Volatile anesthetics gate a chloride current in postnatal rat hippocampal neurons.
A volatile anesthetic-gated current was characterized in patch-clamped cultured postnatal rat hippocampal neurons. In this preparation, the major volatile anesthetics, isoflurane, halothane, and enflurane, open an anion-selective conductance. This volatile anesthetic-gated current exhibits anion selectivity with a chloride-to-acetate permeability ratio of 15, shows outward rectification well described by the constant field equation, and is activated in a dose-dependent fashion with half-maximal response to isoflurane at 0.8 mM (0.032 atm). The current persists in the absence of external Ca2+ and is not blocked by strychnine, a glycine antagonist. However, the gamma-aminobutyric acidA (GABAA) antagonists, bicuculline and picrotoxinin, and the nonspecific anion channel blocker, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), completely block the response. These observations suggest that volatile anesthetics, like several other general anesthetics such as barbiturates, steroids, and etomidate, have a GABA-mimetic effect on vertebrate central neurons in culture. It is not clear whether this GABAA-gating property is a prerequisite for all general anesthetics. However, under normal physiological conditions of low intracellular Cl-, it is likely that drugs with both direct GABA agonist and GABA modulatory properties will produce overall depression of the central nervous system by increasing the normal inhibitory synaptic influence and by directly hyperpolarizing neurons.
Yang
J
J
Department of Anethesiology and Pharmacology, University of Maryland School of Medicine, Baltimore 21201.
Isenberg
K E
KE
Zorumski
C F
CF
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D002713:Chlorine / Q000378:metabolism*; D002849:Chromatography, Gas; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004737:Enflurane / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects*; D007530:Isoflurane / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D010852:Picrotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D054830:Sesterterpenes; D013331:Strychnine / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D000777:Anesthetics; D001640:Bicuculline; D002713:Chlorine; D004737:Enflurane; D006221:Halothane; D007530:Isoflurane; D010852:Picrotoxin; D054830:Sesterterpenes; D013331:Strychnine; D005680:gamma-Aminobutyric Acid; C022961:picrotoxinin