Skip to main content

Advertisement

SpringerLink
Log in

Cellular signaling pathways and molecular mechanisms involving inhalational anesthetics-induced organoprotection

  • Invited Review Article
  • Published:
Journal of Anesthesia Aims and scope Submit manuscript

Abstract

Inhalational anesthetics-induced organoprotection has received much research interest and has been consistently demonstrated in different models of organ damage, in particular, ischemia–reperfusion injury, which features prominently in the perioperative period and in cardiovascular events. The cellular mechanisms accountable for effective organoprotection over heart, brain, kidneys, and other vital organs have been elucidated in turn in the past two decades, including receptor stimulations, second-messenger signal relay and amplification, end-effector activation, and transcriptional modification. This review summarizes the signaling pathways and the molecular participants in inhalational anesthetics-mediated organ protection published in the current literature, comparing and contrasting the ‘preconditioning’ and ‘postconditioning’ phenomena, and the similarities and differences in mechanisms between organs. The salubrious effects of inhalational anesthetics on vital organs, if reproducible in human subjects in clinical settings, would be of exceptional clinical importance, but clinical studies with better design and execution are prerequisites for valid conclusions to be made. Xenon as the emerging inhalational anesthetic, and its organoprotective efficacy, mechanism, and relative advantages over other anesthetics, are also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Pagel PS, Hudetz JA. Delayed cardioprotection by inhaled anesthetics. J Cardiothorac Vasc Anesth. 2002;25:1125–40.

    Google Scholar 

  2. Toller WG, Kersten JR, Gross ER, Pagel PS, Warltier DC. Isoflurane preconditions myocardium against infarction via activation of inhibitory guanine nucleotide binding proteins. Anesthesiology. 2000;92:1400–7.

    PubMed  CAS  Google Scholar 

  3. Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Schaub MC. Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial KATP channels via multiple signaling pathways. Anesthesiology. 2002;97:4–14.

    PubMed  CAS  Google Scholar 

  4. Kersten JR, Orth KG, Pagel PS, Mei DA, Gross GJ, Warltier DC. Role of adenosine in isoflurane-induced cardioprotection. Anesthesiology. 1997;86:1128–39.

    PubMed  CAS  Google Scholar 

  5. Roscoe AK, Christensen JD, Lynch C. Isoflurane, but not halothane, induces protection of human myocardium via adenosine A(1) receptors and adenosine triphosphate-sensitive potassium channels. Anesthesiology. 2000;92:1692–701.

    PubMed  CAS  Google Scholar 

  6. Hanouz J-L, Yvon A, Massetti M, Lepage O, Babatasi G, Khayat A, Bricard H, Gérard JL. Mechanisms of desflurane-induced preconditioning in isolated human right atria in vitro. Anesthesiology. 2002;97:33–41.

    PubMed  CAS  Google Scholar 

  7. Bell SP, Sack MN, Patel A, Opie LH, Yellon DM. Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle. J Am Coll Cardiol. 2000;36:2296–302.

    PubMed  CAS  Google Scholar 

  8. Ludwig LM, Patel HH, Gross GJ, Kersten JR, Pagel PS, Warltier DC. Morphine enhances pharmacological preconditioning by isoflurane: role of mitochondrial KATP channels and opioid receptors. Anesthesiology. 2003;98:705–11.

    PubMed  CAS  Google Scholar 

  9. Zaugg M, Lucchinetti E, Uecker M, Pasch T, Schaub MC. Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms. Br J Anaesth. 2003;91:551–65.

    PubMed  CAS  Google Scholar 

  10. Weber NC, Toma O, Damla H, Wolter JI, Schlack W, Preckel B. Upstream signaling of protein kinase C-ε in xenon-induced pharmacological preconditioning: implication of mitochondrial adenosine triphosphate dependent potassium channels and phosphatidylinositol-dependent kinase-1. Eur J Pharmacol. 2006;539:1–9.

    PubMed  CAS  Google Scholar 

  11. Cope DK, Impastato WK, Cohen MV, Downey JM. Volatile anesthetics protect the ischemic rabbit myocardium from infarction. Anesthesiology. 1997;86:699–709.

    PubMed  CAS  Google Scholar 

  12. Hara T, Tomiyasu S, Sungsam C, Fukusaki M, Sumikawa K. Sevoflurane protects stunned myocardium through activation of mitochondrial ATP-sensitive potassium channels. Anesth Analg. 2001;92:1139–45.

    PubMed  CAS  Google Scholar 

  13. Xu P, Wang J, Kodavatiganti R, Zeng Y, Kass IS. Activation of protein kinase C contributes to the isoflurane-induced improvement of functional and metabolic recovery in isolated ischemic rat hearts. Anesth Analg. 2004;99:993–1000.

    PubMed  CAS  Google Scholar 

  14. Bouwman RA, Musters RJP, van Beek-Harmsen BJ, de Lange JJ, Boer C. Reactive oxygen species precede protein kinase C-delta activation independent of adenosine triphosphate-sensitive mitochondrial channel opening in sevoflurane-induced cardioprotection. Anesthesiology. 2004;100:506–14.

    PubMed  CAS  Google Scholar 

  15. Novalija E, Kevin LG, Camara AKS, Bosnjak ZJ, Kampine JP, Stowe DF. Reactive oxygen species precede the epsilon isoform of protein kinase C in the anesthetic preconditioning signaling cascade. Anesthesiology. 2004;99:421–8.

    Google Scholar 

  16. Uecker M, Da Silva R, Grampp T, Pasch T, Schaub MC, Zaugg M. Translocation of protein kinase C isoforms to subcellular targets in ischemic and anesthetic preconditioning. Anesthesiology. 2003;99:138–47.

