Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1994 Jul;112(3):906–910. doi: 10.1111/j.1476-5381.1994.tb13166.x

Stereoselective and non-stereoselective actions of isoflurane on the GABAA receptor.

A C Hall 1, W R Lieb 1, N P Franks 1
PMCID: PMC1910207  PMID: 7921619

Abstract

1. Acutely dissociated cerebellar Purkinje neurones from 8-14 day old rats were studied under voltage clamp in the whole-cell patch-clamp configuration. Cl- currents induced by bath application of gamma-aminobutyric acid (GABA) were measured (using symmetrical Cl- solutions) at both low (2 microM) non-desensitizing and high (300 microM) desensitizing concentrations of GABA. 2. At 2 microM GABA, the bicuculline-sensitive Cl- currents were potentiated by racemic isoflurane and both of its optical isomers. Isoflurane had no effect on membrane current in the absence of GABA. The dose-response data for potentiation by racemic isoflurane could be fitted with a Hill equation with an EC50 = 320 +/- 20 microM isoflurane and a Hill coefficient of h = 2.7 +/- 0.4 (means +/- s.e.mean). 3. The potentiations produced by the optical isomers of isoflurane at 2 microM GABA were stereoselective at moderate and high anaesthetic concentrations. The maximum stereoselectivity, about two fold, occurred at the EC50 concentration for general anaesthesia (310 microM isoflurane), with S(+)-isoflurane being more effective than R(-)-isoflurane. At sub-anaesthetic concentrations, the stereoselectivity was less marked and vanished at the lowest concentration used (77 microM isoflurane). 4. The sustained residual current remaining after exposure of neurons to a desensitizing concentration of GABA (300 microM) was inhibited non-stereoselectively, but only at high concentrations of isoflurane. The ratio of inhibitions by S(+)- and R(-)-isoflurane (mean +/- s.e.mean) was 1.14 +/- 0.21 at 770 microM isoflurane. At the EC50 concentration for general anaesthesia, however, the inhibition was barely significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
906

