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Possible Mechanisms of Toxicity of Local Aminoamide Anesthetics: Lipid-Mediated Action of Ropivacaine

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Abstract—

This work is devoted to the identification of molecular mechanisms of action of local anesthetic ropivacaine and other aminoamides (mepivacaine and bupivacaine) on the membrane physicochemical properties and formation and functioning of various ion channels in model lipid bilayers. The boundary membrane potential and its components, permeability for fluorescent markers, and the temperature and cooperativity of the melting of membrane lipid, as well as the mosaic organization of the bilayer, were studied. It was found that ropivacaine, as well as mepivacaine and bupivacaine, changed the surface charge of the bilayer and increased the membrane boundary potential. It was demonstrated that the permeability of lipid vesicles for calcein increased with the introduction of aminoamides, while the temperature and cooperativity of the melting of saturated phosphocholines decreased. The effect of anesthetics on the packing density of lipids in the membrane correlated with the hydrophobicity of their molecules. A comparison of the effects of aminoamides allowed three mechanisms of anesthetics action on the functioning of ion channels to be determined: increasing the surface potential of the membrane, decreasing the packing density of lipids in the membrane, and blocking ion channels.

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REFERENCES

  1. Andersen, O.S., Finkelstein, A., Katz, I., and Cass, A., Effect of phloretin on the permeability of thin lipid membranes, J. Gen. Physiol., 1976, vol. 67, pp. 749–771.

    Article  CAS  Google Scholar 

  2. Bidwai, A, P. and Takemoto, J.Y., Bacterial phytotoxin, syringomycin, induces a protein kinase-mediated phosphorylation of red beet plasma membrane polypeptides, Proc. Natl. Acad. Sci. U. S. A., 1987, vol. 84, pp. 6755–6759.

    Article  CAS  Google Scholar 

  3. Chulkov, E.G. and Ostroumova, O.S., Phloretin modulates the rate of channel formation by polyenes, Biochim. Biophys. Acta, 2016, vol. 1858, pp. 289–294.

    Article  CAS  Google Scholar 

  4. Chulkov, E.G., Schagina, L.V., and Ostroumova, O.S., Membrane dipole modifiers modulate single-length nystatin channels via reducing elastic stress in the vicinity of the lipid mouth of a pore, Biochim. Biophys. Acta, 2015, vol. 1848, pp. 192–199.

    Article  CAS  Google Scholar 

  5. Clarke, R.J. and Kane, D, J., Optical detection of membrane dipole potential: avoidance of fluidity and dye-induced effects, Biochim. Biophys. Acta, 1997, vol. 1323, pp. 223–239.

    Article  CAS  Google Scholar 

  6. Efimova, S.S. and Ostroumova, O.S., Modifiers of the dipole potential of lipid bilayers, Acta Naturae, 2015, vol. 7, pp. 73–82.

    Article  Google Scholar 

  7. Efimova, S.S., Medvedev, R Ya., Schagina, L.V., and Ostroumova, O.S., Increasing of the fluidity of model lipid membranes under the influence of local anesthetics, Cell Tissue Biol., 2016a, vol. 58, pp. 378–384.

    CAS  Google Scholar 

  8. Efimova, S.S., Zakharova, A.A., Schagina, L.V., and Ostroumova, O.S., Local anesthetics affect gramicidin a channels via membrane electrostatic potentials, J. Membr. Biol., 2016b, vol. 249, pp. 781–787.

    Article  CAS  Google Scholar 

  9. Efimova, S.S., Medvedev, R.Ya., Chulkov, E G., Schagina, L.V., and Ostroumova, O.S., Regulation of pore-forming activity of cecropins by local anesthetics, Cell Tissue Biol., 2018a, vol. 60, pp. 219–227.

    Google Scholar 

  10. Efimova, S.S., Chulkov, E.G., and Ostroumova, O.S., Lipid-mediated mode of action of local anesthetics on lipid pores induced by polyenes, peptides and lipopeptides, Colloids Surf. B: Biointerfaces, 2018b, vol. 166, pp. 1–8.

