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).

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.