Relaxant Effects of Quercetin and Rutin on Human Isolated Bronchus

Hanifa Djelili, Lekhmici Arrar, Emmanuel Naline, Philippe Devillier

Faculty of Medicine Paris Ile-de-France West, UPRES EA220, Foch Hospital, 92150 Suresnes, France.
Laboratory of Applied Biochemistry, Department of Biochemistry, Faculty of Nature and Life Sciences, University Ferhat Abbas, Setif, Algeria.

DOI: 10.4236/cm.2012.32015                

Abstract

Increasing epidemiological evidence supports the view, that quercetin has protective roles in a multitude of disease states in human who have a high intake of polyphenols. To investigate the ability of quercetin and its rutinoside, rutin, to modulate the relaxation of human airways smooth muscle and to determine the mechanism (s) of such relaxation, isolated human bronchus rings were suspended in individual organ baths, precontracted with acetylcholine or with histamine and the relaxing effects of quercetin and rutin were determined by measurement of isometric tension. Quercetin induced concentration-dependent relaxant responses on acetylcholine or histamine precontracted human bronchial rings and with almost equal effectiveness. In terms of potency (pD₂) and efficacy (E_max), quercetin is more potent than rutin on relaxant responses of human bronchus. K⁺ and Ca²⁺ concentration-dependent contraction curves were inhibited after incubation with increasing concentrations of quercetin. Quercetin potentiated in a concentration-dependent manner the relaxant effects of isoprenaline or sodium nitroprusside. Rutin had no effect on K⁺-induced contraction and on relaxant activity of isoprenaline or sodium nitroprusside. Our results suggest that the bronchodilator effects of quercetin are modulated by an increase in cyclic nucleotide levels as well as an alteration in availability of Ca²⁺ to the contractile machinery.

Keywords

Calcium Channels; Cyclic Nucleotide; Human Bronchus; Quercetin; Relaxant Effects; Rutin

