects were ident ical for both channels. These findings can be explained in terms of th e 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 exp erimental conditions or, in vivo, on the physiological parameters of a particular cell.