    Article  CAS  Google Scholar 

  11. Hickey, R., Hoffman, J., and Ramamurthy, S., A Comparison of 0.5% ropivacaine and 0.5% bupivacaine for brachial plexus block, Anesthesiology, 1991, vol. 74, pp. 639–642.

    Article  CAS  Google Scholar 

  12. Hille, B., Local anesthetics: hydrophilic and hydrophobic pathways for the drug–receptor reaction, J. Gen. Physiol., 1977, vol. 69, pp. 497–515.

    Article  CAS  Google Scholar 

  13. HoËgberg, C.-J. and Lyubartsev, A.P., Effect of local anesthetic lidocaine on electrostatic properties of a lipid bilayer, Biophys. J., 2008, vol. 94, pp. 525–531.

  14. Klein, S.M., Greengrass, RA, Steele, S.M., D’Ercole, F, J., Speer, K, P., Gleason, D.H., DeLong, E.R., and Warner, D.S., A comparison of 0.5% bupivacaine, 0.5% ropivacaine, and 0.75% ropivacaine for interscalene brachial plexus block, Anesth. Analg., 1998, vol. 87, pp. 1316–1319.

    CAS  PubMed  Google Scholar 

  15. Kopeikina, L.T., Kamper, E.F., Siafaka, I., and Stavridis, J., Modulation of synaptosomal plasma membrane-bound enzyme activity through the perturbation of plasma membrane lipid structure by bupivacaine, Anesth. Analg., 1997, vol. 85, pp. 1337–1343.

    Article  CAS  Google Scholar 

  16. Lee, A.G., Model for action of local anesthetics, Nature, 1976, vol. 262, pp. 545–548.

    Article  CAS  Google Scholar 

  17. Malheiros S.V., Pinto, L.M., Gottardo, L., Yokaichiya, D.K., Fraceto, L.F., Meirelles, N.C., and de Paula, E., A new look at the hemolytic effect of local anesthetics, considering their real membrane/water partitioning at pH 7.4, Biophys. Chem., 2004, vol. 110, pp. 213–21.

    Article  CAS  Google Scholar 

  18. Markham, A. and Faulds, D., Ropivacaine. A review of its pharmacology and therapeutic use in regional anaesthesia, Drugs, 1996, vol. 52, pp. 429–449.

    Article  CAS  Google Scholar 

  19. McGlade, D.P., Kalpokas, M.V., Mooney, P, H., Chamley, D., Mark, A.H., and Torda, T.A., A comparison of 0.5% ropivacaine and 0.5% bupivacaine for axillary brachial plexus anaesthesia, Anaesth. Intensive Care, 1998, vol. 26, pp. 515–520.

    Article  CAS  Google Scholar 

  20. Montal, M. and Muller, P., Formation of bimolecular membranes from lipid monolayers and study of their electrical properties, Proc. Natl. Acad. Sci. U. S. A., 1972, vol. 65, pp. 3561–3566.

    Article  Google Scholar 

  21. Ragsdale, D.S., McPhee, J.C., Scheuer, T., and Catterall, W., A, Molecular determinants of state-dependent block of Na+ channels by local anesthetics, Science, 1994, vol. 265, pp. 1724–1728.

    Article  CAS  Google Scholar 

  22. Seeman, P., The membrane actions of anesthetics and tranquilizers, Pharmacol. Rev., 1972, vol. 24, pp. 585–655.

    Google Scholar 

  23. Singer, M.A., Interaction of dibucaine and propanol with phospholipid bilayer membranes—effect of alterations in fatty acyl composition, Biochem. Pharmacol., 1977, vol. 26, pp. 51–57.

    Article  CAS  Google Scholar 

  24. Smith, C.P., Auger, M., and Jarrell, H.C., Molecular details on anesthetic–lipid interaction, Ann. N.Y. Acad. Sci., 1991, vol. 625, pp. 668–684.

    Article  CAS  Google Scholar 

  25. Starke-Peterkovic, T., Turner, N., Vitha, M.F., Waller, M.P., Hibbs, D.E., and Clarke, R.J., Electric field strength of membrane lipids from vertebrate species: membrane lipid composition and Na+-K+-ATPase molecular activity, Biophys. J., 2006, vol. 90, pp. 4060–4070.

