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Lidocaine-Induced Cell Growth of Human Gingival Fibroblasts. Role of Na+-K+-ATPase and PKC Activities

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DOI: 10.4236/pp.2014.58090    2,223 Downloads   2,894 Views   Citations

ABSTRACT

Background: Evidences have shown that local anaesthetics are clinically useful compounds that exert a pharmacological effect by blocking nerve impulse propagation and also it is able to provoke proliferation and cell growth. Aims: The aim of this study was to investigate the proliferation and cell growth capacity of lidocaine on human gingival fibroblast cells and the different signal pathways involved in its effect. Method: For this purpose in vitro cultures of human gingival fibroblasts were assayed and the effects of lidocaine on proliferation and cell DNA synthesis, Na+-K+-ATPase and PKC activities and K+ efflux were also evaluated. Results: Lidocaine stimulated in a concentration-dependent manner proliferation and cell growth of human gingival cells and the mechanism involve an increment in Na+-K+-ATPase and PKC activities, which led to an increase in K+ release. All of these effects were blocked by tetrodotoxin, ouabain and calphostin C. In addition, PMA (activator of PKC) increased per se the DNA synthesis of human gingival fibroblast cells. Conclusions: This work demonstrates that lidocaine increase human gingival fibroblasts DNA synthesis and proliferation through an activation of PKC pathway accompanied by the stimulation of Na+-K+-ATPase activity with an increase in K+ efflux. These results contribute to showing another action of lidocaine different to its general use as a drug that relieves odontologic pain or acts as an anti-arrithmogenic agent.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Villarruel, E. , Orman, B. and Borda, E. (2014) Lidocaine-Induced Cell Growth of Human Gingival Fibroblasts. Role of Na+-K+-ATPase and PKC Activities. Pharmacology & Pharmacy, 5, 796-805. doi: 10.4236/pp.2014.58090.

