Bilirubin potentiates etomidate-induced sedation by enhancing GABA-induced currents after bile duct ligation
Tóm tắt
Our previous clinical trial showed that etomidate requirements to reach an appropriate level of anesthesia in patients with obstructive jaundice were reduced, which means that these patients are more sensitive to etomidate. However, the mechanism is still not completely clear. The present study was aimed to investigate the mechanism by which bilirubin facilitates etomidate induced sedation. A bile duct ligation (BDL) rat model was used to simulate obstructive jaundice. Anesthesia sensitivity to etomidate was determined by the time to loss of righting reflex (LORR). Intrathecal injection of bilirubin was used to test the effects of bilirubin on etomidate induced sedation. The modulating effects of bilirubin on GABA responses were studied using the whole-cell patch clamp technique. The time to LORR induced by etomidate was significantly decreased in the BDL groups (p < 0.05), and unconjugated bilirubin in serum and cerebrospinal fluid (CSF) were markedly increased (p < 0.05). The time to LORR induced by etomidate was decreased after intrathecal injection of bilirubin (p < 0.05). A bilirubin concentration of 1.0 μM increased the GABA-induced currents of rat cortical pyramidal neurons (p < 0.05). Furthermore, 1.0 μM bilirubin enhanced GABA-induced currents modulated by etomidate (p < 0.05). Our results demonstrated that pathologic bilirubin in CSF could enhance etomidate induced sedation. The mechanism may be that bilirubin increase the GABA-induced currents of rat pyramidal neurons.
Tài liệu tham khảo
Green J, Better OS. Systemic hypotension and renal failure in obstructive jaundice-mechanistic and therapeutic aspects. J Am Soc Nephrol. 1995;5(11):1853–71. https://doi.org/10.1681/ASN.V5111853. PMID: 7620083.
Rege RV. Adverse effects of biliary obstruction: implications for treatment of patients with obstructive jaundice. AJR Am J Roentgenol. 1995;164(2):287–93. https://doi.org/10.2214/ajr.164.2.7839957. PMID: 7839957.
Sewnath ME, Karsten TM, Prins MH, Rauws EJ, Obertop H, Gouma DJ. A meta-analysis on the efficacy of preoperative biliary drainage for tumors causing obstructive jaundice. Ann Surg. 2002;236(1):17–27. https://doi.org/10.1097/00000658-200207000-00005. PMID:12131081;PMCID:PMC1422544.
Song JG, Cao YF, Yang LQ, Yu WF, Li Q, Song JC, Fu XY, Fu Q. Awakening concentration of desflurane is decreased in patients with obstructive jaundice. Anesthesiology. 2005;102(3):562–5. https://doi.org/10.1097/00000542-200503000-00014. PMID: 15731594.
Yang LQ, Song JC, Irwin MG, Song JG, Sun YM, Yu WF. A clinical prospective comparison of anesthetics sensitivity and hemodynamic effect among patients with or without obstructive jaundice. Acta Anaesthesiol Scand. 2010;54(7):871–7. https://doi.org/10.1111/j.1399-6576.2010.02222.x. Epub 2010 Mar 10 PMID: 20236100.
Liu K, Jounaidi Y, Forman SA, Feng H-J. Etomidate uniquely modulates the desensitization of recombinant α1β3δ GABA(A) receptors. Neuroscience. 2015;300:307–13. https://doi.org/10.1016/j.neuroscience.2015.05.051. PMID: 26028470.
Krasowski MD, Jenkins A, Flood P, Kung AY, Hopfinger AJ, Harrison NL. General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility. J Pharmacol Exp Ther. 2001;297(1):338–51 PMID: 11259561.
Nelson LE, Guo TZ, Lu J, Saper CB, Franks NP, Maze M. The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci. 2002;5(10):979–84. https://doi.org/10.1038/nn913. PMID: 12195434.
Song JC, Sun YM, Zhang MZ, Yang LQ, Tao TZ, Yu WF. The etomidate requirement is decreased in patients with obstructive jaundice. Anesth Analg. 2011;113(5):1028–32. https://doi.org/10.1213/ANE.0b013e31822dac4a. Epub 2011 Aug 24 PMID: 21865492.
Brito MA, Lima S, Fernandes A, Falcão AS, Silva RF, Butterfield DA, Brites D. Bilirubin injury to neurons: contribution of oxidative stress and rescue by glycoursodeoxycholic acid. Neurotoxicology. 2008;29(2):259–69. https://doi.org/10.1016/j.neuro.2007.11.002. Epub 2007 Nov 19 PMID: 18164405.
Vaz AR, Delgado-Esteban M, Brito MA, Bolaños JP, Brites D, Almeida A. Bilirubin selectively inhibits cytochrome c oxidase activity and induces apoptosis in immature cortical neurons: assessment of the protective effects of glycoursodeoxycholic acid. J Neurochem. 2010;112(1):56–65. https://doi.org/10.1111/j.1471-4159.2009.06429.x. Epub 2009 Oct 10 PMID: 19818102.
