Inhibition of neuronal nitric oxide synthase reduces the propofol requirements in wild-type and nNOS knockout mice

Thomas Engelhardt, Peter Lowe, Nigel Robert Webster, Helen Frances Galley

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background and objective: The glutamate-nitric oxide-cyclic guanosine monophosphate pathway has been identified as a potential target for anaesthetic agents. However, mice deficient in neuronal nitric oxide synthase have a similar susceptibility to volatile anaesthetic agents to wild-type mice and are not affected by non-isoform selective inhibitors. We hypothesized that the neuronal nitric oxide synthase selective inhibitor, 7-nitroindazole, would also reduce the propofol requirements in wild-type mice but would have no effect in neuronal nitric oxide synthase knockout mice. Methods: We determined the time to loss of righting reflex, time to painful stimulus and time to regaining the righting reflex in neuronal nitric oxide synthase knockout and wild-type mice following the intraperitoneal injection of propofol in untreated, 7-nitroindazole and vehicle only treated animals (n = 6 per group). Propofol (200 mg kg(-1)) resulted in loss of righting reflex in the untreated and vehicle only groups but was lethal in 7-nitroindazole pre-treated mice, requiring a reduced dose of propofol (100 mg kg(-1)). Results: 7-nitroindazole pre-treatment significantly reduced the loss of righting reflex (P < 0.001) in both wild-type and knockout mice when compared to untreated and vehicle only pre-treated animals, but had no effect on time to painful stimulus or regaining of the righting reflex. 7-nitroindazole reduced the propofol requirements in knockout mice to the same extent as in wild-type animals. Conclusions: Propofol exerts its anaesthetic effects at least partially via the glutamate-nitric oxide-cyclic guanosine monophosphate pathway. The neuronal nitric oxide synthase knockout mice are sensitive to neuronal nitric oxide synthase selective inhibition suggesting that compensatory pathways in neuronal nitric oxide synthase knockout mice exist.

Original languageEnglish
Pages (from-to)197-201
Number of pages5
JournalEuropean Journal of Anaesthesia
Volume23
Issue number3
DOIs
Publication statusPublished - 2006

Keywords

  • anesthetics
  • intravenous propofol
  • animals mice
  • nitric oxide
  • nucleotides cyclic GMP
  • alveolar anesthetic concentration
  • 7-nitro indazole
  • isoflurane aneshesia
  • binding-kinetics
  • NOS inhibitor
  • 7-nitroindazole
  • halothane
  • threshold
  • rats
  • disruption

Cite this

Inhibition of neuronal nitric oxide synthase reduces the propofol requirements in wild-type and nNOS knockout mice. / Engelhardt, Thomas; Lowe, Peter; Webster, Nigel Robert; Galley, Helen Frances.

In: European Journal of Anaesthesia, Vol. 23, No. 3, 2006, p. 197-201.

Research output: Contribution to journalArticle

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abstract = "Background and objective: The glutamate-nitric oxide-cyclic guanosine monophosphate pathway has been identified as a potential target for anaesthetic agents. However, mice deficient in neuronal nitric oxide synthase have a similar susceptibility to volatile anaesthetic agents to wild-type mice and are not affected by non-isoform selective inhibitors. We hypothesized that the neuronal nitric oxide synthase selective inhibitor, 7-nitroindazole, would also reduce the propofol requirements in wild-type mice but would have no effect in neuronal nitric oxide synthase knockout mice. Methods: We determined the time to loss of righting reflex, time to painful stimulus and time to regaining the righting reflex in neuronal nitric oxide synthase knockout and wild-type mice following the intraperitoneal injection of propofol in untreated, 7-nitroindazole and vehicle only treated animals (n = 6 per group). Propofol (200 mg kg(-1)) resulted in loss of righting reflex in the untreated and vehicle only groups but was lethal in 7-nitroindazole pre-treated mice, requiring a reduced dose of propofol (100 mg kg(-1)). Results: 7-nitroindazole pre-treatment significantly reduced the loss of righting reflex (P < 0.001) in both wild-type and knockout mice when compared to untreated and vehicle only pre-treated animals, but had no effect on time to painful stimulus or regaining of the righting reflex. 7-nitroindazole reduced the propofol requirements in knockout mice to the same extent as in wild-type animals. Conclusions: Propofol exerts its anaesthetic effects at least partially via the glutamate-nitric oxide-cyclic guanosine monophosphate pathway. The neuronal nitric oxide synthase knockout mice are sensitive to neuronal nitric oxide synthase selective inhibition suggesting that compensatory pathways in neuronal nitric oxide synthase knockout mice exist.",
keywords = "anesthetics, intravenous propofol, animals mice, nitric oxide, nucleotides cyclic GMP, alveolar anesthetic concentration, 7-nitro indazole, isoflurane aneshesia, binding-kinetics, NOS inhibitor, 7-nitroindazole, halothane, threshold, rats, disruption",
author = "Thomas Engelhardt and Peter Lowe and Webster, {Nigel Robert} and Galley, {Helen Frances}",
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TY - JOUR