References

[1] Butterworth, J.F. and Strichartz, G.R. (1990) Molecular Mechanism of Local Anesthesia: A Review. Anesthesiology, 72, 711-734.
http://dx.doi.org/10.1097/00000542-199004000-00022
[2] Karniel, M. and Beitner, R. (2000) Local Anesthetics Induce a Decrease in the Level of Glucose 1,6-Bisphosphate, Fructose 1,6-Bisphosphate, and ATP, and in the Viability of Melanoma Cells. Molecular Genetics and Metabolism, 69, 40-45.
http://dx.doi.org/10.1006/mgme.1999.2954
[3] Bjorcrk, S., Dahlstrom, A. and Ahlman, H. (2002) Treatment of Distal Colitis with Local Anesthetics Agents. Pharmacology & Toxicology, 90, 173-180.
http://dx.doi.org/10.1034/j.1600-0773.2002.900401.x
[4] Eroglu, E., Eroglu, F., Agalar, F., Altuntas, I., Sutcu, R. and Ozbasar, D. (2001) The Effect of Lidocaine/Prilocaine Cream on a Experimental Wound Healing Model. European Journal of Emergency Medicine, 8, 199-201.
http://dx.doi.org/10.1097/00063110-200109000-00007
[5] Friederich, P. and Schmitz, T.P. (2002) Lidocaine-Induced Cell Death in a Human Model of Neuronal Apoptosis. European Journal of Anaesthesiology, 19, 564-570.
http://dx.doi.org/10.1017/S0265021502000911
[6] Boselli, E., Duflo, F., Debon, R., Allaouchiche, B., Chassard, D., Thomas, L. and Portoukalian, J. (2003) The Induction of Apoptosis by Local Anesthetics: A Comparison between Lidocaine and Ropicavaine. Anesthesia & Analgesia, 96, 755-756.
http://dx.doi.org/10.1213/01.ANE.0000047201.85815.9D
[7] Perez-Castro, R., Patel, S., Garavito-Aguilar, Z.V., Rosenberg, A., Recio-Pinto, E., Zhang, J., Blanck, T.J. and Xu, F. (2009) Citotoxicity of Local Anesthetics in Human Neuronal Cells. Anesthesia & Analgesia, 108, 997-1007.
http://dx.doi.org/10.1213/ane.0b013e31819385e1
[8] Jorgensen, P.L. (1982) Mechanism of Na+ K+ Pump, Protein Structure and Conformations of the Pure Na++K+-ATPase. Biochimica et Biophysica Acta (BBA)—Reviews on Biomembranes, 694, 27-68.
http://dx.doi.org/10.1016/0304-4157(82)90013-2
[9] Kurihara, K., Hosoi, K., Kodama, A. and Uhea, T. (1990) A New Electrophoretic Variant of Alpha Subunit of Na+/K+-ATPase from the Submandibular Gland of Rats. Biochimica et Biophysica Acta (BBA)—Reviews on Biomembranes, 1039, 234-240.
http://dx.doi.org/10.1016/0167-4838(90)90191-H
[10] Efendiev, R., Bertorello, A.M., Zandomeni, R., Cinelli, A.R. and Pedemonte, C.H. (2002) Agonist-Dependent Regulation of Renal Na+,K+-ATPase Activity Is Modulated by Intracellular Sodium Concentration. Journal of Biological Chemistry, 277, 11489-11496.
http://dx.doi.org/10.1074/jbc.M108182200
[11] Ridge, K.M., Dada, L., Lecuona, E., Bertorello, A.M., Katz, A.I., Mochly-Rosen, D. and Sznajder, J.I. (2002) Dopamine-Induced Exocytosis of Na, K-ATPase Is Dependent on Activation of Protein Kinase C-Epsilon and -Delta. Molecular Biology of the Cell, 277, 11489-11496.
[12] Kutchai, H., Geddis, L.M. and Farley, R.A. (2000) Effects of Local Anaesthetics on the Activity of the Na+-K+-ATPase of Canine Renal Medulla. Pharmacological Research, 41, 1-6.
http://dx.doi.org/10.1006/phrs.1999.0547
[13] Murphy, B.J. and Catterall, W.A. (1992) Phosphorilation of Purified Rat Brain Na+ Channel Reconstituted into Phospholipid Vesicles by Protein Kinase C. The Journal of Biological Chemistry, 267, 16129-16134.
[14] Costa, M.R. and Catterall, W.A. (1984) Cyclic AMP-Dependent Phosphorylation of the Alfa Subunit of the Sodium Channel in Synaptic Nerve Ending Particles. The Journal of Biological Chemistry, 259, 8210-8218.
[15] Nivarthi, R.N., Grant, G.J., Turndorf, H. and Bansinath, M.R. (1996) Spinal Anesthesia by Local Anesthetics Stimulates the Enzyme Protein Kinase C and Induces the Expression of an Immediate Early Oncogene, c-Fos. Anesthesia & Analgesia, 83, 542-547.
