Abstract
1,8-Cineole is a cyclic monoterpenoid used in folk medicine for treatment of numerous respiratory diseases and other infections. 1,8-Cineole has anti-inflammatory, antioxidant, and myorelaxant effects, as well as low toxicity. In the present study, the effects of 1,8-cineole on contractility and voltage-gated calcium channels (VGCC) in tracheal smooth muscle were investigated. Intact and dissociated tracheal smooth muscle were used for muscle contraction and patch-clamp recordings, respectively. In experiments involving muscle contraction, 1,8-cineole potentiated contractions at low concentrations and relaxed contractions induced by isotonic K+ at high concentrations. AMTB (a TRPM8 channel blocker) reduced the potentiation induced by 1,8-cineole while indomethacin (a COX inhibitor) did not block this effect. In dissociated myocytes, 1,8-cineole partially blocked Ba2+ currents through VGCC in a concentration-dependent manner. 1,8-Cineole shifted the steady-state activation and inactivation curves to the left and also reduced the current decay time constant. In conclusion, 1,8-cineole has a dual effect on tracheal smooth muscle contraction resulting in a biphasic effect. Our data suggest that the potentiation effect is mediated by activation of TRPM8 channels and the relaxation effect is mediated by the blockage of L-type VGCC.
Similar content being viewed by others
References
Bastos VP, Brito TS, Lima FJ, Pinho JP, Lahlou S, Abreu Matos FJ, Santos AA, Caldas Magalhães PJ (2009) Inhibitory effect of 1,8-cineole on guinea-pig airway challenged with ovalbumin involves a preferential action on electromechanical coupling. Clin Exp Pharmacol Physiol 36:1120–1126. https://doi.org/10.1111/j.1440-1681.2009.05189.x
Bean BP (1984) Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state. Proc Natl Acad Sci U S A 81:6388–6392. https://doi.org/10.1073/pnas.81.20.6388
Becq F (1995) Ionic channel rundown in excised membrane patches. Biochim Biophys Acta 1251:210–215. https://doi.org/10.1016/0304-4157(96)00002-0
Berridge MJ (2008) Smooth muscle cell calcium activation mechanisms. J Physiol 586:5047–5061. https://doi.org/10.1113/jphysiol.2008.160440
Bezanilla F, Armstrong CM (1977) Inactivation of the sodium channel. I. Sodium current experiments. J Gen Physiol 70:549–566. https://doi.org/10.1085/jgp.70.5.567
Boda D, Valisko M, Henderson D, Eisenberg B, Gillespie D, Nonner W (2009) Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion. J Gen Physiol 133:497–509. https://doi.org/10.1085/jgp.200910211
Caldas GFR, Limeira MMF, Araújo AV, Albuquerque GS, Silva-Neto J d C, da Silva TG, Costa-Silva JH, de Menezes IRA, da Costa JGM, Wanderley AG (2016) Repeated-doses and reproductive toxicity studies of the monoterpene 1,8-cineole (eucalyptol) in Wistar rats. Food Chem Toxicol 97:297–306. https://doi.org/10.1016/j.fct.2016.09.020
Catterall WA (2011) Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 3:1–23. https://doi.org/10.1101/cshperspect.a003947
Cho JS, Kim TH, Lim J-M, Song J-H (2008) Effects of eugenol on Na+ currents in rat dorsal root ganglion neurons. Brain Res 1243:53–62. https://doi.org/10.1016/j.brainres.2008.09.030