Rodrigues CM, Solá S, Brites D. Bilirubin induces apoptosis via the mitochondrial pathway in developing rat brain neurons. Hepatology. 2002;35(5):1186–95. https://doi.org/10.1053/jhep.2002.32967. PMID: 11981769.
Watchko JF, Tiribelli C. Bilirubin-induced neurologic damage–mechanisms and management approaches. N Engl J Med. 2013;369(21):2021–30. https://doi.org/10.1056/NEJMra1308124. PMID: 24256380.
Jones EA. Fatigue associated with chronic liver disease: a riddle wrapped in a mystery inside an enigma. Hepatology. 1995;22(5):1606–8 PMID: 7590682.
Swain MG, Maric M. Improvement in cholestasis-associated fatigue with a serotonin receptor agonist using a novel rat model of fatigue assessment. Hepatology. 1997;25(2):291–4. https://doi.org/10.1002/hep.510250206. PMID: 9021936.
Burak KW, Le T, Swain MG. Increased midbrain 5-HT1A receptor number and responsiveness in cholestatic rats. Brain Res. 2001;892(2):376–9. https://doi.org/10.1016/s0006-8993(00)03058-4. PMID: 11172786.
Haustein MD, Read DJ, Steinert JR, Pilati N, Dinsdale D, Forsythe ID. Acute hyperbilirubinaemia induces presynaptic neurodegeneration at a central glutamatergic synapse. J Physiol. 2010;588(Pt 23):4683–93. https://doi.org/10.1113/jphysiol.2010.199778. Epub 2010 Oct 11. PMID: 20937712; PMCID: PMC3010138.
Silva R, Mata LR, Gulbenkian S, Brito MA, Tiribelli C, Brites D. Inhibition of glutamate uptake by unconjugated bilirubin in cultured cortical rat astrocytes: role of concentration and pH. Biochem Biophys Res Commun. 1999;265(1):67–72. https://doi.org/10.1006/bbrc.1999.1646. PMID: 10548492.
Silva RF, Rodrigues CM, Brites D. Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin. Pediatr Res. 2002;51(4):535–41. https://doi.org/10.1203/00006450-200204000-00022. PMID: 11919342.
Ostrow JD, Pascolo L, Brites D, Tiribelli C. Molecular basis of bilirubin-induced neurotoxicity. Trends Mol Med. 2004;10(2):65–70. https://doi.org/10.1016/j.molmed.2003.12.003. PMID: 15102359.
Desai R, Ruesch D, Forman SA. Gamma-amino butyric acid type A receptor mutations at beta2N265 alter etomidate efficacy while preserving basal and agonist-dependent activity. Anesthesiology. 2009;111(4):774–84. https://doi.org/10.1097/ALN.0b013e3181b55fae. PMID:19741491;PMCID:PMC2798018.
Martin LJ, Oh GH, Orser BA. Etomidate targets alpha5 gamma-aminobutyric acid subtype A receptors to regulate synaptic plasticity and memory blockade. Anesthesiology. 2009;111(5):1025–35. https://doi.org/10.1097/ALN.0b013e3181bbc961. PMID: 19809285.
Forman SA, Miller KW. Anesthetic sites and allosteric mechanisms of action on Cys-loop ligand-gated ion channels. Can J Anaesth. 2011;58(2):191–205. https://doi.org/10.1007/s12630-010-9419-9. Epub 2011 Jan 7. PMID: 21213095; PMCID: PMC3108180.
Tung A, Szafran MJ, Bluhm B, Mendelson WB. Sleep deprivation potentiates the onset and duration of loss of righting reflex induced by propofol and isoflurane. Anesthesiology. 2002;97(4):906–11. https://doi.org/10.1097/00000542-200210000-00024. PMID: 12357158.
Devor M, Zalkind V. Reversible analgesia, atonia, and loss of consciousness on bilateral intracerebral microinjection of pentobarbital. Pain. 2001;94(1):101–12. https://doi.org/10.1016/S0304-3959(01)00345-1. PMID: 11576749.
Palombo JD, Bistrian BR, Blackburn GL. Assessment of the effects of above-normal bilirubin on radioimmunoassay of conjugated bile acids in serum. Clin Chem. 1986;32(12):2204 PMID: 3779984.
Shi HB, Kakazu Y, Shibata S, Matsumoto N, Nakagawa T, Komune S. Bilirubin potentiates inhibitory synaptic transmission in lateral superior olive neurons of the rat. Neurosci Res. 2006;55(2):161–70. https://doi.org/10.1016/j.neures.2006.02.015. Epub 2006 Apr 3 PMID: 16595155.
Zhang C, Wang Z, Dong J, Pan R, Qiu H, Zhang J, Zhang P, Zheng J, Yu W. Bilirubin modulates acetylcholine receptors in rat superior cervical ganglionic neurons in a bidirectional manner. Sci Rep. 2014;15(4):7475. https://doi.org/10.1038/srep07475. PMID:25503810;PMCID:PMC4265787.