Membrane Interactivity of Anesthetic Adjuvant Dexmedetomidine Discriminable from Clonidine and Enantiomeric Levomedetomidine

Main Article Content

Maki Mizogami
Hironori Tsuchiya


Aims: Dexmedetomidine, which has been increasingly used as an anesthetic adjuvant, is more lipophilic and more active than another α2-adrenergic agonist clonidine and enantiomeric levomedetomidine. Lipophilicity and stereostructure affect the clinical effects of α2-adrenergic agonists. We aimed to compare the membrane interactivity of dexmedetomidine with clonidine and levomedetomidine from a point of view different from the mode of action on α2-adrenergic receptors.

Methodology: Unilamellar vesicles were prepared with phospholipids and cholesterol to mimic the lipid compositions of peripheral nerve cell, central nerve cell and cardiomyocyte membranes, and lipid rafts. They were subjected to the reactions with dexmedetomidine, clonidine and levomedetomidine at 10-200 μM, followed by measuring fluorescence polarization to determine the membrane interactivity to change membrane fluidity and specify the membrane region for the stereostructure-specific interaction.

Results: Dexmedetomidine and clonidine acted on lipid bilayers to increase the membrane fluidity with potencies varying by a compositional difference of membrane lipids. Dexmedetomidine showed greater interactivity with neuro-mimetic and cardiomyocyte-mimetic membranes than clonidine, being consistent with their comparative lipophilicity and activity. The effects of α2-adrenergic agonists on lipid raft model membranes were much weaker than those on other membranes, indicating that lipid rafts are not mechanistically relevant to them. Higher interactive dexmedetomidine was discriminated from lower interactive levomedetomidine in the presence of chiral cholesterol in membranes. An interactivity difference between two enantiomers was largest in the superficial region of lipid bilayers and the rank order of their membrane-interacting potency was reversed by replacing cholesterol with epicholesterol, suggesting that cholesterol’s 3β-hydroxyl groups positioned close to the membrane surface are responsible for the enantioselective interaction.

Conclusion: Dexmedetomidine structure-specifically interacts with biomimetic membranes depending on their lipid compositions more potently than clonidine and levomedetomidine. Such membrane interactivity associated with higher lipophilicity and stereostructure characterizes dexmedetomidine in addition to higher affinity for α2-adrenergic receptors.

Dexmedetomidine, membrane interactivity, structure-specific, α2-adrenergic agonist, clonidine, enantiomeric levomedetomidine.

Article Details

How to Cite
Mizogami, M., & Tsuchiya, H. (2019). Membrane Interactivity of Anesthetic Adjuvant Dexmedetomidine Discriminable from Clonidine and Enantiomeric Levomedetomidine. Journal of Advances in Medicine and Medical Research, 29(11), 1-15.
Original Research Article


Kamibayashi T, Maze M. Clinical uses of α2-adrenergic agonists. Anesthesiology. 2000;93(5):1345-1349.
[PMID: 11046225]

Mantz J, Josserand J, Hamada S. Dexmedetomidine: New insights. Eur J Anaesthesiol. 2011;28(1):3-6
DOI: 10.1097/EJA.0b013e32833e266d
[PMID: 20881501]

Arcangeli A, D’Alò C, Gaspari R. Dexmedetomidine use in general anaesthesia. Curr Drug Targets. 2009;10(8):687-695.
DOI: 10.2174/138945009788982423
[PMID: 19702517]

El-Boghdadly K, Brull R, Sehmbi H, Abdallah FW. Perineural dexmedetomidine is more effective than clonidine when added to local anesthetic for supraclavicular brachial plexus block: A systematic review and meta-analysis. Anesth Analg. 2017;124(6):2008-2020. DOI: 10.1213/ANE.0000000000002014
[PMID: 28525514]

Bergese SD, Khabiri B, Roberts WD, Howie MB, McSweeney TD, Gerhardt MA. Dexmedetomidine for conscious sedation in difficult awake fiberoptic intubation cases. J Clin Anesth. 2007;19(2):141-144. DOI: 10.1016/j.jclinane.2006.07.005
[PMID: 17379129]