    PubMed  CAS  Google Scholar 

  17. Ludwig LM, Weihrauch D, Kersten JR, Pagel PS, Warltier DC. Protein kinase C translocation and Src protein tyrosine kinase activation mediate isoflurane-induced preconditioning in vivo: potential downstream targets of mitochondrial adenosine triphosphate-sensitive potassium channels and reactive oxygen species. Anesthesiology. 2004;100:532–9.

    PubMed  CAS  Google Scholar 

  18. Julier K, da Silva R, Garcia C, Bestmann L, Frascarolo P, Zollinger A, Chassot PG, Schmid ER, Turina MI, von Segesser LK, Pasch T, Spahn DR, Zaugg M. Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: a double-blinded, placebo-controlled, multicenter study. Anesthesiology. 2003;98:1315–27.

    Google Scholar 

  19. da Silva R, Grampp T, Pasch T, Schaub MC, Zaugg M. Differential activation of mitogen-activated protein kinases in ischemic and anesthetic preconditioning. Anesthesiology. 2004;100:59–69.

    PubMed  Google Scholar 

  20. Toma O, Weber NC, Wolter JI, Obal D, Preckel B, Schlack W. Desflurane preconditioning induces time-dependent activation of protein kinase C epsilon and extracellular signal-regulated kinase 1 and 2 in the rat heart in vivo. Anesthesiology. 2004;101:1372–80.

    PubMed  CAS  Google Scholar 

  21. Wang C, Weihrauch D, Schwabe DA, Bienengraeber M, Warltier DC, Kersten JR, Pratt PF Jr, Pagel PS. Extracellular signal-regulated kinases trigger isoflurane preconditioning concomitant with upregulation of hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in rats. Anesth Analg. 2006;106:281–8.

    Google Scholar 

  22. Weber NC, Toma O, Wolter JI, Obal D, Müllenheim J, Preckel B, Schlack W. The noble gas xenon induces pharmacological preconditioning in the rat heart in vivo via induction of PKC-epsilon and p38 MAPK. Br J Pharmacol. 2005;144:123–32.

    PubMed  CAS  PubMed Central  Google Scholar 

  23. Weber NC, Toma O, Wolter JI, Wirthle NM, Schlack W, Preckel B. Mechanisms of xenon- and isoflurane-induced preconditioning—a potential link to the cytoskeleton via the MAPKAPK-2/HSP27 pathway. Br J Pharmacol. 2005;146:445–55.

    PubMed  CAS  PubMed Central  Google Scholar 

  24. Obal D, Weber NC, Zacharowski K, Toma O, Dettwiler S, Wolter JI, Kratz M, Müllenheim J, Preckel B, Schlack W. Role of protein kinase C (PKC) in isoflurane-induced cardioprotection. Br J Anaesth. 2005;94:166–73.

    PubMed  CAS  Google Scholar 

  25. Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD. Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria. Am J Physiol Heart Circ Physiol. 2001;280:H649–57.

    PubMed  CAS  Google Scholar 

  26. O’Rourke B. Myocardial KATP channels in preconditioning. Circ Res. 2000;87:845–55.

    PubMed  Google Scholar 

  27. Riess ML, Camara AKS, Novalija E, Chen Q, Rhodes SS, Stowe DF. Anesthetic preconditioning attenuates mitochondrial Ca2+ overload during ischemia in guinea pig intact hearts: reversal by 5-hydroxydecanoic acid. Anesth Analg. 2002;95:1540–6.

    PubMed  CAS  Google Scholar 

  28. Kersten JR, Schmeling TJ, Pagel PS, Gross GJ, Warltier DC. Isoflurane mimics ischemic preconditioning via activation of K-ATP channel: reduction of myocardial infarct size with an acute memory phase. Anesthesiology. 1998;87:361–70.

    Google Scholar 

  29. Kersten JR, Lowe D, Hettrick DA, Pagel PS, Gross GJ, Warltier DC. Glyburide, a KATP channel antagonist, attenuates the cardioprotective effects of isoflurane in stunned myocardium. Anesth Analg. 1996;83:27–33.

    PubMed  CAS  Google Scholar 

  30. Kohro S, Hogan QH, Nakae Y, Yamakage M, Bosnjak ZJ. Anesthetic effects on mitochondrial ATP-sensitive K channel. Anesthesiology 2001;95:1435–1440.

    Google Scholar 

  31. Li Q, Lian C, Zhou R, Li T, Xiang X, Liu B. Pretreatment with xenon protected immature rabbit heart from ischaemia/reperfusion injury by opening of the mitoKATP channel. Heart Lung Circ. 2013;22:276–83.

    PubMed  Google Scholar 

  32. Piriou V, Chiari P, Knezynski S, Bastien O, Loufoua J, Lehot JJ, Foëx P, Annat G, Ovize M. Prevention of isoflurane-induced preconditioning by 5-hydroxydecanoate and gadolinium: possible involvement of mitochondrial adenosine triphosphate-sensitive potassium and stretch-activated channels. Anesthesiology. 2000;93:756–64.

    PubMed  CAS  Google Scholar 

  33. Shimizu J, Sakamoto A, Ogawa R. Activation of the adenosine triphosphate sensitive mitochondrial potassium channel is involved in the cardioprotective effect of isoflurane. J Nippon Med School. 2001;68:238–45.

    CAS  Google Scholar 

  34. Tanaka K, Weihrauch D, Ludwig LM, Kersten JR, Pagel PS, Warltier DC. Mitochondrial adenosine triphosphate-regulated potassium channel opening acts as a trigger for isoflurane-induced preconditioning by generating reactive oxygen species. Anesthesiology. 2003;98:935–43.

