Macrokinetic analysis of blockade of NMDA-gated currents by substituted alcohols, alkanes and ethers.
Volatile hydrocarbon based CNS depressants including short chain alcohols and anesthetics act, in part, by inhibition of the excitatory effect of glutamate at the NMDA receptor. While effects of several of these volatile agents on NMDA-gated currents have been demonstrated, there has been no direct comparison of different chemical classes of CNS depressant drugs on NMDA-gated currents. Here, whole-cell voltage clamp measurements of currents gated by 100 microM NMDA from cultured cerebrocortical neurons were examined in the presence of varying concentrations of the alcohols ethanol and hexanol, the halogenated alcohol trichloroethanol, the halogenated alkane halothane and the halogenated ethers isoflurane and sevoflurane. All drugs tested showed concentration-dependent inhibition of NMDA-gated currents with anesthetic concentrations of each agent producing approximately 30% inhibition of the NMDA-gated current. A rapid-translation perfusion system was used to study the onset and offset kinetics of each of the volatile agents. Onset kinetics for the CNS depressants was similar with tau values near 100 ms. Offset kinetics was more variable with tau ranging from 88.2 ms for ethanol to 221.4 ms for trichloroethanol. These data indicate that a wide variety of volatile hydrocarbon based CNS depressants produce a similar inhibition of NMDA-gated currents and that the kinetics for these agents are inconsistent with an open channel block.
Criswell
Hugh E
HE
Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA. hec@med.unc.edu
Ming
Zhen
Z
Pleasant
Nathanial
N
Griffith
Benjamin L
BL
Mueller
Robert A
RA
Breese
George R
GR
D000438:Alcohols / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D000441:Hexanols / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D007530:Isoflurane / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects*; D008738:Methyl Ethers / Q000494:pharmacology; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D000077149:Sevoflurane
D000438:Alcohols; D018685:Anesthetics, Inhalation; D002492:Central Nervous System Depressants; D000441:Hexanols; D008738:Methyl Ethers; D016194:Receptors, N-Methyl-D-Aspartate; D000077149:Sevoflurane; D000431:Ethanol; D005023:Ethylene Chlorohydrin; C005849:2,2,2-trichloroethanol; D007530:Isoflurane; D006221:Halothane