Keniya VM, Ladi S, Naphade R. Dexmedetomidine attenuates sympathoadrenal response to tracheal intubation and reduces perioperative anaesthetic requirement. Indian J Anaesth. 2011;55(4):352-357.
DOI: 10.4103/0019-5049.84846
[PMID: 22013250]

Naaz S, Ozair E. Dexmedetomidine in current anaesthesia practice – A review. J Clin Diagn Res. 2014;8(10):GE01-GE04. DOI: 10.7860/JCDR/2014/9624.4946
[PMID: 25478365]

Yoshikawa Y, Hirata N, Kawaguchi R, Tokinaga Y, Yamakage M. Dexmedetomidine maintains its direct cardioprotective effects against ischemia/reperfusion injury in hypertensive hypertrophied myocardium. Anesth Analg. 2018(2);126:443-452.
DOI: 10.1213/ANE.0000000000002452
[PMID: 28914648]

Cai Y, Xu H, Yan J, Zhang L, Lu Y. Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury. Mol Med Rep. 2014;9(5):1542-1550.
DOI: 10.3892/mmr.2014.2034
[PMID: 24627001]

Li B, Li Y, Tian S, Wang H, Wu H, Zhang A, et al. Anti-inflammatory effects of perioperative dexmedetomidine administered as an adjunct to general anesthesia: a meta-analysis. Sci Rep. 2015;5:12342.
DOI: 10.1038/srep12342
[PMID: 26196332]

Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia. 1999;54(2):146-165.
DOI: 10.1046/j.1365-2044.1999.00659.x
[PMID: 10215710]

Virtanen R, Savola JM, Saano V, Nyman L. Characterization of selectivity, specificity and potency of medetomidine as alpha 2-adrenoceptor agonist. Eur J Pharmacol. 1988;150(1-2):9-14.
DOI: 10.1016/0014-2999(88)90744-3
[PMID: 2900154]

Bajwa SJ, Bajwa SK, Kaur J, Singh G, Arora V, Gupta S, et al. Dexmedetomidine and clonidine in epidural anaesthesia: a comparative evaluation. Indian J Anaesth. 2011;55(2):116-121.
DOI: 10.4103/0019-5049.79883
[PMID: 21712865]

Swaml SS, Kenlya VM, Ladl SD, Rao R. Comparison of dexmedetomidine and clonidine (α2 agonist drugs) as an adjuvant to local anaesthesia in supraclavicular branchial plexus block: A randomised double-blind prospective study. Indian J Anaesth. 2012;56(3):243-249.
DOI: 10.4103/0019-5049.98767
[PMID: 22923822]

Eisenach JC, Shafer SL, Bucklin BA, Jackson C, Kallio A. Pharmacokinetics and intraspinal dexmedetomdine in sheep. Anesthesiology. 1994;80(6):1349-1359.
[PMID: 7912045]

Kaur M, Singh PM. Current role of dexmedetomidine in clinical anesthesia and intensive care. Anesth Essays Res. 2011;5(2):128-133.
DOI: 10.4103/0259-1162.94750
[PMID: 25885374]

Ishii H, Kohno T, Yamakura T, Ikoma M, Baba H. Action of dexmedetomidine on the substantia gelatinosa neuron of the rat spinal cord. Eur J Neurosci. 2008;27(12):3182-3190.
DOI: 10.1111/j.1460-9568.2008.06260.x
[PMID: 18554299]

Yagmurdur H, Ozcan N, Dokumaci F, Kilinc K, Yilmaz F, Basar H. Dexmedetomidine reduces the ischemia-reperfusion injury markers during extremity surgery with tourniquet. J Hand Surg Am. 2008;33(6):941-947.
DOI: 10.1016/j.jhsa.2008.01.014
[PMID: 18656769]