    PubMed  CAS  Google Scholar 

  35. Yvon A, Hanouz J-L, Haelewyn B, Terrien X, Massetti M, Babatasi G, Khayat A, Ducouret P, Bricard H, Gérard JL. Mechanisms of sevoflurane-induced myocardial preconditioning in isolated human right atria in vitro. Anesthesiology. 2003;99:27–33.

    PubMed  CAS  Google Scholar 

  36. Toller WG, Gross ER, Kersten JR, Pagel PS, Gross GJ, Warltier DC. Sarcolemmal and mitochondrial adenosine triphosphate-dependent potassium channels: mechanism of desflurane-induced cardioprotection. Anesthesiology. 2000;92:1731–9.

    PubMed  CAS  Google Scholar 

  37. Ohnuma Y, Miura T, Miki T, Tanno M, Kuno A, Tsuchida A, Shimamoto K. Opening of mitochondrial K(ATP) channel occurs downstream of PKC-epsilon activation in the mechanism of preconditioning. Am J Physiol Heart Circ Physiol. 2003;283:H440–7.

    Google Scholar 

  38. Sato T, O’Rourke B, Marbán E. Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. Circ Res. 1998;83:110–4.

    PubMed  CAS  Google Scholar 

  39. Wang Y, Hirai K, Ashraf M. Activation of mitochondrial ATP-sensitive K(+) channel for cardiac protection against ischemic injury is dependent on protein kinase C activity. Circ Res. 1999;85:731–41.

    PubMed  CAS  Google Scholar 

  40. Novalija E, Kevin LG, Camara AKS, Bosnjak ZJ, Kampine JP, Stowe DF. Reactive oxygen species precede the epsilon isoform of protein kinase C in the anesthetic preconditioning signaling cascade. Anesthesiology. 2003;99:421–8.

    PubMed  CAS  Google Scholar 

  41. Pravdic D, Sedlic F, Mio Y, Vladic N, Bienengraeber M, Bosnjak ZJ. Anesthetic-induced preconditioning delays opening of mitochondrial permeability transition pore via protein kinase C-epsilon-mediated pathway. Anesthesiology. 2009;111:267–74.

    PubMed  CAS  PubMed Central  Google Scholar 

  42. Piriou V, Chiari P, Gateau-Roesch O, Argaud L, Muntean D, Salles D, Loufouat J, Gueugniaud PY, Lehot JJ, Ovize M. Desflurane-induced preconditioning alters calcium-induced mitochondrial permeability transition. Anesthesiology. 2004;100:581–8.

    PubMed  CAS  Google Scholar 

  43. Mio Y, Shim YH, Richards E, Bosnjak ZJ, Pagel PS, Bienengraeber M. Xenon preconditioning: the role of prosurvival signaling, mitochondrial permeability transition and bioenergetics in rats. Anesth Analg. 2009;108:858–66.

    PubMed  CAS  PubMed Central  Google Scholar 

  44. Hanouz J-L, Zhu L, Lemoine S, Durand C, Lepage O, Massetti M, Khayat A, Plaud B, Gérard JL. Reactive oxygen species mediate sevoflurane- and desflurane-induced preconditioning in isolated human right atria in vitro. Anesth Analg. 2007;105:1534–9.

    PubMed  CAS  Google Scholar 

  45. Müllenheim J, Ebel D, Frässdorf J, Preckel B, Thämer V, Schlack W. Isoflurane preconditions myocardium against infarction via release of free radicals. Anesthesiology. 2002;96:934–40.

    PubMed  Google Scholar 

  46. Tanaka K, Weihrauch D, Kehl F, Ludwig LM, LaDisa JF, Kersten JR, Pagel PS, Warltier DC. Mechanism of preconditioning by isoflurane in rabbits: a direct role for reactive oxygen species. Anesthesiology. 2002;97:1485–90.

    PubMed  CAS  Google Scholar 

  47. Kevin LG, Novalija E, Riess ML, Camara AKS, Rhodes SS, Stowe DF. Sevoflurane exposure generates superoxide but leads to decreased superoxide during ischemia and reperfusion in isolated hearts. Anesth Analg. 2003;96:949–55.

    PubMed  CAS  Google Scholar 

  48. Novalija E, Kevin LG, Eells JT, Henry MM, Stowe DF. Anesthetic preconditioning improves adenosine triphosphate synthesis and reduces reactive oxygen species formation in mitochondria after ischemia by a redox dependent mechanism. Anesthesiology. 2003;98:1155–63.

    PubMed  CAS  Google Scholar 

  49. Ludwig LM, Tanaka K, Eells JT, Weihrauch D, Pagel PS, Kersten JR, Warltier DC. Preconditioning by isoflurane is mediated by reactive oxygen species generated from mitochondrial electron transport chain complex III. Anesth Analg. 2004;99:1308–15.

    PubMed  CAS  Google Scholar 

  50. Riess ML, Kevin LG, McCormick J, Jiang MT, Rhodes SS, Stowe DF. Anesthetic preconditioning: the role of free radicals in sevoflurane-induced attenuation of mitochondrial electron transport in guinea pig isolated hearts. Anesth Analg. 2005;100:46–53.

    PubMed  CAS  Google Scholar 

  51. Tsai S-K, Lin S-M, Huang C-H, Hung W-C, Chih C-L, Huang S-S. Effect of desflurane-induced preconditioning following ischemia-reperfusion on nitric oxide release in rabbits. Life Sci. 2004;76:651–60.

    PubMed  CAS  Google Scholar 

  52. Novalija E, Varadarajan SG, Camara AKS, An J, Chen Q, Riess ML, Hogg N, Stowe DF. Anesthetic preconditioning: triggering role of reactive oxygen and nitrogen species in isolated hearts. Am J Physiol Heart Circ Physiol. 2002;283:H44–52.