[16] Nixon, A.B., Seeds, M.C., Bass, D.A., Smitherman, P.K., O’Flaherty, J.T., Daniel, L.W. and Wykle, R.L. (1997) Comparison of Alkylacylglycerol vs. Diacylglycerol as Activators of Mitogen-Activated Protein Kinase and Cytosolic Phospholipase A2 in Human Neutrophil Priming. Biochimica et Biophysica Acta, 1347, 219-230.
http://dx.doi.org/10.1016/S0005-2760(97)00077-5
[17] Varani, J., Mitra, R.S., Gibbs, D., Phan, S.H., Dixit, V.M., Mitra Jr., R., Wang, T., Siebert, K.J., Nickoloff, B.J. and Voorhees, J.J. (1990) All-Trans Retinoic Acid Stimulates Growth and Extracellular Matrix Production in Growth-Inhibited Cultured Human Skin Fibroblasts. Journal of Investigative Dermatology, 94, 717-723.
http://dx.doi.org/10.1111/1523-1747.ep12876294
[18] Villarruel, E.Q., Borda, E., Sterin-Borda, L. and Orman, B. (2011) Lidocaine-Induced Apoptosis of Gingival Fibroblasts: Participation of cAMP and PKC Activity. Cell Biology International, 35, 783-788.
[19] Ledbetter, M.L. and Lubin, M. (1977) Control of Protein Synthesis in Human Fibroblasts by Intracellular Potassium. Experimental Cell Research, 105, 223-236.
http://dx.doi.org/10.1016/0014-4827(77)90120-3
[20] Quastel, M.R. and Kaplan, J.G. (1970) Lymphocyte Stimulation: The Effect of Ouabain on Nucleic Acid and Protein Synthesis. Experimental Cell Research, 62, 407-420.
http://dx.doi.org/10.1016/0014-4827(70)90572-0
[21] Cuff, J.M. and Lichtman, M.A. (1975) The Effects of Ouabain on the Cell Mitotic Cycle of Mouse Lymphoblasts. Journal of Cellular Physiology, 85, 227-234.
[22] Quissell, D.O. and Suttie, J.W. (1973) Effect of Fluoride and Other Metabolic Inhibitors on Intracellular Sodium and Potassium Concentrations in L Cells. Journal of Cellular Physiology, 82, 59-64.
http://dx.doi.org/10.1002/jcp.1040820107
[23] Spivak, J.L., Misiti, J., Stuart, R., Sharkis, S.J. and Sensenbrenner, L.L. (1980) Suppression and Potentiation of Mouse Hematopoietic Progenitor Cell Proliferation by Ouabain. Blood, 56, 315-317.
[24] Savickiene, J., Gineitis, A. and Stigbrand, T. (1999) Modulation of Apoptosis of Proliferating and Differentiating HL-60 Cells by Protein Kinase Inhibitors: Suppression of PKC or PKA Differently Affects Cell Differentiation and Apoptosis. Cell Death and Differentiation, 6, 698-709.
http://dx.doi.org/10.1038/sj.cdd.4400541
[25] Shen, S., Alt, A., Wertheimer, E., Gartsbein, M., Kuroki, T., Ohba, M., Braiman, L., Sampson, S.R. and Tennenbaum, T. (2001) PKCdelta Activation: A Divergence Point in the Signaling of Insulin and IGF-1-Induced Proliferation of Skin Keratinocytes. Diabetes, 50, 255-264.
http://dx.doi.org/10.2337/diabetes.50.2.255
[26] Pedemonte, C.H., Pressley, T.A., Lokhandwala, M.F. and Cinelli, A.R. (1997) Regulation of Na,K-ATPase Transport Activity by Protein Kinase C. Journal of Membrane Biology, 155, 219-227.
http://dx.doi.org/10.1007/s002329900174
[27] Feltes, T.F., Seidel, C.L., Dennison, D.K., Amick, S. and Allen, J.C. (1993) Relationship between Functional Na+ Pumps and Mitogenesis in Cultured Coronary Artery Smooth Muscle Cells. American Journal of Physiology, 264, C169-C178.
[28] Murata, Y., Matsuda, T., Tamada, K., Hosoi, R., Asano, S., Takuma, K., Tanaka, K. and Baba, A. (1996) Ouabain-Induced Cell Proliferation in Cultured Rat Astrocytes. Japanese Journal of Pharmacology, 72, 347-353.
http://dx.doi.org/10.1254/jjp.72.347
[29] Golomb, E., Hill, M.R., Brown, R.G. and Keiser, H.R. (1994) Ouabain Enhances the Mitogenic Effect of Serum in Vascular Smooth Muscle Cells. American Journal of Hypertension, 7, 69-74.
[30] Wald, M.R., Borda, E.S. and Sterin-Borda, L. (1996) Mitogenic Effect of Erythropoietin on Neonatal Rat Cardiomyocytes: Signal Transduction Pathways. Journal of Cellular Physiology, 167, 461-468.
http://dx.doi.org/10.1002/(SICI)1097-4652(199606)167:3<461::AID-JCP10>3.0.CO;2-7

  
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