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

Abstract

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. 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. 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). 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.