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

BMC Anesthesiology

Research Article

Emmanuel S. Buys¹  Ken Solt¹  Vincent Yao¹  Yasuko Nagasaka¹  Fumito Ichinose¹  Warren M. Zapol¹  Stefan Muenster¹  Keith Miller¹  Peter Brouckaert¹  Martin Wepler¹  Jan A. Graw¹  Kaitlin Allen¹  Sara M. Burns²  Patrick Y. Sips³  Robrecht Thoonen⁴ 

[1]Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

[2]Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium and Inflammation Research Center, VIB, Ghent, Belgium

[3]Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA

[4]Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA

关键词: Nitric oxide;    Soluble guanylyl cyclase;    Knock-out mouse;    Volatile anesthetics;    Sevoflurane;    Righting reflex;    Cyclic guanosine monophosphate;   

DOI  :  10.1186/s12871-017-0368-5

 received in 2016-09-30, accepted in 2017-05-31,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2017