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Franks N. P., Lieb W. R. Molecular and cellular mechanisms of general anaesthesia. Nature. 1994 Feb 17;367(6464):607–614. doi: 10.1038/367607a0. [DOI] [PubMed] [Google Scholar]
  2. Franks N. P., Lieb W. R. Selective actions of volatile general anaesthetics at molecular and cellular levels. Br J Anaesth. 1993 Jul;71(1):65–76. doi: 10.1093/bja/71.1.65. [DOI] [PubMed] [Google Scholar]
  3. Franks N. P., Lieb W. R. Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels. Science. 1991 Oct 18;254(5030):427–430. doi: 10.1126/science.1925602. [DOI] [PubMed] [Google Scholar]
  4. Fujiwara N., Higashi H., Nishi S., Shimoji K., Sugita S., Yoshimura M. Changes in spontaneous firing patterns of rat hippocampal neurones induced by volatile anaesthetics. J Physiol. 1988 Aug;402:155–175. doi: 10.1113/jphysiol.1988.sp017198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gage P. W., Robertson B. Prolongation of inhibitory postsynaptic currents by pentobarbitone, halothane and ketamine in CA1 pyramidal cells in rat hippocampus. Br J Pharmacol. 1985 Jul;85(3):675–681. doi: 10.1111/j.1476-5381.1985.tb10563.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  7. Harris B., Moody E., Skolnick P. Isoflurane anesthesia is stereoselective. Eur J Pharmacol. 1992 Jul 7;217(2-3):215–216. doi: 10.1016/0014-2999(92)90875-5. [DOI] [PubMed] [Google Scholar]
  8. Huidobro-Toro J. P., Bleck V., Allan A. M., Harris R. A. Neurochemical actions of anesthetic drugs on the gamma-aminobutyric acid receptor-chloride channel complex. J Pharmacol Exp Ther. 1987 Sep;242(3):963–969. [PubMed] [Google Scholar]
  9. Jones M. V., Brooks P. A., Harrison N. L. Enhancement of gamma-aminobutyric acid-activated Cl- currents in cultured rat hippocampal neurones by three volatile anaesthetics. J Physiol. 1992 Apr;449:279–293. doi: 10.1113/jphysiol.1992.sp019086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jones M. V., Harrison N. L. Effects of volatile anesthetics on the kinetics of inhibitory postsynaptic currents in cultured rat hippocampal neurons. J Neurophysiol. 1993 Oct;70(4):1339–1349. doi: 10.1152/jn.1993.70.4.1339. [DOI] [PubMed] [Google Scholar]
  11. Kaneda M., Wakamori M., Akaike N. GABA-induced chloride current in rat isolated Purkinje cells. Am J Physiol. 1989 Jun;256(6 Pt 1):C1153–C1159. doi: 10.1152/ajpcell.1989.256.6.C1153. [DOI] [PubMed] [Google Scholar]
  12. Longoni B., Demontis G. C., Olsen R. W. Enhancement of gamma-aminobutyric acidA receptor function and binding by the volatile anesthetic halothane. J Pharmacol Exp Ther. 1993 Jul;266(1):153–159. [PubMed] [Google Scholar]
  13. Mintz I. M., Adams M. E., Bean B. P. P-type calcium channels in rat central and peripheral neurons. Neuron. 1992 Jul;9(1):85–95. doi: 10.1016/0896-6273(92)90223-z. [DOI] [PubMed] [Google Scholar]
  14. Mody I., Tanelian D. L., MacIver M. B. Halothane enhances tonic neuronal inhibition by elevating intracellular calcium. Brain Res. 1991 Jan 11;538(2):319–323. doi: 10.1016/0006-8993(91)90447-4. [DOI] [PubMed] [Google Scholar]
  15. Moody E. J., Harris B. D., Skolnick P. Stereospecific actions of the inhalation anesthetic isoflurane at the GABAA receptor complex. Brain Res. 1993 Jun 25;615(1):101–106. doi: 10.1016/0006-8993(93)91119-d. [DOI] [PubMed] [Google Scholar]
  16. Moody E. J., Suzdak P. D., Paul S. M., Skolnick P. Modulation of the benzodiazepine/gamma-aminobutyric acid receptor chloride channel complex by inhalation anesthetics. J Neurochem. 1988 Nov;51(5):1386–1393. doi: 10.1111/j.1471-4159.1988.tb01102.x. [DOI] [PubMed] [Google Scholar]
  17. Nakahiro M., Yeh J. Z., Brunner E., Narahashi T. General anesthetics modulate GABA receptor channel complex in rat dorsal root ganglion neurons. FASEB J. 1989 May;3(7):1850–1854. doi: 10.1096/fasebj.3.7.2541038. [DOI] [PubMed] [Google Scholar]
  18. Parker I., Gundersen C. B., Miledi R. Actions of pentobarbital on rat brain receptors expressed in Xenopus oocytes. J Neurosci. 1986 Aug;6(8):2290–2297. doi: 10.1523/JNEUROSCI.06-08-02290.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Regan L. J. Voltage-dependent calcium currents in Purkinje cells from rat cerebellar vermis. J Neurosci. 1991 Jul;11(7):2259–2269. doi: 10.1523/JNEUROSCI.11-07-02259.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Tanelian D. L., Kosek P., Mody I., MacIver M. B. The role of the GABAA receptor/chloride channel complex in anesthesia. Anesthesiology. 1993 Apr;78(4):757–776. doi: 10.1097/00000542-199304000-00020. [DOI] [PubMed] [Google Scholar]
  21. Wakamori M., Ikemoto Y., Akaike N. Effects of two volatile anesthetics and a volatile convulsant on the excitatory and inhibitory amino acid responses in dissociated CNS neurons of the rat. J Neurophysiol. 1991 Dec;66(6):2014–2021. doi: 10.1152/jn.1991.66.6.2014. [DOI] [PubMed] [Google Scholar]
  22. Yoshimura M., Higashi H., Fujita S., Shimoji K. Selective depression of hippocampal inhibitory postsynaptic potentials and spontaneous firing by volatile anesthetics. Brain Res. 1985 Aug 12;340(2):363–368. doi: 10.1016/0006-8993(85)90933-3. [DOI] [PubMed] [Google Scholar]
  23. el-Beheiry H., Puil E. Anaesthetic depression of excitatory synaptic transmission in neocortex. Exp Brain Res. 1989;77(1):87–93. doi: 10.1007/BF00250570. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES