Abstract
Membranous lipid bilayers have been reconsidered as the site of action of local anesthetics (LAs). Recent understanding of biomembranes indicates the existence of lipid raft microdomains enriched in cholesterol and sphingolipids as potential platforms for channels and receptors. Based on the hypothesis that LAs may interact preferentially with lipid rafts over non-raft membranes, we compared their effects on raft model membranes and cardiolipin-containing biomimetic membranes. Liposomes were prepared with phospholipids, sphingomyelin, cerebroside, and cholesterol to have compositions corresponding to lipid rafts and cardiomyocyte mitochondrial membranes. After reacting LAs (50–200 μM) with the membrane preparations, their interactivities were determined by measuring fluorescence polarization with 1,6-diphenyl-1,3,5-hexatriene. Although bupivacaine and lidocaine acted on different raft-like liquid-ordered membranes to reduce polarization values, their effects on biomimetic less ordered membranes were much greater. LAs interacted with biomimetic membranes with the potency being R(+)-bupivacaine > racemic bupivacaine > S(−)-bupivacaine > ropivacaine > lidocaine > prilocaine, which is consistent with the rank order of pharmacotoxicological potency. However, raft model membranes showed neither structure-dependence nor stereoselectivity. The relevance of membrane lipid rafts to LAs is questionable at least in their effects on raft-like liquid-ordered membranes.
This is a preview of subscription content, log in via an institution to check access.
References
Lynch C III. Meyer and Overton revisited. Anesth Analg. 2008;107:864–7.
Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1:31–9.
Parat M-O. Could endothelial caveolae be the target of general anaesthetics? Br J Anaesth. 2006;96:547–50.
Morgan PG, Hubbard M, Eckenhoff RG, Sedensky MM. Halothane partitions to lipid rafts in C. elegans. Anesthesiology. 2004;101:A105.
O’Connell KM, Martens JR, Tamkun MM. Localization of ion channels to lipid raft domains within the cardiovascular system. Trends Cardiovasc Med. 2004;14:37–42.
Xiang Y, Rybin VO, Steinberg SF, Kobilka B. Caveolar localization dictates physiologic signaling of β2-adrenoceptors in neonatal cardiac myocytes. J Biol Chem. 2002;277:34280–6.
Kamata K, Manno S, Ozaki M, Takakuwa Y. Functional evidence for presence of lipid rafts in erythrocyte membranes: Gsα in rafts is essential for signal transduction. Am J Hematol. 2008;83:371–5.
Kamata K, Manno S, Takakuwa Y, Ozaki M. Reversible effect of lidocaine on raft formation. Int Congr Ser. 2005;1283:281–2.
Dietrich C, Bagatolli LA, Volovyk ZN, Thompson NL, Levi M, Jacobson K, Gratton E. Lipid rafts reconstituted in model membranes. Biophys J. 2001;80:1417–28.
Tsuchiya H, Ueno T, Mizogami M, Takakura K. Local anesthetics structure-dependently interact with anionic phospholipid membranes to modify the fluidity. Chem Biol Interact. 2010;183:19–24.
Schroeder R, London E, Brown D. Interactions between saturated acyl chains confer detergent resistance on lipids and glycosylphosphatidylinositol (GPI)-anchored proteins: GPI-anchored proteins in liposomes and cells show similar behavior. Proc Natl Acad Sci USA. 1994;91:12130–4.
Gandhavadi M, Allende D, Vidal A, Simon SA, McIntosh TJ. Structure, composition, and peptide binding properties of detergent soluble bilayers and detergent resistant rafts. Biophys J. 2002;82:1469–82.
Koumanov KS, Tessier C, Momchilova AB, Rainteau D, Wolf C, Quinn PJ. Comparative lipid analysis and structure of detergent-resistant membrane raft fractions isolated from human and ruminant erythrocytes. Arch Biochem Biophys. 2005;434:150–8.
Tsuchiya H, Mizogami M. Membrane interactivity of charged local anesthetic derivative and stereoselectivity in membrane interaction of local anesthetic enantiomers. Local Reg Anesth. 2008;1:1–9.
Shibata A, Ikawa K, Terada H. Site of action of the local anesthetic tetracaine in a phosphatidylcholine bilayer with incorporated cardiolipin. Biophys J. 1995;69:470–7.
Groban L, Deal DD, Vernon JC, James RL, Butterworth J. Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs. Anesth Analg. 2001;92:37–43.
Heavner JE. Cardiac toxicity of local anesthetics in the intact isolated heart model: a review. Reg Anesth Pain Med. 2002;27:545–55.
Önyüksel H, Sethi V, Weinberg GL, Dudeja PK, Rubinstein I. Bupivacaine, but not lidocaine, disrupts cardiolipin-containing small biomimetic unilamellar liposomes. Chem Biol Interact. 2007;169:154–9.
Grouselle M, Tueux O, Dabadie P, Georgescaud D, Mazat J-P. Effect of local anaesthetics on mitochondrial membrane potential in living cells. Biochem J. 1990;271:269–72.
Acknowledgments
The authors thank Maruishi Pharmaceutical Co. and AstraZeneca for the supply of LAs. This study was supported by a Grant-in-Aid for Scientific Research 20592381 (to H.T.) from the Japan Society for the Promotion of Science.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Tsuchiya, H., Ueno, T., Mizogami, M. et al. Do local anesthetics interact preferentially with membrane lipid rafts? Comparative interactivities with raft-like membranes. J Anesth 24, 639–642 (2010). https://doi.org/10.1007/s00540-010-0943-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00540-010-0943-0