The benzodiazepine midazolam preferentially blocks inactivated Na channels in skeletal muscle fibre.

The effects of the benzodiazepine midazolam were studied on frog skeletal muscle fibres held under current- or voltage-clamp conditions. Midazolam induced a concentration-dependent (10(-5) mol/l to 10(-3) mol/l) block of the action potential and of the underlying Na current. Block of the Na current occurred without any changes in its voltage dependence or in its activation and inactivation kinetics. An apparent dissociation constant of 223 mumol/l was determined for midazolam from the rested Na channels of well polarized fibres. The blocking effect of a threshold concentration (10(-5) mol/l) could be greatly enhanced (up to the complete suppression of the current) by predepolarizations, positive holding potentials or high stimulation frequencies. This apparent voltage- and frequency-dependent block (no use dependence, i.e., no activation block) could be ascribed to a blockade of inactivated Na channels. From the apparent shift towards negative potentials of the steady-state inactivation curve, a dissociation constant of 6.0 mumol/l was calculated for midazolam from the inactivated Na channels, according to the modulated-receptor model. These results show that midazolam preferentially blocks inactivated rather than rested Na channels, and suggest that this mechanism of action might contribute to the well-known myorelaxant effect of the benzodiazepines.