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Pancuronium enhances isoflurane anesthesia in rats via inhibition of cerebral nicotinic acetylcholine receptors

Abstract

Purpose

This study was conducted to elucidate the mechanism of enhancement of volatile anesthetics by neuromuscular blocking agents in rats and to consider the relevance of this enhancement to clinical anesthesia.

Methods

Male Sprague–Dawley rats were used. After confirming a movement in response to tail clamping under 1.1 % isoflurane anesthesia, response was determined when the tail clamp was applied at several points after microinjection of pancuronium into the lateral ventricle. Arousal responses to microinjection of nicotine into the lateral ventricle were assessed with or without pretreatment with intraventricular pancuronium. The intravenous 50 % effective dose (ED50) and 95 % effective dose (ED95) for neuromuscular blockade with pancuronium administered in a cumulative fashion at 1.1 % isoflurane were calculated.

Results

Intraventricular pancuronium dose-dependently reduced the response to tail clamping, and the dose required to show immobilization of 50 % of rats (intraventricular ED50) was 1.62 µg/kg. Pretreatment with pancuronium at 6 µg/kg significantly reduced the effect of awakening by nicotine under isoflurane anesthesia (P = 0.044). The intravenous ED50 and ED95 for neuromuscular blockade were 63 µg/kg (90 % confidence interval [CI] 52–75 µg/kg) and 133 µg/kg (90 % CI 109–158 µg/kg), respectively. The ratio of intraventricular ED50 to intravenous ED50 was 0.026.

Conclusion

Pancuronium microinjection into the lateral ventricle dose-dependently enhances the depth of isoflurane anesthesia, which might be caused by inhibition of neuronal nicotinic acetylcholine receptor transmission in the cerebrum. Intravenous injection of pancuronium at high doses might increase the cerebrospinal concentration to a level at which an effect can be observed.

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References

  1. 1.

    Whittington RA, Virág L. The differential effects of equipotent doses of isoflurane and desflurane on hippocampal acetylcholine levels in young and aged rats. Neurosci Lett. 2010;471:166–70.

  2. 2.

    Westphalen RI, Desai KM, Hemmings HC Jr. Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane. Br J Anaesth. 2013;110:592–9.

  3. 3.

    Zucker J. Central cholinergic depression reduces MAC for isoflurane in rats. Anesth Anal. 1991;72:790–5.

  4. 4.

    Alkire MT, McReynolds JR, Hahn EL, Trivedi AN. Thalamic microinjection of nicotine reverses sevoflurane-induced loss of righting reflex in the rat. Anesthesiology. 2007;107:264–72.

  5. 5.

    Fagerlund MJ, Eriksson LI. Current concepts in neuromuscular transmission. Br J Anaesth. 2009;103:108–14.

  6. 6.

    Tassonyi E, Fathi M, Hughes GJ, Chiodini F, Bertrand D, Muller D, Fuchs-Buder T. Cerebrospinal fluid concentrations of atracurium, laudanosine and vecuronium following clinical subarachnoid hemorrhage. Acta Anaesthesiol Scand. 2002;46:1236–41.

  7. 7.

    Fuchs-Buder T, Strowitzki M, Rentsch K, Schreiber JU, Philipp-Osterman S, Kleinschmidt S. Concentration of rocuronium in cerebrospinal fluid of patients undergoing cerebral aneurysm clipping. Br J Anaesth. 2004;92:419–21.

  8. 8.

    Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 6th ed. Burlington: Academic Press; 2006.

  9. 9.

    White PF, Johnston RR, Eger EI 2nd. Determination of anesthetic requirement in rats. Anesthesiology. 1974;40:52–7.

  10. 10.

    Quasha AL, Eger EI 2nd, Tinker JH. Determination and applications of MAC. Anesthesiology. 1980;53:315–34.

  11. 11.

    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

  12. 12.

    Flood P, Ramirez-Latorre J, Role L. Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected. Anesthesiology. 1997;86:859–65.

  13. 13.

    Violet JM, Downie DL, Nakisa RC, Lieb WR, Franks NP. Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics. Anesthesiology. 1997;86:866–74.

  14. 14.

    Gallezot JD, Bottlaender M, Gregoire MC, Roumenov D, Deverre JR, Coulon C, Ottaviani M, Dolle F, Syrota A, Valette H. In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET. J Nucl Med. 2005;46:240–7.

  15. 15.

    Chiodini F, Charpantier E, Muller D, Tassonyi E, Fuchs-Buder T, Bertrand D. Blockade and activation of the human neuronal nicotinic acetylcholine receptors by atracurium and laudanosine. Anesthesiology. 2001;94:643–51.

  16. 16.

    Jonsson M, Gurley D, Dabrowski M, Larsson O, Johnson EC, Eriksson LI. Distinct pharmacologic properties of neuromuscular blocking agents on human neuronal nicotinic acetylcholine receptors: a possible explanation for the train-of-four fade. Anesthesiology. 2006;105:521–33.

  17. 17.

    Drummond JC. MAC for halothane, enflurane, and isoflurane in the New Zealand white rabbit: and a test for the validity of MAC determinations. Anesthesiology. 1985;62:336–8.

  18. 18.

    Rampil IJ, Mason P, Singh H. Anesthetic potency (MAC) is independent of forebrain structures in the rat. Anesthesiology. 1993;78:707–12.

  19. 19.

    Antognini JF, Schwartz K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology. 1993;79:1244–9.

  20. 20.

    Borges M, Antognini JF. Does the brain influence somatic responses to noxious stimuli during isoflurane anesthesia? Anesthesiology. 1994;81:1511–5.

  21. 21.

    Stabernack C, Zhang Y, Sonner JM, Laster M, Eger EI 2nd. Thiopental produces immobility primarily by supraspinal actions in rats. Anesth Anal. 2005;100:128–36.

  22. 22.

    Harris RS, Lazar O, Johansen JW, Sebel PS. Interaction of propofol and sevoflurane on loss of consciousness and movement to skin incision during general anesthesia. Anesthesiology. 2006;104:1170–5.

  23. 23.

    Luo LL, Zhou LX, Wang J, Wang RR, Huang W, Zhou J. Effects of propofol on the minimum alveolar concentration of sevoflurane for immobility at skin incision in adult patients. J Clin Anesth. 2010;22:527–32.

  24. 24.

    Werba A, Gilly H, Weindlmayr-Goettel M, Spiss CK, Steinbereithner K, Czech T, Agoston S. Porcine model for studying the passage of non-depolarizing neuromuscular blockers through the blood-brain barrier. Br J Anaesth. 1992;69:382–6.

  25. 25.

    Rosenberg GA. Neurological diseases in relation to the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32:1139–51.

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Author information

Correspondence to Hiroshi Sunaga.

Ethics declarations

Conflict of interest

Yusuke Miyazaki, Hiroshi Sunaga, Shotaro Hobo, and Kazuko Miyano have no conflicts to disclose. Shoichi Uezono is a paid consultant of Edwards Lifesciences, Corp.

Funding

This work was funded by MEXT KAKENHI Grant No. 24592317 and the Department of Anesthesiology, Jikei University School of Medicine.

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Miyazaki, Y., Sunaga, H., Hobo, S. et al. Pancuronium enhances isoflurane anesthesia in rats via inhibition of cerebral nicotinic acetylcholine receptors. J Anesth 30, 671–676 (2016). https://doi.org/10.1007/s00540-016-2178-1

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Keywords

  • Pancuronium
  • Central nervous system
  • Isoflurane
  • Rat
  • Acetylcholine receptor