    Article  CAS  Google Scholar 

  26. Strichartz, G.R., Sanchez, V., Arthur, G.R., Chafetz, R., and Martin, D., Fundamental properties of local anesthetics. II. Measured octanol: buffer partition coefficients and pKa values of clinically used drugs, Anesth. Analg., 1990, vol. 71, pp. 158–170.

    Article  CAS  Google Scholar 

  27. Wright, S.N., Wang, S.-Y., Xiao, Y.-F., and Wang, G.K., State-dependent cocaine block of sodium channel isoforms, chimeras, and channels coexpressed with the β1 subunit, Biophys. J., 1999, vol. 76, pp. 233–245.

    Article  CAS  Google Scholar 

  28. Yarov-Yarovoy, V., Brown, J., Sharp, E.M., Clare, J.J., Scheuer, T., and Catterall, W.A., Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na(+) channel α subunit, J. Biol. Chem., 2001, vol. 276, pp. 20–27.

    Article  CAS  Google Scholar 

  29. Yokoyama, S., Correlation between pharmacological potency and micellar surface potential of local anesthetic, Toxicol. Lett., 1998, vol. 100–101, pp. 365–368.

    Article  Google Scholar 

  30. Yun, I., Cho, E.S., Jang, H.O., Kim, U.K., Choi, C.H., Chung, I.K., Kim, I.S., and Wood, W.G., Amphiphilic effects of local anesthetics on rotational mobility in neuronal and model membranes, Biochim. Biophys. Acta, 2002, vol. 1564, pp. 123–132.

    Article  CAS  Google Scholar 

  31. Zakharova, A.A., Efimova, S.S., Schagina, L.V., Malev, V.V., and Ostroumova, O.S., Blocking ion channels induced by antifungal lipopeptide syringomycin E with amide-linked local anesthetics, Sci. Rep., 2018, vol. 8, p. 11543.

    Article  Google Scholar 

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ACKNOWLEDGMENTS

We are grateful to E.G. Chulkova and R.Ya. Medvedev for participating in some experiments, as well as L.V. Shchagina and V.V. Malev for discussion and critical analysis of the results.

Funding

The study was supported by the Russian Science Foundation, project no. 19-14-00110. S.S. Efimova was awarded a Russian Presidential Scholarship. SP-484.2018.4.

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Authors and Affiliations

  1. Institute of Cytology of the Russian Academy of Sciences, 194064, St. Petersburg, Russia

    A. A. Zakharova, S. S. Efimova & O. S. Ostroumova

  2. St. Petersburg State Pediatric Medical University, 194100, St. Petersburg, Russia

    V. A. Koryachkin & D. V. Zabolotskii

Authors
  1. A. A. Zakharova
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  2. S. S. Efimova
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  3. V. A. Koryachkin
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  4. D. V. Zabolotskii
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  5. O. S. Ostroumova
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Correspondence to A. A. Zakharova.

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The authors declare that they have no conflict of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.

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Translated by I. Fridlyanskaya

Abbreviations: BPC—bupivacaine, gA—antimicrobial peptide gramicidin A, DOPS—1,2-dioleoyl-sn-glycero-3-phospho-L-serine, DOPC—1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPE—1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, DPPC—1,2-diphitonoyl-sn-glycero-3-phosphocholine, MPC—mepivacaine, RPC—ropivacaine, SRE—antifungal cyclic lipopeptide syringomycin E produced by Pseudmonas syringae, CA—antimicrobial peptide cecropin A, α-HL—α-hemolysin, a protein toxin of Staphylococcus aureus.

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Zakharova, A.A., Efimova, S.S., Koryachkin, V.A. et al. Possible Mechanisms of Toxicity of Local Aminoamide Anesthetics: Lipid-Mediated Action of Ropivacaine. Cell Tiss. Biol. 14, 218–227 (2020). https://doi.org/10.1134/S1990519X20030098

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