title: Action of diazepam on the voltage-dependent Na+ current. Comparison with the effects of phenytoin, carbamazepine, lidocaine and flumazenil.
abstract: The influence of diazepam, an agonist, and flumazenil (Ro 15-1788), an antagonist of the benzodiazepine receptor, on repetitive firing of action potentials in cultured spinal neurons and on voltage-dependent Na+ currents in cultured N2A neuroblastoma cells was examined. The effects were compared to those of the antiepileptics phenytoin and carbamazepine and the local anesthetic lidocaine. The whole-cell configuration of the patch-clamp technique was used for potential and current recording. Diazepam (10 microM) or phenytoin (10 microM) reduced the duration of repetitive action potential discharges in 50 or 67% of the spinal neurons, respectively. At a concentration of 100 microM repetitive firing was completely blocked. Flumazenil (100 microM) had no effect. In N2A neuroblastoma cells diazepam, phenytoin, carbamazepine and lidocaine, but not flumazenil, at a concentration of 100 microM reduced the Na+ current to 60-67% of control. At 10 microM no or only a weak depression was seen with any drug. In the presence of diazepam (100 microM) the Na+ channel inactivation curve was shifted in the hyperpolarizing direction by -4.8 +/- 0.5 mV. Phenytoin, carbamazepine and lidocaine (all 100 microM) caused stronger shifts of -17.4 +/- 2.1, -10.6 +/- 0.9 and -17.0 +/- 2.1 mV, respectively. Inhibition of the Na+ current by diazepam increased use-dependently over 9 depolarizing pulses repeated at high frequency (200 Hz), whereas use-dependent effects of the other compounds developed less rapidly. At a low stimulation rate (7 Hz) use-dependent block was pronounced with lidocaine, but weak or absent with diazepam and carbamazepine.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: K H
authors.initials: KH
authors.lastname: Backus
authors.forename: P
authors.initials: P
authors.lastname: Pflimlin
authors.forename: G
authors.initials: G
authors.lastname: Trube
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D003975:Diazepam / Q000494:pharmacology*; D004622:Embryo, Mammalian; D005442:Flumazenil / Q000494:pharmacology*; D007700:Kinetics; D008012:Lidocaine / Q000494:pharmacology*; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010672:Phenytoin / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology*
chemical_list: D015222:Sodium Channels; D002220:Carbamazepine; D005442:Flumazenil; D010672:Phenytoin; D008012:Lidocaine; D003975:Diazepam