    PubMed  CAS  Google Scholar 

  53. Smul TM, Lange M, Redel A, Burkhard N, Roewer N, Kehl F. Desflurane-induced preconditioning against myocardial infarction is mediated by nitric oxide. Anesthesiology. 2006;105:719–25.

    PubMed  CAS  Google Scholar 

  54. Amour J. Role of heat shock protein 90 and endothelial nitric oxide synthase during early anesthetic and ischemic preconditioning. Anesthesiology. 2009;110:317–25.

    PubMed  CAS  PubMed Central  Google Scholar 

  55. Raphael J, Abedat S, Rivo J, Meir K, Beeri R, Pugatsch T, Zuo Z, Gozal Y. Volatile anesthetic preconditioning attenuates myocardial apoptosis in rabbits after regional ischemia and reperfusion via Akt signaling and modulation of Bcl-2 family proteins. J Pharmacol Exp Ther. 2006;318:186–94.

    PubMed  CAS  Google Scholar 

  56. Lu XY, Liu H, Wang LG, Schaefer S. Activation of NF-kappa B is a critical element in the antiapoptotic effect of anesthetic preconditioning. Am J Physiol Heart Circ Physiol. 2009;296:H1296–304.

    PubMed  CAS  Google Scholar 

  57. Zhong CY, Zhou YM, Liu H. Nuclear factor kappa B and anesthetic preconditioning during myocardial ischemia-reperfusion. Anesthesiology. 2004;100:540–6.

    PubMed  CAS  Google Scholar 

  58. Wang C, Xie H, Liu X, Qin Q, Wu X, Liu H, Liu C. Role of nuclear factor-kB in volatile anaesthetic preconditioning with sevoflurane during myocardial ischaemia/reperfusion. Eur J Anaesthesiol. 2010;27:747–56.

    PubMed  CAS  Google Scholar 

  59. Chiari PC, Bienengraeber MW, Weihrauch D, Krolikowski JG, Kersten JR, Warltier DC, Pagel PS. Role of endothelial nitric oxide synthase as a trigger and mediator of isoflurane-induced delayed preconditioning in rabbit myocardium. Anesthesiology. 2005;103:74–83.

    PubMed  CAS  Google Scholar 

  60. Shi Y, Hutchins WC, Su J, Siker D, Hogg N, Pritchard KA, Keszler A, Tweddell JS, Baker JE. Delayed cardioprotection with isoflurane: role of reactive oxygen and nitrogen. Am J Physiol Heart Circ Physiol. 2005;288:H175–84.

    PubMed  CAS  Google Scholar 

  61. Chen CH, Chuang JH, Liu K, Chan JYH. Nitric oxide triggers delayed anesthetic preconditioning-induced cardiac protection via activation of nuclear factor-kappaB and upregulation of inducible nitric oxide synthase. Shock. 2008;30:241–9.

    PubMed  CAS  Google Scholar 

  62. Feng J, Lucchinetti E, Fischer G, Zhu M, Zaugg K, Schaub MC, Zaugg M. Cardiac remodelling hinders activation of cyclooxygenase-2, diminishing protection by delayed pharmacological preconditioning: role of HIF-1 alpha and CREB. Cardiovasc Res. 2008;78:98–107.

    PubMed  CAS  Google Scholar 

  63. Wakeno-Takahashi M, Otani H, Nakao S, Imamura H, Shingu K. Isoflurane induces second window of preconditioning through upregulation of inducible nitric oxide synthase in rat heart. Am J Physiol Heart Circ Physiol. 2005;289:H2585–91.

    PubMed  CAS  Google Scholar 

  64. Tanaka K, Ludwig LM, Krolikowski JG, Alcindor D, Pratt PF, Kersten JR, Pagel PS, Warltier DC. Isoflurane produces delayed preconditioning against myocardial ischemia and reperfusion injury: role of cyclooxygenase-2. Anesthesiology. 2004;100:525–31.

    PubMed  CAS  Google Scholar 

  65. Tsutsumi YM, Patel HH, Huang D, Roth DM. Role of 12-lipoxygenase in volatile anesthetic-induced delayed preconditioning in mice. Am J Physiol Heart Circ Physiol. 2006;291:H979–93.

    PubMed  CAS  Google Scholar 

  66. Tsutsumi YM, Kawaraguchi Y, Horikawa YT, Niesman IR, Kidd MW, Chin-Lee B, Head BP, Patel PM, Roth DM, Patel HH. Role of caveolin-3 and glucose transporter-4 in isoflurane-induced delayed cardiac protection. Anesthesiology. 2010;112:1136–45.

    PubMed  CAS  PubMed Central  Google Scholar 

  67. Pagel PS. Postconditioning by volatile anesthetics: salvaging ischemic myocardium at reperfusion by activation of prosurvival signaling. J Cardiothorac Vasc Anesth. 2008;22:753–65.

    PubMed  CAS  Google Scholar 

  68. Krolikowski JG, Bienengraeber M, Weihrauch D, Warltier DC, Kersten JR, Pagel PS. Inhibition of mitochondrial permeability transition enhances isoflurane-induced cardioprotection during early reperfusion: the role of mitochondrial KATP channels. Anesth Analg. 2005;101:1590–6.

    PubMed  CAS  Google Scholar 

  69. Obal D, Dettwiler S, Favoccia C, Scharbatke H, Preckel B, Schlack W. The influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesth Analg. 2005;101:1252–60.

    PubMed  CAS  Google Scholar 

  70. Stumpner J, Lange M, Beck A, Smul TM, Lotz CA, Kehl F, Roewer N, Redel A. Desflurane-induced post-conditioning against myocardial infarction is mediated by calcium-activated potassium channels: role of the mitochondrial permeability transition pore. Br J Anaesth. 2012;108:594–601.