Karmen NB. Oxidative modification of erythrocyte membranes in the acute stage of severe craniocerebral trauma and its correction with clonidine. Bull Exp Biol Med. 2003;136(4):362-365.
[PMID: 14714083]

Aniya Y, Fong KF, Naito A, Sakanashi M. Antioxidative action of the beta-adrenoceptor antagonist bopindolol and its metabolite 18-502. Jpn J Pharmacol. 1995;68(3):323-329.
DOI: 10.1254/jjp.68.323
[PMID: 7474556]

Tsuchiya H, Mizogami M. Characteristic interactivity of landiolol, an ultra-short-acting highly selective β1-blocker, with biomimetic membranes: comparisons with β1-selective esmolol and non-selective propranolol and alprenolol. Front Pharmacol. 2013;4:150.
DOI: 10.3389/fphar.2013.00150
[PMID: 24339816]

Tsuchiya H, Mizogami M. Discrimination of stereoisomers by their enantioselective interactions with chiral cholesterol-containing membranes. Molecules. 2018;23(1):E49.
[PMID: 29295605]

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.
[PMID: 22915858]

Ueno T, Tsuchiya H, Mizogami M, Takakura K. Local anesthetic failure associated with inflammation: verification of the acidosis mechanism and the hypothetic participation of inflammatory peroxynitrite. J Inflamm Res. 2008;1:41-48.
[PMID: 22096346]

Butler S, Wang R, Wunder SL, Cheng HY, Randall CS. Perturbing effects of carvedilol on a model membrane system: Role of lipophilicity and chemical structure. Biophys Chem. 2006;119(3):307-315.
DOI: 10.1016/j.bpc.2005.09.004
[PMID: 16243429]

Svennerholm L, Boström K, Fredman P, Jungbjer B, Månsson JE, Rynmark BM. Membrane lipids of human peripheral nerve and spinal cord. Biochim Biophys Acta. 1992;1128 (1):1-7.
DOI: 10.1016/0005-2760(92)90250-Y
[PMID: 1390872]

Tsuchiya H, Mizogami M. Analgesic agents share the membrane interactivity possibly associated with the diversity of their pharmacological properties. Br J Pharm Res. 2015;7(2):110-121.
DOI: 10.9734/BJPR/2015/18269

Chi Y, Gupta RK. Alterations in heart and kidney membrane phospholipids in hypertension as observed by 31P nuclear magnetic resonance. Lipids. 1998;33(10):1023-1030.
DOI: 10.1007/s11745-998-0301-z
[PMID: 9832083]

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(25):12130-12134.
DOI: 10.1073/pnas.91.25.12130
[PMID: 7991596]

Ushijima H, Tanaka K, Takeda M, Katsu T, Mima S, Mizushima T. Geranylgeranylacetone protects membranes against nonsteroidal anti-inflammatory drugs. Mol Pharmacol. 2005;68(4):1156-1161.
DOI: 10.1124/mol.105.015784
[PMID: 16046660]

Tsuchiya H. Effects of red wine flavonoid components on biomembranes and cell proliferation. Int J Wine Res. 2011;3:9-17.
DOI: 10.2147/IJWR.S19033

Hjalmarson Å. Cardioprotection with beta-adrenoceptor blockers. Does lipophilicity matter? Basic Res Cardiol. 2000;95(Suppl. 1):I/41-I/45.
DOI: 10.1007/s003950070008
[PMID: 11192352]

Mizogami M, Takakura K, Tsuchiya H. The interactivities with lipid membranes differentially characterize selective and nonselective β1-blockers. Eur J Anaesthesiol. 2010;27(9):829-834.
DOI: 10.1097/EJA.0b013e32833bf5e4
[PMID: 20601889]

Lombardi D, Cuenoud B, Krämer SD. Lipid membrane interactions of indacaterol and salmeterol. Do they influence their pharmacological properties? Eur J Pharm Sci. 2009;38(5):533-547.
DOI: 10.1016/j.ejps.2009.10.001
[PMID: 19819331]

