Inhibition of neuronal nitric oxide synthase reduces isoflurane MAC and motor activity even in nNOS knockout mice

T Engelhardt, P R Lowe, H F Galley, N R Webster

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background. The glutamate-nitric oxide-cyclic GMP pathway has been identified as a potential target for volatile anaesthetic agents as acute inhibition of nitric oxide synthase ( NOS) reduces the minimum alveolar concentration ( MAC) in most animal studies. However, mice deficient in the type I NOS isoform ( nNOS) are reported to have a similar MAC for isoflurane and are not affected by non-isoform specific inhibitors.

Methods. We determined whether the nNOS specific inhibitor, 7-nitroindazole ( 7-NI), had an effect on isoflurane MAC and righting reflex ( RRF) and investigated spontaneous motor activity in an open-field study in wild-type ( WT) and knockout ( KO) mice.

Results. 7-NI reduced isoflurane MAC and RRF in both WT and KO animals ( all P < 0.04). 7-NI profoundly reduced spontaneous motor activity in both the WT and KO animals in the open-field study as indicated by a reduction in the number of line crossings and rearings in both WT and KO mice ( both P < 0.001).

Conclusion. We conclude that isoform specific inhibition of nNOS reduces MAC and spontaneous motor activity even in nNOS KO animals. Our results indicate that the NMDA receptor-nitric oxide-cyclic GMP pathway remains a credible target in modulating the effects of isoflurane.

Original languageEnglish
Pages (from-to)361-366
Number of pages6
JournalBritish Journal of Anaesthesia
Volume96
DOIs
Publication statusPublished - 2006

Keywords

  • anaesthetics volatile, isoflurane
  • inhibitor, 7-Nl
  • isoform, nNOS
  • mice, open-field
  • ALVEOLAR ANESTHETIC CONCENTRATION
  • 7-NITRO INDAZOLE
  • BINDING-KINETICS
  • NOS INHIBITOR
  • 7-NITROINDAZOLE
  • HALOTHANE
  • THRESHOLD
  • RATS
  • DISRUPTION
  • ANXIETY

Cite this

Inhibition of neuronal nitric oxide synthase reduces isoflurane MAC and motor activity even in nNOS knockout mice. / Engelhardt, T ; Lowe, P R ; Galley, H F ; Webster, N R .

In: British Journal of Anaesthesia, Vol. 96, 2006, p. 361-366.

Research output: Contribution to journalArticle

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abstract = "Background. The glutamate-nitric oxide-cyclic GMP pathway has been identified as a potential target for volatile anaesthetic agents as acute inhibition of nitric oxide synthase ( NOS) reduces the minimum alveolar concentration ( MAC) in most animal studies. However, mice deficient in the type I NOS isoform ( nNOS) are reported to have a similar MAC for isoflurane and are not affected by non-isoform specific inhibitors.Methods. We determined whether the nNOS specific inhibitor, 7-nitroindazole ( 7-NI), had an effect on isoflurane MAC and righting reflex ( RRF) and investigated spontaneous motor activity in an open-field study in wild-type ( WT) and knockout ( KO) mice.Results. 7-NI reduced isoflurane MAC and RRF in both WT and KO animals ( all P < 0.04). 7-NI profoundly reduced spontaneous motor activity in both the WT and KO animals in the open-field study as indicated by a reduction in the number of line crossings and rearings in both WT and KO mice ( both P < 0.001).Conclusion. We conclude that isoform specific inhibition of nNOS reduces MAC and spontaneous motor activity even in nNOS KO animals. Our results indicate that the NMDA receptor-nitric oxide-cyclic GMP pathway remains a credible target in modulating the effects of isoflurane.",
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AU - Lowe, P R

AU - Galley, H F

AU - Webster, N R

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N2 - Background. The glutamate-nitric oxide-cyclic GMP pathway has been identified as a potential target for volatile anaesthetic agents as acute inhibition of nitric oxide synthase ( NOS) reduces the minimum alveolar concentration ( MAC) in most animal studies. However, mice deficient in the type I NOS isoform ( nNOS) are reported to have a similar MAC for isoflurane and are not affected by non-isoform specific inhibitors.Methods. We determined whether the nNOS specific inhibitor, 7-nitroindazole ( 7-NI), had an effect on isoflurane MAC and righting reflex ( RRF) and investigated spontaneous motor activity in an open-field study in wild-type ( WT) and knockout ( KO) mice.Results. 7-NI reduced isoflurane MAC and RRF in both WT and KO animals ( all P < 0.04). 7-NI profoundly reduced spontaneous motor activity in both the WT and KO animals in the open-field study as indicated by a reduction in the number of line crossings and rearings in both WT and KO mice ( both P < 0.001).Conclusion. We conclude that isoform specific inhibition of nNOS reduces MAC and spontaneous motor activity even in nNOS KO animals. Our results indicate that the NMDA receptor-nitric oxide-cyclic GMP pathway remains a credible target in modulating the effects of isoflurane.

AB - Background. The glutamate-nitric oxide-cyclic GMP pathway has been identified as a potential target for volatile anaesthetic agents as acute inhibition of nitric oxide synthase ( NOS) reduces the minimum alveolar concentration ( MAC) in most animal studies. However, mice deficient in the type I NOS isoform ( nNOS) are reported to have a similar MAC for isoflurane and are not affected by non-isoform specific inhibitors.Methods. We determined whether the nNOS specific inhibitor, 7-nitroindazole ( 7-NI), had an effect on isoflurane MAC and righting reflex ( RRF) and investigated spontaneous motor activity in an open-field study in wild-type ( WT) and knockout ( KO) mice.Results. 7-NI reduced isoflurane MAC and RRF in both WT and KO animals ( all P < 0.04). 7-NI profoundly reduced spontaneous motor activity in both the WT and KO animals in the open-field study as indicated by a reduction in the number of line crossings and rearings in both WT and KO mice ( both P < 0.001).Conclusion. We conclude that isoform specific inhibition of nNOS reduces MAC and spontaneous motor activity even in nNOS KO animals. Our results indicate that the NMDA receptor-nitric oxide-cyclic GMP pathway remains a credible target in modulating the effects of isoflurane.

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