    PubMed  CAS  Google Scholar 

  71. Chiari PC, Bienengraeber MW, Pagel PS, Krolikowski JG, Kersten JR, Warltier DC. Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits. Anesthesiology. 2005;102:102–9.

    PubMed  CAS  Google Scholar 

  72. Feng J, Fischer G, Lucchinetti E, Zhu M, Bestmann L, Jegger D, Arras M, Pasch T, Perriard JC, Schaub MC, Zaugg M. Infarct-remodeled myocardium is receptive to protection by isoflurane postconditioning: role of protein kinase B/Akt signaling. Anesthesiology. 2006;104:1004–14.

    PubMed  CAS  Google Scholar 

  73. Weihrauch D, Krolikowski JG, Bienengraeber M, Kersten JR, Warltier DC, Pagel PS. Morphine enhances isoflurane-induced postconditioning against myocardial infarction: the role of phosphatidylinositol-3-kinase and opioid receptors in rabbits. Anesth Analg. 2005;101:942–9.

    PubMed  CAS  Google Scholar 

  74. Ge Z-D, Pravdic D, Bienengraeber M, Pratt PF, Auchampach JA, Gross GJ, Kersten JR, Warltier DC. Isoflurane postconditioning protects against reperfusion injury by preventing mitochondrial permeability transition by an endothelial nitric oxide synthase-dependent mechanism. Anesthesiology. 2010;112:73–85.

    PubMed  CAS  Google Scholar 

  75. Krolikowski JG, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC, Pagel PS. Role of Erk1/2, p70s6K, and eNOS in isoflurane-induced cardioprotection during early reperfusion in vivo. Can J Anaesth. 2006;53:174–82.

    PubMed  Google Scholar 

  76. Chen HT, Yang CX, Li H, Zhang CJ, Wen XJ, Zhou J, Fan YL, Huang T, Zeng YM. Cardioprotection of sevoflurane postconditioning by activating extracellular signal‐regulated kinase 1/2 in isolated rat hearts 1. Acta Pharmacol Sin. 2008;29:931–41.

    PubMed  CAS  Google Scholar 

  77. Feng J, Lucchinetti E, Ahuja P, Pasch T, Perriard J-C, Zaugg M. Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta. Anesthesiology. 2005;103:987–95.

    PubMed  CAS  Google Scholar 

  78. Pagel PS, Krolikowski JG, Neff DA, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC. Inhibition of glycogen synthase kinase enhances isofluorane-induced protection against myocardial infarction during early reperfusion in vivo. Anesth Analg. 2006;102:1348–54.

    Google Scholar 

  79. Wang C, Neff DA, Krolikowski JG, Weihrauch D, Bienengraeber M, Warltier DC, Kersten JR, Pagel PS. The influence of B-cell lymphoma 2 protein, an antiapoptotic regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic postconditioning in rabbits. Anesth Analg. 2006;102:1355–60.

    PubMed  CAS  Google Scholar 

  80. Inamura Y, Miyamae M, Sugioka S, Domae N, Kotani J. Sevoflurane postconditioning prevents activation of caspase 3 and 9 through antiapoptotic signaling after myocardial ischemia–reperfusion. J Anesth. 2010;24:215–24.

    PubMed  Google Scholar 

  81. Kitano H, Jeffrey RK, Patricia DH, Stephanie JM. Inhalational anesthetics as neuroprotectants or chemical preconditioning agents in ischemic brain. J Cereb Blood Flow Metab. 2007;27:1108–28.

    PubMed  CAS  PubMed Central  Google Scholar 

  82. Sanders RD, Ma D, Maze M. Anaesthesia induced neuroprotections. Best Pract Res Clin Anesthesiol. 2005;19:461–74.

    CAS  Google Scholar 

  83. Wang L, Traystman RJ, Murphy SJ. Inhalational anesthetics as preconditioning agents in ischemic brain. Curr Opin Pharmacol. 2008;8:104–10.

    PubMed  CAS  PubMed Central  Google Scholar 

  84. Clarkson AN. Anesthetic-mediated protection/preconditioning during cerebral ischemia. Life Sci. 2007;80:1157–75.

    PubMed  CAS  Google Scholar 

  85. Popovic R, Liniger R, Bickler PE. Anesthetics and mild hypothermia similarly prevent hippocampal neuron death in an in vitro model of cerebral ischemia. Anesthesiology. 2000;92:1343–9.

    PubMed  CAS  Google Scholar 

  86. Harada H, Kelly PJ, Cole DJ, Drummond JC, Patel PM. Isoflurane reduces N-methyl-d-aspartate toxicity in vivo in the rat cerebral cortex. Anesth Analg. 1999;89:1442–7.

    PubMed  CAS  Google Scholar 

  87. Kelly P, Patel PM, Drummond JC, Cole DJ, Kimbro JR. Isoflurane and pentobarbital reduce AMPA toxicity in vivo in the rat cerebral cortex. Anesthesiology. 2000;92:1485–91.

    Google Scholar 

  88. Wilhelm S, Ma D, Maze M, Franks NP. Effects of xenon on in vitro and in vivo models of neuronal injury. Anesthesiology. 2002;96:1485–91.

    PubMed  CAS  Google Scholar 

  89. Kaneko T, Yokoyama K, Makita K. Late preconditioning with isoflurane in cultured rat cortical neurones. Br J Anaesth. 2005;95:662–8.

    PubMed  CAS  Google Scholar 

  90. Zheng S, Zuo Z. Isoflurane preconditioning reduces Purkinje cell death in an in vitro model of rat cerebellar ischemia. Neuroscience. 2003;118:99–106.

