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Sensitivity to sevoflurane anesthesia is decreased in mice with a congenital deletion of guanylyl cyclase-1 alpha

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Abstract
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.
Keywords
Nitric oxide, Soluble guanylyl cyclase, Knock-out mouse, Volatile anesthetics, Sevoflurane, Righting reflex, Cyclic guanosine monophosphate, NUCLEOTIDE-GATED CHANNELS, BRAIN CYCLIC-NUCLEOTIDE, NITRIC-OXIDE RECEPTOR, ISOFLURANE ANESTHESIA, RAT-BRAIN, HALOTHANE ANESTHESIA, INTRAOPERATIVE AWARENESS, KNOCKOUT MICE, NO SYNTHASE, MOUSE-BRAIN

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MLA
Nagasaka, Yasuko et al. “Sensitivity to Sevoflurane Anesthesia Is Decreased in Mice with a Congenital Deletion of Guanylyl Cyclase-1 Alpha.” BMC ANESTHESIOLOGY 17 (2017): n. pag. Print.
APA
Nagasaka, Y., Wepler, M., Thoonen, R., Sips, P., Allen, K., Graw, J. A., Yao, V., et al. (2017). Sensitivity to sevoflurane anesthesia is decreased in mice with a congenital deletion of guanylyl cyclase-1 alpha. BMC ANESTHESIOLOGY, 17.
Chicago author-date
Nagasaka, Yasuko, Martin Wepler, Robrecht Thoonen, Patrick Sips, Kaitlin Allen, Jan A Graw, Vincent Yao, et al. 2017. “Sensitivity to Sevoflurane Anesthesia Is Decreased in Mice with a Congenital Deletion of Guanylyl Cyclase-1 Alpha.” Bmc Anesthesiology 17.
Chicago author-date (all authors)
Nagasaka, Yasuko, Martin Wepler, Robrecht Thoonen, Patrick Sips, Kaitlin Allen, Jan A Graw, Vincent Yao, Sara M Burns, Stefan Muenster, Peter Brouckaert, Keith Miller, Ken Solt, Emmanuel Buys, Fumito Ichinose, and Warren M Zapol. 2017. “Sensitivity to Sevoflurane Anesthesia Is Decreased in Mice with a Congenital Deletion of Guanylyl Cyclase-1 Alpha.” Bmc Anesthesiology 17.
Vancouver
1.
Nagasaka Y, Wepler M, Thoonen R, Sips P, Allen K, Graw JA, et al. Sensitivity to sevoflurane anesthesia is decreased in mice with a congenital deletion of guanylyl cyclase-1 alpha. BMC ANESTHESIOLOGY. 2017;17.
IEEE
[1]
Y. Nagasaka et al., “Sensitivity to sevoflurane anesthesia is decreased in mice with a congenital deletion of guanylyl cyclase-1 alpha,” BMC ANESTHESIOLOGY, vol. 17, 2017.
@article{8524021,
  abstract     = {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.},
  articleno    = {76},
  author       = {Nagasaka, Yasuko and Wepler, Martin and Thoonen, Robrecht and Sips, Patrick and Allen, Kaitlin and Graw, Jan A and Yao, Vincent and Burns, Sara M and Muenster, Stefan and Brouckaert, Peter and Miller, Keith and Solt, Ken and Buys, Emmanuel and Ichinose, Fumito and Zapol, Warren M},
  issn         = {1471-2253},
  journal      = {BMC ANESTHESIOLOGY},
  keywords     = {Nitric oxide,Soluble guanylyl cyclase,Knock-out mouse,Volatile anesthetics,Sevoflurane,Righting reflex,Cyclic guanosine monophosphate,NUCLEOTIDE-GATED CHANNELS,BRAIN CYCLIC-NUCLEOTIDE,NITRIC-OXIDE RECEPTOR,ISOFLURANE ANESTHESIA,RAT-BRAIN,HALOTHANE ANESTHESIA,INTRAOPERATIVE AWARENESS,KNOCKOUT MICE,NO SYNTHASE,MOUSE-BRAIN},
  language     = {eng},
  pages        = {10},
  title        = {Sensitivity to sevoflurane anesthesia is decreased in mice with a congenital deletion of guanylyl cyclase-1 alpha},
  url          = {http://dx.doi.org/10.1186/s12871-017-0368-5},
  volume       = {17},
  year         = {2017},
}

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