title: Mechanism of action of a structural analog of alphaxalone on myelinated nerve fibre.
abstract: 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.
authors.affiliation: Laboratoire de Biomembranes et des Ensembles neuronaux associé au CNRS, UA 1121, Université Paris-XI, Orsay, France.
authors.forename: E
authors.initials: E
authors.lastname: Benoit
authors.forename: M R
authors.initials: MR
authors.lastname: Carratù
authors.forename: D
authors.initials: D
authors.lastname: Mitolo-Chieppa
mesh_terms: D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D066298:In Vitro Techniques; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011277:Pregnanediones / Q000008:administration & dosage / Q000494:pharmacology*; D011893:Rana esculenta; D011901:Ranvier's Nodes / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
chemical_list: D000777:Anesthetics; D015221:Potassium Channels; D011277:Pregnanediones; D015222:Sodium Channels; C033418:alphadolone