Mahendru V, Tewari A, Katyal S, Grewal A, Singh MR, Katyal R. A comparison of intrathecal dexmedetomidine, clonidine, and fentanyl as adjuvants to hyperbaric bupivacaine for lower limb surgery: A double blind controlled study. J Anaesthesiol Clin Pharmacol. 2013;29(4):496-502.
DOI: 10.4103/0970-9185.119151
[PMID: 24249987]

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(1):19-24.
DOI: 10.1016/j.cbi.2009.10.006
[PMID: 19853592]

Abdallah FW, Brull R. Facilitatory effects of perineural dexmedetomidine on neuraxial and peripheral nerve block: a systematic review and meta-analysis. Br J Anaesth. 2013;110(6):915-925.
DOI: 10.1093/bja/aet066
[PMID: 23587874]

Ingólfsson HI, Carpenter TS, Bhatia H, Bremer PT, Marrink SJ, Lightstone FC. Computational lipidomics of the neuronal plasma membrane. Biophys J. 2017;113(10):2271-2280.
DOI: 10.1016/j.bpj.2017.10.017
[PMID: 29113676]

Parat MO. Could endothelial caveolae be the target of general anaesthetics? Br J Anaesth. 2006;96(5):547-550.
DOI: 10.1093/bja/ael079
[PMID: 16600902]

Weinrich M, Worcester DL. Xenon and other volatile anesthetics change domain structure in model lipid raft membranes. J Phys Chem B. 2013;117(50):16141-16147.
DOI: 10.1021/jp411261g
[PMID: 24299622]

Sierra-Valdez FJ, Ruiz-Suárez JC, Delint-Ramirez I. Pentobarbital modifies the lipid raft-protein interaction: A first clue about the anesthesia mechanism on NMDA and GABAA receptors. Biochim Biophys Acta. 2016;1858(11):2603-2610.
DOI: 10.1016/j.bbamem.2016.07.011
[PMID: 27457704]

Dietrich C, Bagatolli LA, Volovyk ZN, Thompson NL, Levi M, Jacobson K, et al. Lipid rafts reconstituted in model membranes. Biophys J. 2001;80(3):1417-1428.
DOI: 10.1016/S0006-3495(01)76114-0
[PMID: 11222302]

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(37):34280-34286.
DOI: 10.1074/jbc.M201644200
[PMID: 12097322]

Morris JB, Huynh H, Vasilevski O, Woodcock EA. α1-Adrenergic receptor signaling is localized to caveolae in neonatal rat cardiomyocytes. J Mol Cell Cardiol. 2006;41(1):17-25.
DOI: 10.1016/j.yjmcc.2006.03.011
[PMID: 16730745]

Allen JA, Halverson-Tamboli RA, Rasenick MM. Lipid raft microdomains and neurotransmitter signaling. Nat Rev Neurosci. 2007;8(2):128-140.
DOI: 10.1038/nrn2059
[PMID: 17195035]

Burger K, Gimpl G, Fahrenholz F. Regulation of receptor function by cholesterol. Cell Mol Life Sci. 2000;57(11):1577-1592.
DOI: 10.1007/PL00000643
[PMID: 11092453]

Ohvo-Rekilä H, Ramstedt B, Leppimäki P, Slotte JP. Cholesterol interactions with phospholipids in membranes. Prog Lipid Res. 2002;41(1):66-97.
DOI: 10.1016/S0163-7827(01)00020-0
[PMID: 11694269]

Róg T, Pasenkiewicz-Gierula M. Effects of epicholesterol on the phosphatidylcholine bilayer: a molecular simulation study. Biophys J. 2003;84(3):1818-1826.
DOI: 10.1016/S0006-3495(03)74989-3
[PMID: 12609883]

Nandi N, Vollhardt D. Chiral discrimination and recognition in Langmuir monolayers. Curr Opin Colloid Interface Sci. 2008;13(1-2):40-46.
DOI: 10.1016/j.cocis.2007.07.016

