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


CONCLUSIONS
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.
Engelhardt
T
T
Academic Unit of Anaesthesia and Intensive Care, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK. t.engelhardt@abdn.uk
Lowe
P R
PR
Galley
H F
HF
Webster
N R
NR
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007191:Indazoles / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D007191:Indazoles; D001120:Arginine; D007530:Isoflurane; D052248:Nitric Oxide Synthase Type I; C080122:7-nitroindazole