T1 - Inhibition of neuronal nitric oxide synthase reduces the propofol requirements in wild-type and nNOS knockout mice

AU - Engelhardt, Thomas

AU - Lowe, Peter

AU - Webster, Nigel Robert

AU - Galley, Helen Frances

PY - 2006

Y1 - 2006

N2 - Background and objective: The glutamate-nitric oxide-cyclic guanosine monophosphate pathway has been identified as a potential target for anaesthetic agents. However, mice deficient in neuronal nitric oxide synthase have a similar susceptibility to volatile anaesthetic agents to wild-type mice and are not affected by non-isoform selective inhibitors. We hypothesized that the neuronal nitric oxide synthase selective inhibitor, 7-nitroindazole, would also reduce the propofol requirements in wild-type mice but would have no effect in neuronal nitric oxide synthase knockout mice. Methods: We determined the time to loss of righting reflex, time to painful stimulus and time to regaining the righting reflex in neuronal nitric oxide synthase knockout and wild-type mice following the intraperitoneal injection of propofol in untreated, 7-nitroindazole and vehicle only treated animals (n = 6 per group). Propofol (200 mg kg(-1)) resulted in loss of righting reflex in the untreated and vehicle only groups but was lethal in 7-nitroindazole pre-treated mice, requiring a reduced dose of propofol (100 mg kg(-1)). Results: 7-nitroindazole pre-treatment significantly reduced the loss of righting reflex (P < 0.001) in both wild-type and knockout mice when compared to untreated and vehicle only pre-treated animals, but had no effect on time to painful stimulus or regaining of the righting reflex. 7-nitroindazole reduced the propofol requirements in knockout mice to the same extent as in wild-type animals. Conclusions: Propofol exerts its anaesthetic effects at least partially via the glutamate-nitric oxide-cyclic guanosine monophosphate pathway. The neuronal nitric oxide synthase knockout mice are sensitive to neuronal nitric oxide synthase selective inhibition suggesting that compensatory pathways in neuronal nitric oxide synthase knockout mice exist.

AB - Background and objective: The glutamate-nitric oxide-cyclic guanosine monophosphate pathway has been identified as a potential target for anaesthetic agents. However, mice deficient in neuronal nitric oxide synthase have a similar susceptibility to volatile anaesthetic agents to wild-type mice and are not affected by non-isoform selective inhibitors. We hypothesized that the neuronal nitric oxide synthase selective inhibitor, 7-nitroindazole, would also reduce the propofol requirements in wild-type mice but would have no effect in neuronal nitric oxide synthase knockout mice. Methods: We determined the time to loss of righting reflex, time to painful stimulus and time to regaining the righting reflex in neuronal nitric oxide synthase knockout and wild-type mice following the intraperitoneal injection of propofol in untreated, 7-nitroindazole and vehicle only treated animals (n = 6 per group). Propofol (200 mg kg(-1)) resulted in loss of righting reflex in the untreated and vehicle only groups but was lethal in 7-nitroindazole pre-treated mice, requiring a reduced dose of propofol (100 mg kg(-1)). Results: 7-nitroindazole pre-treatment significantly reduced the loss of righting reflex (P < 0.001) in both wild-type and knockout mice when compared to untreated and vehicle only pre-treated animals, but had no effect on time to painful stimulus or regaining of the righting reflex. 7-nitroindazole reduced the propofol requirements in knockout mice to the same extent as in wild-type animals. Conclusions: Propofol exerts its anaesthetic effects at least partially via the glutamate-nitric oxide-cyclic guanosine monophosphate pathway. The neuronal nitric oxide synthase knockout mice are sensitive to neuronal nitric oxide synthase selective inhibition suggesting that compensatory pathways in neuronal nitric oxide synthase knockout mice exist.

KW - anesthetics

KW - intravenous propofol

KW - animals mice

KW - nitric oxide

KW - nucleotides cyclic GMP

KW - alveolar anesthetic concentration

KW - 7-nitro indazole

KW - isoflurane aneshesia

KW - binding-kinetics

KW - NOS inhibitor

KW - 7-nitroindazole

KW - halothane

KW - threshold

KW - rats

KW - disruption

U2 - 10.1017/S0265021505002188

DO - 10.1017/S0265021505002188

M3 - Article

VL - 23

SP - 197

EP - 201

JO - European Journal of Anaesthesia

JF - European Journal of Anaesthesia

SN - 0265-0215

IS - 3

ER -