Coelho-De-Souza LN, Leal-Cardoso JH, De Abreu Matos FJ, Lahlou S, Magalhães PJC (2005) Relaxant effects of the essential oil of Eucalyptus tereticornis and its main constituent 1,8-cineole on guinea-pig tracheal smooth muscle. Planta Med 71:1173–1175. https://doi.org/10.1055/s-2005-873173
Dieniffer p-N, Jose HL, Jonathan JJ (2015) Eugenol dilates rat cerebral arteries by inhibiting smooth muscle cell voltage - dependent calcium channels. J Cardiovasc Pharmacol 64:401–406. https://doi.org/10.1097/FJC.0000000000000131
Elaissi A, Rouis Z, Mabrouk S, Bel Haj Salah K, Aouni M, Khouja ML, Farhat F, Chemli R, Harzallah-Skhiri F (2012) Correlation between chemical composition and antibacterial activity of essential oils from fifteen Eucalyptus species growing in the Korbous and Jbel Abderrahman arboreta (North East Tunisia). Molecules 17:3044–3057. https://doi.org/10.3390/molecules17033044
Ferreira-Da-Silva FW, Barbosa R, Moreira-Júnior L, Dos Santos-Nascimento T, De Oliveira-Martins MD, Coelho-De-Souza AN, Cavalcante FS, Ceccatto VM, De Lemos TL, Magalhães PJ, Lahlou S, Leal-Cardoso JH (2009) Effects of 1,8-cineole on electrophysiological parameters of neurons of the rat superior cervical ganglion. Clin Exp Pharmacol Physiol 36:1068–1073. https://doi.org/10.1111/j.1440-1681.2009.05188.x
Ferreira-da-Silva FW, da Silva-Alves KS, Alves-Fernandes TA, Coelho-de-Souza AN, Leal-Cardoso JH (2015) Effects of 1,8-cineole on Na+ currents of dissociated superior cervical ganglia neurons. Neurosci Lett 595:45–49. https://doi.org/10.1016/j.neulet.2015.04.005
Hajagos-Tóth J, Hódi Á, Seres AB, Gáspár R (2015) Effects of d- and l-limonene on the pregnant rat myometrium in vitro. Croat Med J 56:431–438. https://doi.org/10.3325/cmj.2015.56.431
Hille B (2001) Ionic channels of excitable membranes. In: Calcium channels, 2nd edn. Sinauer, Sunderland, pp 83–113
Jalilzadeh-Amin G, Maham M (2015) The application of 1,8-cineole, a terpenoid oxide present in medicinal plants, inhibits castor oil-induced diarrhea in rats. Pharm Biol 53:594–599. https://doi.org/10.3109/13880209.2014.935862
Jarvis GE, Barbosa R, Thompson AJ (2016) Noncompetitive inhibition of 5-HT3 receptors by citral, linalool, and eucalyptol revealed by nonlinear mixed-effects modeling. J Pharmacol Exp Ther 356:549–562. https://doi.org/10.1124/jpet.115.230011
Jiang CY, Wang C, Xu NX, Fujita T, Murata Y, Kumamoto E (2016) 1,8- and 1,4-cineole enhance spontaneous excitatory transmission by activating different types of transient receptor potential channels in the rat spinal substantia gelatinosa. J Neurochem 136:764–777. https://doi.org/10.1111/jnc.13433
Juergens URR (2014) Anti-inflammatory properties of the monoterpene 1.8-cineole : current evidence for co-medication in inflammatory airway diseases. Drug Res (Stuttg) 64:638–646. https://doi.org/10.1055/s-0034-1372609
Juergens UR, Dethlefsen U, Steinkamp G, Gillissen A, Repges R, Vetter H (2003) Anti-inflammatory activity of 1.8-cineol (eucalyptol) in bronchial asthma: a double-blind placebo-controlled trial. Respir Med 97:250–256. https://doi.org/10.1053/rmed.2003.1432
Kennedy-Feitosa E, Okuro RT, Pinho Ribeiro V, Lanzetti M, Barroso MV, Zin WA, Porto LC, Brito-Gitirana L, Valenca SS (2016) Eucalyptol attenuates cigarette smoke-induced acute lung inflammation and oxidative stress in the mouse. Pulm Pharmacol Ther 41:11–18. https://doi.org/10.1016/j.pupt.2016.09.004
