Sensitivity to Sevoflurane anesthesia is decreased in mice with a congenital deletion of Guanylyl Cyclase-1 alpha

Background: Volatile anesthetics increase levels of the neurotransmitter nitric oxide (NO) and the secondary messenger molecule cyclic guanosine monophosphate (cGMP) in the brain. NO activates the enzyme guanylyl cyclase (GC) to produce cGMP. We hypothesized that the NO-GC-cGMP pathway contributes to anesthesia-induced unconsciousness. Methods: Sevoflurane-induced loss and return of righting reflex (LORR and RORR, respectively) were studied in wild-type mice (WT) and in mice congenitally deficient in the GC-1 alpha subunit (GC-1(-/-) mice). Spatial distributions of GC-1 alpha and the GC-2 alpha subunit in the brain were visualized by in situ hybridization. Brain cGMP levels were measured in WT and GC-1(-/-) mice after inhaling oxygen with or without 1.2% sevoflurane for 20 min. Results: Higher concentrations of sevoflurane were required to induce LORR in GC-1(-/-) mice than in WT mice (1. 5 +/- 0.1 vs. 1.1 +/- 0.2%, respectively, n = 14 and 14, P < 0.0001). Similarly, RORR occurred at higher concentrations of sevoflurane in GC-1(-/-) mice than in WT mice (1.0 +/- 0.1 vs. 0.8 +/- 0.1%, respectively, n = 14 and 14, P < 0.0001). Abundant GC-1 alpha and GC-2 alpha mRNA expression was detected in the cerebral cortex, medial habenula, hippocampus, and cerebellum. Inhaling 1.2% sevoflurane for 20 min increased cGMP levels in the brains of WT mice from 2.6 +/- 2.0 to 5.5 +/- 3.7 pmol/mg protein (n = 13 and 10, respectively, P = 0.0355) but not in GC-1(-/-) mice. Conclusion: Congenital deficiency of GC-1 alpha abolished the ability of sevoflurane anesthesia to increase cGMP levels in the whole brain, and increased the concentration of sevoflurane required to induce LORR. Impaired NO-cGMP signaling raises the threshold for producing sevoflurane-induced unconsciousness in mice.