    PubMed  CAS  Google Scholar 

  91. Bickler PE, Warner DS, Stratmann G, Schuyler JA. γ-Aminobutyric acid-A receptors contribute to isoflurane neuroprotection in organotypic hippocampal cultures. Anesth Analg. 2003;97:564–71.

    PubMed  CAS  Google Scholar 

  92. Ma D, Hossain M, Rajakumaraswamy N, Franks NP, Maze M. Combination of xenon and isoflurane produces a synergistic protective effect against oxygen-glucose deprivation injury in a neuronal-glial co-culture model. Anesthesiology. 2003;99:748–51.

    PubMed  Google Scholar 

  93. Bickler PE, Buck LT, Hansen BM. Effects of isoflurane and hypothermia on glutamate receptor-mediated calcium influx in brain slices. Anesthesiology. 1994;81:1461–9.

    PubMed  CAS  Google Scholar 

  94. Gray JJ, Bickler PE, Fahlman CS, Zhan X, Schuyler JA. Isoflurane neuroprotection in hypoxic hippocampal slice cultures involves increases in intracellular Ca2+ and mitogen-activated protein kinases. Anesthesiology. 2005;102:606–15.

    PubMed  CAS  Google Scholar 

  95. Bickler PE, Zhan X, Fahlman CS. Isoflurane preconditions hippocampal neurons against oxygen-glucose deprivation: role of intracellular Ca2+ and mitogen-activated protein kinase signaling. Anesthesiology. 2005;103:532–9.

    PubMed  CAS  Google Scholar 

  96. Blanck TJJ, Haile M, Xu F, Zhang J, Heerdt P, Veselis RA, Beckman J, Kang R, Adamo A, Hemmings H. Isoflurane pretreatment ameliorates postischemic neurologic dysfunction and preserves hippocampal Ca2+/calmodulin-dependent protein kinase in a canine cardiac arrest model. Anesthesiology. 2000;93:1285–93.

    PubMed  CAS  Google Scholar 

  97. Zheng SQ, Zuo ZY. Isoflurane preconditioning induces neuroprotection against ischemia via activation of P38 mitogen-activated protein kinases. Mol Pharmacol. 2004;65:1172–80.

    PubMed  CAS  Google Scholar 

  98. Ye Z, Guo Q, Wang N, Xia P, Yuan Y, Wang E. Delayed neuroprotection induced by sevoflurane via opening mitochondrial ATP-sensitive potassium channels and p38 MAPK phosphorylation. Neurol Sci. 2012;33:239–49.

    PubMed  Google Scholar 

  99. Ye Z, Huang Y-M, Wang E, Zuo Z-Y, Guo Q-L. Sevoflurane-induced delayed neuroprotection involves mitoK ATP channel opening and PKC-ε activation. Mol Biol Rep. 2012;39:5049–57.

    PubMed  CAS  Google Scholar 

  100. Xiong L, Zheng Y, Wu M, Hou L, Zhu Z, Zhang X, Lu Z. Preconditioning with isoflurane produces dose-dependent neuroprotection via activation of adenosine triphosphate-regulated potassium channels after focal cerebral ischemia in rats. Anesth Analg. 2003;96:233–7.

    PubMed  CAS  Google Scholar 

  101. Adamczyk S, Robin E, Simerabet M, Kipnis E, Tavernier B, Vallet B, Bordet R, Lebuffe G. Sevoflurane pre- and post-conditioning protect the brain via the mitochondrial KATP channel. Br J Anaesth. 2010;104:191–200.

    PubMed  CAS  Google Scholar 

  102. Kehl F, Payne RS, Roewer N, Schurr A. Sevoflurane-induced preconditioning of rat brain in vitro and the role of KATP channels. Brain Res. 2004;1021:76–81.

    PubMed  CAS  Google Scholar 

  103. Lee JJ, Li L, Jung HH, Zuo Z. Postconditioning with isoflurane reduced ischemia-induced brain injury in rats. Anesthesiology. 2008;108:1055–62.

    PubMed  CAS  PubMed Central  Google Scholar 

  104. Kapinya KJ, Löwl D, Fütterer C, Maurer M, Waschke KF, Isaev NK, Dirnagl U. Tolerance against ischemic neuronal injury can be induced by volatile anesthetics and is inducible NO synthase dependent. Stroke. 2002;33:1889–98.

    PubMed  CAS  Google Scholar 

  105. Zhao P, Zuo Z. Isoflurane preconditioning induces neuroprotection that is inducible nitric oxide synthase-dependent in neonatal rats. Anesthesiology. 2004;101:695–703.

    PubMed  CAS  Google Scholar 

  106. Kitano H, Jennifer MY, Cheng J, Wang L, Patricia DH, Stephanie JM. Gender-specific response to isoflurane preconditioning in focal cerebral ischemia. J Cereb Blood Flow Metab. 2007;27:1377–86.

    PubMed  CAS  PubMed Central  Google Scholar 

  107. Limatola V, Ward P, Cattano D, Gu J, Giunta F, Maze M, Ma D. Xenon preconditioning confers neuroprotection regardless of gender in a mouse model of transient middle cerebral artery occlusion. Neuroscience. 2010;165:874–81.

    PubMed  CAS  Google Scholar 

  108. Wang J-K, Yu L-N, Zhang F-J, Yang M-J, Yu J, Yan M, Chen G. Postconditioning with sevoflurane protects against focal cerebral ischemia and reperfusion injury via PI3K/Akt pathway. Brain Res. 2010;1357:142–51.

    PubMed  CAS  Google Scholar 

  109. Li L, Peng L, Zuo Z. Isoflurane preconditioning increases B-cell lymphoma-2 expression and reduces cytochrome c release from the mitochondria in the ischemic penumbra of rat brain. Eur J Pharmacol. 2008;586:106–13.