Kumamoto E, Fujita T (2016) Differential activation of TRP channels in the adult rat spinal substantia gelatinosa by stereoisomers of plant-derived chemicals. Pharmaceuticals 9:8–10. https://doi.org/10.3390/ph9030046
Lacinová L (2005) Voltage-dependent calcium channels. Gen Physiol Biophys 24(Suppl 1):1–78. https://doi.org/10.1002/jcp.1041460203
Lahlou S, Figueiredo AF, Magalhães PJC, Leal-Cardoso JH (2002) Cardiovascular effects of 1,8-cineole, a terpenoid oxide present in many plant essential oils, in normotensive rats. Can J Physiol Pharmacol 80:1125–1131. https://doi.org/10.1139/y02-142
Lee H-S, Park D-E, Song W-J, Park H-W, Kang H-R, Cho S-H, Sohn S-W (2016) Effect of 1.8-Cineole in Dermatophagoides pteronyssinus-stimulated bronchial epithelial cells and mouse model of asthma. Biol Pharm Bull 39:946–952. https://doi.org/10.1248/bpb.b15-00876
Liao P, Yu D, Li G, Tan FY, Jia LS, Yeow LC, Tuck WS (2007) A smooth muscle Cav1.2 calcium channel splice variant underlies hyperpolarized window current and enhanced state-dependent inhibition by nifedipine. J Biol Chem 282:35133–35142. https://doi.org/10.1074/jbc.M705478200
Liapi C, Anifantis G, Chinou I, Kourounakis AP, Theodosopoulos S, Galanopoulou P (2007) Antinociceptive properties of 1,8-cineole and β- pinene, from the essential oil of Eucalyptus camaldulensis leaves, in rodents. Planta Med 73:1247–1254. https://doi.org/10.1111/j.1440-1681.2009.05189.x
Lima-Accioly PM, Lavor-Porto PR, Cavalcante FS, Magalhães PJC, Lahlou S, Morais SM, Leal-Cardoso JH (2006) Essential oil of Croton nepetaefolius and its main constituent, 1,8-cineole, block excitability of rat sciatic nerve in vitro. Clin Exp Pharmacol Physiol 33:1158–1163. https://doi.org/10.1111/j.1440-1681.2006.04494.x
Melanaphy D, Johnson CD, Kustov MV, Watson CA, Borysova L, Burdyga TV, Zholos AV (2016) Ion channel mechanisms of rat tail artery contraction-relaxation by menthol involving, respectively, TRPM8 activation and L-type ca 2+ channel inhibition. Am J Physiol Heart Circ Physiol 311:1416–1430. https://doi.org/10.1152/ajpheart.00222.2015
Melo Júnior J d M d A d, Damasceno M de BMV, Santos SAAR, Barbosa TM, Araújo JRC, Vieira-Neto AE, Wong DVT, Lima-Júnior RCP, Campos AR (2017) Acute and neuropathic orofacial antinociceptive effect of eucalyptol. Inflammopharmacology 25:247–254. https://doi.org/10.1007/s10787-017-0324-5
Murata S, Shiragami R, Kosugi C, Tezuka T, Yamazaki M, Hirano A, Yoshimura Y, Suzuki M, Shuto K, Ohkohchi N, Koda K (2013) Antitumor effect of 1, 8-cineole against colon cancer. Oncol Rep 30:2647–2652. https://doi.org/10.3892/or.2013.2763
Nascimento NRF, Refosco RMDC, Vasconcelos ECF, Kerntopf MR, Santos CF, Batista FJA, De Sousa CM, Fonteles MC (2009) 1,8-Cineole induces relaxation in rat and guinea-pig airway smooth muscle. J Pharm Pharmacol 61:361–366. https://doi.org/10.1211/jpp/61.03.0011
Ouedraogo N, Roux E (2014) Pulmonary & respiratory medicine physiology of airway smooth muscle contraction : an overview. J Pulm Respir Med 4. https://doi.org/10.4172/2161-105X.100022
