Inhibition of neuronal nitric oxide synthase reduces the propofol requirements in wild-type and nNOS knockout mice.
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.
Engelhardt
T
T
Academic Unit of Anaesthesia and Intensive Care, School of Medicine and Life Sciences, University of Aberdeen, Scotland, UK. t.engelhardt@abdn.ac.uk
Lowe
P R
PR
Galley
H F
HF
Webster
N R
NR
D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017931:DNA Primers; D004351:Drug Resistance / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009355:Neomycin / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000235:genetics*; D004856:Postural Balance / Q000187:drug effects; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology*; D012018:Reflex / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018686:Anesthetics, Intravenous; D017931:DNA Primers; D004791:Enzyme Inhibitors; D007191:Indazoles; D052248:Nitric Oxide Synthase Type I; D009355:Neomycin; C080122:7-nitroindazole; D015742:Propofol