Mechanism of action of a structural analog of alphaxalone on myelinated nerve fibre.

The action of alphadolone acetate (0.05-5 mM), a steroid anaesthetic and structural analog of alphaxalone, was investigated on frog myelinated axons under voltage-clamp conditions. When applied externally, alphadolone acetate reduced K and Na currents, with apparent dissociation constants of 0.70 and 1.74 mM, respectively, and without noticeable modification in their time course. In addition, Na conductance-voltage and steady-state inactivation-voltage curves were shifted towards negative voltages. This effect was more pronounced on the steady-state inactivation-voltage relationship. These results suggest that alphadolone acetate blocked K channels indifferently in their resting or open state, and Na channels preferentially in their inactivated state. Alphaxalone has been shown to preferentially block open K and inactivated Na channels (Benoit et al., 1988, Br. J. Pharmacol. 94, 635). Thus, a structural change of a steroid molecule can lead to differences in its mechanism of action. This supports the hypothesis of direct interactions between steroid molecules and target membrane proteins with resulting anaesthetic activity.