    PubMed  CAS  PubMed Central  Google Scholar 

  110. Li L, Zuo Z. Isoflurane postconditioning induces neuroprotection via Akt activation and attenuation of increased mitochondrial membrane permeability. Neuroscience. 2011;199:44–50.

    PubMed  CAS  PubMed Central  Google Scholar 

  111. Ma DQ, Hossain M, Pettet GKJ, Luo Y, Lim T, Akimov S, Sanders RD, Franks NP, Maze M. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. J Cereb Blood Flow Metab. 2006;26:199–208.

    PubMed  CAS  Google Scholar 

  112. Luo Y, Ma D, Leong E, Sanders RD, Yu B, Hossain M, Maze M. Xenon and sevoflurane protect against brain injury in a neonatal asphyxia model. Anesthesiology. 2008;109:782–9.

    PubMed  CAS  Google Scholar 

  113. Ma D, Lim T, Xu J, Tang H, Wan Y, Zhao H, Hossain M, Maxwell PH, Maze M. Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation. J Am Soc Nephrol. 2009;20:713–20.

    PubMed  CAS  PubMed Central  Google Scholar 

  114. Zhang L, Huang H, Cheng J, Liu J, Zhao H, Vizcaychipi MP, Ma D. Pre-treatment with isoflurane ameliorates renal ischemic–reperfusion injury in mice. Life Sci. 2011;88:1102–7.

    PubMed  CAS  Google Scholar 

  115. Rizvi M, Jawad N, Li Y, Vizcaychipi MP, Maze M, Ma D. Effect of noble gases on oxygen and glucose deprived injury in human tubular kidney cells. Exp Biol Med. 2010;235:886–91.

    CAS  Google Scholar 

  116. Lee HT, Kim M, Jan M, Emala CW. Anti-inflammatory and antinecrotic effects of the volatile anesthetic sevoflurane in kidney proximal tubule cells. Am J Physiol Ren Physiol. 2006;291:F67–78.

    CAS  Google Scholar 

  117. Lee HT, Chen SW, Doetschman TC, Deng C, D’Agati VD, Kim M. Sevoflurane protects against renal ischemia and reperfusion injury in mice via the transforming growth factor-beta 1 pathway. Am J Physiol Ren Physiol. 2008;295:F128–36.

    CAS  Google Scholar 

  118. Zhao H, Watts HR, Chong M, Huang H, Tralau-Steward C, Maxwell PH, Maze M, George AJ, Ma D. Xenon treatment protects against cold ischemia associated delayed graft function and prolongs graft survival in rats. Am J Transplant. 2013;13:2006–18.

    PubMed  CAS  PubMed Central  Google Scholar 

  119. Zhao H, Luo X, Zhou Z, Liu J, Tralau-Stewart C, George JTA, Ma D. Early treatment with xenon protects against the cold ischemia associated with chronic allograft nephropathy in rats. Kidney Int. 2014;85:112–23.

    PubMed  CAS  Google Scholar 

  120. Zhao H, Ning J, Savage S, Kang H, Lu K, Zheng X, George AJ, Ma D. A novel strategy for preserving renal grafts in an ex vivo setting: potential for enhancing the marginal donor pool. J Fed Am Soc Exp Biol. 2013;27:4822–33.

    CAS  Google Scholar 

  121. Zhao H, Yoshida A, Xiao W, Ologunde R, O’Dea KP, Takata M, Tralau-Stewart C, George AJ, Ma D. Xenon treatment attenuates early renal allograft injury associated with prolonged hypothermic storage in rats. J Fed Am Soc Exp Biol. 2013;27:4076–88.

    CAS  Google Scholar 

  122. Lin E, Symons JA. Volatile anaesthetic myocardial protection: a review of the current literature. HSR Proc Intensive Care Cardiovasc Anesth. 2010;2:105–9.

    PubMed  CAS  PubMed Central  Google Scholar 

  123. Landoni G, Biondi-Zoccai G, Zangrillo A, Bignami E, D’Avolio S, Marchetti C, Calabrò MG, Fochi O, Guarracino F, Tritapepe L, De Hert S, Torri G. Desflurane and sevoflurane in cardiac surgery: a meta-analysis of randomized clinical trials. J Cardiothorac Vasc Anesth. 2007;21:502–11.

    PubMed  CAS  Google Scholar 

  124. Kadoi Y, Goto F. Sevoflurane anesthesia did not affect postoperative cognitive dysfunction in patients undergoing coronary artery bypass graft surgery. J Anesth. 2007;21(3):330–5.

    PubMed  Google Scholar 

  125. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876–82.

    PubMed  CAS  Google Scholar 

  126. Shu Y, Zhou Z, Wan Y, Sanders RD, Li M, Pac-Soo CK, Maze M, Ma D. Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain. Neurobiol Disc. 2012;45:743–50.

    CAS  Google Scholar 

  127. Sanders RD, Hassell J, Davidson AJ, Robertson NJ, Ma D. Impact of anaesthetics and surgery on neurodevelopment: an update. Br J Anaesth. 2013;110(suppl 1):i53–72.

    PubMed  CAS  PubMed Central  Google Scholar 

  128. Sindhvananda W, Phisaiphun K, Prapongsena P. No renal protection from volatile-anesthetic preconditioning in open heart surgery. J Anesth. 2005;27:48–55.

    Google Scholar 

  129. Sanders RD, Ma D, Maze M. Xenon: elemental anaesthesia in clinical practice. Br Med Bull. 2005;71:115.

    PubMed  Google Scholar 

  130. Pagel PS. Cardioprotection by noble gases. J Cardiothorac Vasc Anesth. 2010;24:143–63.

    PubMed  CAS  Google Scholar 

  131. Ma D, Hossain M, Chow A, Arshad M, Battson RM, Sanders RD, Mehmet H, Edwards AD, Franks NP, Maze M. Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol. 2005;58:182–93.

