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

Abstract

BackgroundVolatile 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.MethodsSevoflurane-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-1α subunit (GC-1−/− mice). Spatial distributions of GC-1α and the GC-2α 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.ResultsHigher 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-1α and GC-2α 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.ConclusionCongenital deficiency of GC-1α 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.

The CNS-Penetrant Soluble Guanylate Cyclase Stimulator CY6463 Reveals its Therapeutic Potential in Neurodegenerative Diseases

“…Additionally, PDE inhibitors and sGC stimulators may modulate different cell types. PDEs are expressed in discrete brain areas, while sGC is expressed throughout the brain ( Bollen and Prickaerts, 2012 ; Nagasaka et al, 2017 ), which may allow sGC stimulation to broadly modulate CNS physiology in the brain ( Hollas et al, 2019 ). Perhaps most important, yet least understood, is that these mechanisms may impact different intracellular pools of cGMP.…”

Low guanylyl cyclase activity in Weddell seals: implications for peripheral vasoconstriction and perfusion of the brain during diving

“…Furthermore, although GC mRNA was similar between seal and sheep kidneys, GC protein abundance was lower in seals, pointing to differences in stability or translation of the GC subunit isoforms. Whether differences in GC activity between species are solely driven by differential GC expression and activity in vascular cell types or also by differences in nonvascular cells [e.g., fibroblasts and podocytes in the kidney (54) or neurons in the brain (43)], remains to be determined.…”

Volatile anesthetics inhibit presynaptic cGMP signaling to depress presynaptic excitability in rat hippocampal neurons

“…A number of studies have reported volatile anesthetic effects on brain NO/cGMP concentrations. Halothane, isoflurane, and sevoflurane all increase cerebral NO 8–10 and cGMP 7, 11, 12 concentrations, although decreased NO and cGMP levels have also been reported 13 .…”

“…Pharmacological studies have shown increased sensitivity to loss of righting reflex with inhibition of NOS and sGC, which suggests a contribution of reduced NO signaling to anesthetic-induced hypnosis 4–6 . However, knockout of the sGC-1α isoform in mice was recently shown to reduce sensitivity to sevoflurane anesthesia as measured by both loss and return of righting reflex, suggesting that sGC1α-derived cGMP contributes to volatile anesthetic actions 7 . Although one study found that knockout of neuronal NOS (nNOS) did not alter sensitivity to isoflurane anesthesia 4 , nNOS inhibitors can increase sensitivity to volatile anesthetic-induced loss of righting reflex, suggesting nonspecific pharmacological and/or genetic effects.…”