Westover EJ, Covey DF. The enantiomer of cholesterol. J Membr Biol. 2004;202(2):61-72.
DOI: 10.1007/s00232-004-0714-7
[PMID: 15702370]

Venn RM, Karol MD, Grounds RM. Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive care. Br J Anaesth. 2002;88(5):669-675.
DOI: 10.1093/bja/88.5.669
[PMID: 12067004]

Kopeć W, Telenius J, Khandelia H. Molecular dynamics simulations of the interactions of medicinal plant extracts and drugs with lipid bilayer membranes. FEBS J. 2013;280(12):2785-2805.
DOI: 10.1111/febs.12286
[PMID: 23590201]

Mazzanti L, Pastuszko A, Lenaz G. Effects of ketamine anesthesia on rat-brain membranes: fluidity changes and kinetics of acetylcholinesterase. Biochim Biophys Acta. 1986;861(1):105-110.
DOI: 10.1016/0005-2736(86)90408-6
[PMID: 3756149]

Yun I, Cho ES, Jang HO, Kim UK, Choi CH, Chung IK, et al. Amphiphilic effects of local anesthetics on rotational mobility in neuronal and model membranes. Biochim Biophys Acta. 2002;1564(1):123-132.
DOI: 10.1016/S0005-2736(02)00409-1
[PMID: 12101004]

Kuusela E, Vainio O, Kaistinen A. Sedative, analgesic and cardiovascular effects of levomedetomidine alone and in combination with dexmedetomidine in dogs. Am J Vet Res. 2001;62(4):616-621.
DOI: 10.2460/ajvr.2001.62.616.
[PMID: 11327474]

Burgess GM, Giraud F, Poggioli J, Claret M. α-Adrenergically mediated changes in membrane lipid fluidity and Ca2+ binding in isolated rat liver plasma membranes. Biochim Biophys Acta. 1983;731(3):387-396.
DOI: 10.1016/0005-2736(83)90033-0
[PMID: 6305417]

Gzyl-Malcher B, Handzlik J, Klekowska E. Temperature dependence of the interaction of prazosin with lipid Langmuir monolayers. Colloids Surf B Biointerfaces. 2013;112:171-176.
DOI: 10.1016/j.colsurfb.2013.07.030
[PMID: 23973675]

Kroin JS, Buvanendran A, Beck DR, Topic JE, Watts DE, Tuman KJ. Clonidine prolongation of lidocaine analgesia after sciatic nerve block in rats is mediated via the hyperpolarization-activated cation current, not by α-adrenoreceptors. Anesthesiology. 2004;101(2):488-494.
[PMID: 15277933]

Brummett CM, Hong EK, Janda AM, Amodeo FS, Lydic R. Peripheral dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current. Anesthesiology. 2011;115(4):836-843.
DOI: 10.1097/ALN.0b013e318221fcc9
[PMID: 2166643]

Lee AG. How lipids affect the activities of integral membrane proteins. Biochim Biophys Acta. 2004;1666(1-2):62-87.
DOI: 10.1016/j.bbamem.2004.05.012
[PMID: 15519309]

Hershkowitz M, Heron D, Csamuel D, Shinitzky M. The modulation of protein phosphorylation and receptor binding in synaptic membranes by changes in lipid fluidity: implications for aging. Prog Brain Res. 1982;56:419-434.
DOI: 10.1016/S0079-6123(08)63788-7
[PMID: 6298878]

Escribá PV, González-Ros JM, Goñi FM, Kinnunen PK, Vigh L, Sánchez-Magraner L, et al. Membranes: A meeting point for lipids, proteins and therapies. J Cell Mol Med. 2008;12(3):829-875.
DOI: 10.1111/j.1582-4934.2008.00281.x
[PMID: 18266954]

Cantor RS. Receptor desensitization by neurotransmitters in membranes: Are neurotransmitters the endogenous anesthetics? Biochemistry. 2003;42(41):11891-11897.
DOI: 10.1021/bi034534z
[PMID: 14556619]