    PubMed  CAS  Google Scholar 

  132. Ma D, Yang H, Lynch J, Franks NP, Maze M, Grocott HP. Xenon attenuates cardiopulmonary bypass-induced neurologic and neurocognitive dysfunction in the rat. Anesthesiology. 2005;98:690–8.

    Google Scholar 

  133. Ma D, Wilhelm S, Maze M, Franks NP. Neuroprotective and neurotoxic properties of the inert gas, xenon. Br J Anaesth. 2002;89:739–46.

    PubMed  CAS  Google Scholar 

  134. Ma D, Williamson P, Januszewski A, Nogaro MC, Hossain M, Ong LP, Shu Y, Franks NP, Maze M. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology. 2007;106:746–53.

    PubMed  CAS  Google Scholar 

  135. McMurtrey RJ, Zuo Z. Isoflurane preconditioning and postconditioning in rat hippocampal neurons. Brain Res. 2010;1358:184–90.

    PubMed  CAS  PubMed Central  Google Scholar 

  136. Venkatapuram S, Wang C, Krolikowski JG, Weihrauch D, Kersten JR, Warltier DC, Pratt PF Jr, Pagel PS. Inhibition of apoptotic protein p53 lowers the threshold of isoflurane-induced cardioprotection during early reperfusion in rabbits. Anesth Analg. 2006;103:1400–5.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work was supported by the grants from Medical Research Council (MRC), Alzheimer’s Society, BJA/RCoA, SPARKS, London, UK, Action Medical Research, West Sussex, UK and European Society of Anaesthesiology, Brussels, Belgium.

Conflict of interest

Authors claim no conflict of interest.

Author information

Authors and Affiliations

  1. Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK

    Lingzhi Wu, Hailin Zhao, Chen Pac-Soo & Daqing Ma

  2. Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, China

    Tianlong Wang

  3. Department of Anaesthetics, Wycombe Hospital, Buckinghamshire Hospitals NHS Trust, High Wycombe, Buckinghamshire, UK

    Chen Pac-Soo

Authors
  1. Lingzhi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hailin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tianlong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chen Pac-Soo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daqing Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daqing Ma.

Appendix

Appendix

Appendix-Abbreviations used in the tables

2-MPG:

N-(2-Mercapto propionyl)glycine, free radical ROS scavenger

5-HD:

5-Hydroxydecanoate, selective mitochondrial KATP channel antagonist

7-NI:

7-Nitroindazole, selective neuronal NOS inhibitor

AG:

Aminoguanidine, selective iNOS inhibitor

AIP:

Autocamtide-2-related inhibitory peptide, specific peptide inhibitor of calmodulin kinase II

APV:

(2R)-Amino-5-phosphonovaleric acid, specific NMDA receptor antagonist

ATR:

Atractyloside, mitochondrial permeability transition pore opener

BAL:

Balcalein, selective 12-lipoxygenase inhibitor

CDC:

Cinnamyl-3,4-dihydroxy cyanocinnamate, selective 12-lipoxygenase inhibitor

CEL:

Celecoxib, selective COX-2 inhibitor

CGS-21680:

Selective agonist of adenosine A2A receptor

CHE:

Chelerythrine, PKC inhibitor that affects cellular PKC translocation

CsA:

Cyclosporine A, specific mitochondrial permeability transition pore inhibitor

DDTC:

Diethyldithiocarbamate, NFκB inhibitor

DIAZO:

Diazoxide, specific mitoKATP channel opener

GELD:

Geldanamycin, specific HSP90 inhibitor

GLB:

Glyburide, nonselective KATP channel inhibitor

IbTX:

Iberiotoxin, selective BKCa inhibitor

KN93:

Specific inhibitor of calmodulin kinase II

L-NAME:

N G-nitro-l-arginine methyl ester (L-NAME), nonselective nitric oxide synthase inhibitor

L-NMMA:

N-G-mono-methyl-l-arginine monoacetate, methyl-derivative of arginine and a NOS inhibitor

LY294002:

Specific PI3K inhibitor

M[beta]CD:

Methyl-[beta]-cyclodextrin, depletes membrane cholesterol and disrupts caveolae

MOR:

Morphine

NAC:

N-Acetyl-l-cysteine, antioxidant and free radical scavenger

NAL:

Naloxone, nonselective opioid receptor antagonist

NS-398:

N-2-Cyclohexyloxy-4-nitrophenyl-methanesulphonamide, selective COX-2 inhibitor

NS1619:

Selective BKCa activator

PD98059:

Specific inhibitor of MEK1 and ERK1/2

PFT-α, pifithrin-α:

Specific p53 inhibitor

PKC3V1-2:

PKC-ε-specific inhibitor

PTN:

Parthenolide, NFκB inhibitor

RAD:

Radicicol, specific HSP90 inhibitor

RAP:

Rapamycin, specific mTOR/p70s6K inhibitor

Rottlerin:

PKC-δ-specific inhibitor

SC-514:

Selective IKK-2/beta inhibitor to activate NFκB

SMT:

S-Methylisothiourea, selective iNOS inhibitor

Wort:

Wortmannin, specific PI3K inhibitor

About this article

Cite this article

Wu, L., Zhao, H., Wang, T. et al. Cellular signaling pathways and molecular mechanisms involving inhalational anesthetics-induced organoprotection. J Anesth 28, 740–758 (2014). https://doi.org/10.1007/s00540-014-1805-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00540-014-1805-y

Keywords

Search

Navigation