Peixoto-Neves D, Wang Q, Leal-Cardoso JH, Rossoni LV, Jaggar JH (2015) Eugenol dilates mesenteric arteries and reduces systemic BP by activating endothelial cell TRPV4 channels. Br J Pharmacol 172:3484–3494. https://doi.org/10.1111/bph.13156
Perez-Zoghbi JF, Karner C, Ito S, Shepherd M, Alrashdan Y, Sanderson MJ (2009) Ion channel regulation of intracellular calcium and airway smooth muscle function. Pulm Pharmacol Ther 22:388–397. https://doi.org/10.1016/j.pupt.2008.09.006
Pinho-Da-Silva L, Mendes-Maia PV, Do Nascimento Garcia TM, Cruz JS, De Moráis SM, Coelho-De-Souza AN, Lahlou S, Leal-Cardoso JH (2010) Crotori sonderianus essential oil samples distinctly affect rat airway smooth muscle. Phytomedicine 17:721–725. https://doi.org/10.1016/j.phymed.2010.01.015
Pinto NV, Assreuy AMS, Coelho-de-Souza AN, Ceccatto VM, Magalhães PJC, Lahlou S, Leal-Cardoso JH (2009) Endothelium-dependent vasorelaxant effects of the essential oil from aerial parts of Alpinia zerumbet and its main constituent 1,8-cineole in rats. Phytomedicine 16:1151–1155. https://doi.org/10.1016/j.phymed.2009.04.007
Remberg P, Bjork L, Hedner T, Sterner O (2004) Characteristics, clinical effect profile and tolerability of a nasal spray preparation of Artemisia abrotanum L. for allergic rhinits. Phytomedicine 11:36–42. https://doi.org/10.1078/0944-7113-00350
Soares PMG, Lima RF, de Freitas Pires A, Souza EP, Assreuy AMS, Criddle DN (2007) Effects of anethole and structural analogues on the contractility of rat isolated aorta: involvement of voltage-dependent Ca2+−channels. Life Sci 81:1085–1093. https://doi.org/10.1016/j.lfs.2007.08.027
Takaishi M, Fujita F, Uchida K, Yamamoto S, Shimizu MS, Uotsu CH, Shimizu M, Tominaga M (2012) 1,8-cineole, a TRPM8 agonist, is a novel natural antagonist of human TRPA1. Mol Pain 8:1744-8069-8-86. https://doi.org/10.1186/1744-8069-8-86
Tschiggerl C, Bucar F (2010) Investigation of the volatile fraction of rosemary infusion extracts. Sci Pharm 78:483–492. https://doi.org/10.3797/scipharm.1004-23
Tsien RW (1983) Calcium channels in excitable cell membranes. Annu Rev Physiol 45:341–358. https://doi.org/10.1146/annurev.ph.45.030183.002013
Xu J, Hu Z, Wang C, Yin Z, Wei Q, Zhou L, Li L, Du Y (2014) Acute and subacute toxicity study of 1,8-cineole in mice. Int J Clin Exp Pathol 7:1495–1501
Yudin Y, Rohacs T (2012) Regulation of TRPM8 channel activity. Mol Cell Endocrinol 353:68–74. https://doi.org/10.1016/j.mce.2011.10.023
Acknowledgments
The authors would like to thank Mr. Pedro Militão de Albuquerque-Neto for the technical support and Dr. Daniel Weinreich for reviewing this manuscript. This work was supported by Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Universidade Estadual do Ceará (UECE).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The study was ethically approved by the research ethics committee at the Universidade Estadual do Ceará, Brazil.
Rights and permissions
About this article
Cite this article
Pereira-Gonçalves, Á., Ferreira-da-Silva, F.W., de Holanda-Angelin-Alves, C.M. et al. 1,8-Cineole blocks voltage-gated L-type calcium channels in tracheal smooth muscle. Pflugers Arch - Eur J Physiol 470, 1803–1813 (2018). https://doi.org/10.1007/s00424-018-2201-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-018-2201-5