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	I. C. Arts and P. C. Hollman, “Polyphenols and Disease Risk in Epidemiologic Studies,” The American Journal of Clinical Nutrition, Vol. 81, No. 1, 2005, pp. 317S-325S.
[2]	M. G. L. Hertog, E. J. M. Feskens, P. C. H. Hollman, M. B. Katan and D. Kromhout, “Dietary Antioxidant Flavonoids and Risk of Coronary Heart Disease: The Zutphen Elderly Study,” Lancet, Vol. 342, 1993, pp. 1007-1011. doi:10.1016/0140-6736(93)92876-U
[3]	P. C. H. Hollman and I. C. W. Arts, “Flavonols, Flavones and Flavanols: Nature, Occurrence and Dietary Burden,” Journal of the Science of Food and Agriculture, Vol. 80, No. 7, 2000, pp. 1081-1093. doi:10.1002/(SICI)1097-0010(20000515)80:7<1081::AID-JSFA566>3.0.CO;2-G
[4]	Y. J. Yang, Z. L. Yang, D. C. Wang, X. C. Xiao and P. Li, “Comparative Study on Effects of Rutin and Quercetin on Metabolism in Osteoblast Cells,” Zhong Yao Cai, Vol. 29, No. 5, 2006, pp. 467-470.
[5]	J. Terao and M. K. Piskula, “Flavonoids as Inhibitors of Lipid Peroxidation in Membranes,” In: C. A. Rice-Evans, L. Packer, Eds., Flavonoids in Health and Disease, Marcel Dekker, New York, Basel, 1998, 277-293.
[6]	A. Scalbert, I. T. Johnson and M. Saltmarsh, “Polyphenols: Antioxidants and Beyond,” The American Journal of Clinical Nutrition, Vol. 81, No. 1, 2005, pp. 215S-217S.
[7]	C. Tabak, I. C. Arts, H. A. Smit, D. Heederik and D. Kromhout, “Chronic Obstructive Pulmonary Disease and Intake of Catechins, Flavonols, and Flavones: The MORGEN Study,” American Journal of Respiratiory and Criticle Care Medicine, Vol. 164, No. 1, 2001, pp. 61-64.
[8]	P. Knekt, J. Kumpulainen, R. J?rvinen, H. Rissanen, M. Heli?vaara, A. Reunanen, T. Hakulinen and A. Aroma, “Flavonoid Intake and Risk of Chronic Diseases,” The American Journal of Clinical Nutrition, Vol. 76, No. 3, 2002, pp. 560-568.
[9]	C. Walda, C. Tabak, H. A. Smit, L. R?s?nen, F. Fidanza, A. Menotti, A. Nissinen, E. J. M. Feskens and D. Kromhout, “Diet and 20-Year Chronic Obstructive Pulmonary Disease Mortality in Middle-Aged Men from Three European Countries,” European Journal of Clinical Nutrition, Vol. 56, No. 7, 2002, pp. 638-643. doi:10.1038/sj.ejcn.1601370
[10]	F. Pérez-Vizcaino, M. Ibarra, A. L. Cogolludo, J. Duarte, F. Zaragoza-Arnaez, L. Moreno, G. Lopez-Lopez and J. Tamargo, “Endothelium-Independent Vasodilator Effects of the Flavonoid Quercetin and Its Methylated Metabolites in Rat Conductance and Resistance Arteries,” Journal of Pharmacology and Experimental, Vol. 302, No. 1, 2002, pp. 66-72. doi:10.1124/jpet.302.1.66
[11]	F. Fusi, S. Saponara, F. Pessina, B. Gorelli and G. Sgaragli, “Effects of Quercetin and Rutin on Vascular Preparations: A Comparison between Mechanical and Electrophysiological Phenomena,” European Journal of Nutrition, Vol. 42, No. 1, 2003, pp. 10-17. doi:10.1007/s00394-003-0395-5
[12]	W. D. H. Chiwororo and J. O. A. Ojewole, “Dual Effects of Quercetin on Rat Isolated Portal Vein Smooth Muscle Contractility,” Cardiovascular Journal of Africa, Vol. 21, No. 3, 2010, pp. 132-136.
[13]	P. J. Macander, “Flavonoids Affect Acetylcholine, Prostaglandin E2 and Antigen-Mediated Smooth Muscle Contraction,” Progress in Clinical and Biological Research, Vol. 213, 1986, pp. 489-492.
[14]	W.-C. Ko, P.-Y. Liu, J.-L. Chen, I.-J. Leu and C.-M. Shih, “Relaxant Effects of Flavonoids in Isolated Guinea Pig Trachea and Their Structure-Activity Relationships,” Planta Medica, Vol. 69, No. 12, 2003, pp. 1086-1090. doi:10.1055/s-2003-45187
[15]	Y. C. Xu, S. W. S. Leung, D. K. Y. Yeung, L. H. Hu, G. H. Chen, C. M. Che and R. Y. K. Man, “Structure Activity Relationships of Flavonoids for Vascular Relaxation in Porcine Coronary Artery,” Phytochemistry, 2007, Vol. 68, No. 8, 1179-1188. doi:10.1016/j.phytochem.2007.02.013
[16]	J. Duarte, F. Perez-Vizcaino, A. Zarzuelo, J. Jiménez and J. Tamargo, “Vasodilator Effects of Quercetin in Isolated Rat Vascular Smooth Muscle,” European Journal Pharmacology, Vol. 239, No. 1-3, 1993, pp. 1-7. doi:10.1016/0014-2999(93)90968-N
[17]	E. J. Middleton, C. Kandaswami and T. C. Theoharides, “The Effects of Plant Flavonoids on Mammalian Cells: Implications for Inflammation, Heart Disease, and Cancer,” Pharmacological Reviews, Vol. 52, No. 4, 2000, pp. 673-751.
[18]	V. Calderone, S. Chericoni, C. Martinelli, L. Testai, A. Nardi, I. Morelli, M. C. Breschi and E. Martinotti, “Vasorelaxing Effects of Flavonoids: Investigation on the Possible Involvement of Potassium Channels,” Naunyn-Schmiedeberg’s Archives of Pharmacology, Vol. 370, No. 4, 2004, pp. 290-298. doi:10.1007/s00210-004-0964-z
[19]	R. W. Foster, R. C. Small, A. H. Weston, “Evidence That the Spasmogenic Action of Tetraethylammonium in Guinea-Pig Trachealis is Both Direct and Dependent on the Cellular Influx of Calcium Ion,” British Journal Pharmacology, Vol. 79, No. 1, 1983, pp. 255-263.
[20]	C. Advenier, J. Cerrina, P. Duroux, A. Floch and A. Renier, “Effects of Five Different Organic Calcium Antagonists on Guinea-Pig Isolated Trachea,” British Journal Pharmacology, Vol. 82, No. 3, 1984, pp. 727-733.
[21]	W.-C. Ko, H.-L. Wang, C.-B. Lei, C.-H. Shih, M.-I. Chung and C.-N. Lin, “Mechanisms of Relaxant Action of 3-O-Methylquercetin in Isolated Guinea Pig Trachea,” Planta Medica, Vol. 68, No. 1, 2002, pp. 30-35. doi:10.1055/s-2002-20059
[22]	T. Ahmed and W. M. Abraham, “Role of Calcium-Channel Blockers in Obstructive Airway Disease,” Chest, Vol. 88, No. 2, 1985, pp. 142S-151S.
[23]	J. Duarte, F. Perez-Vizcaino, A. Zarzuelo, J. Jimenez and J. Tamargo, “Inhibitory Effects of Quercetin and Staurosporine on Phasic Contractions in Rat Vascular Smooth Muscle,” European Journal of Pharmacology, Vol. 262, No. 1-2, 1994, pp. 149-156. doi:10.1016/0014-2999(94)90038-8
[24]	H. Masatoshi, I. Shigeo, T. Toshio, N, Kazuo, I. Masaaki and H. Hiroyoshi, “Differential Effects of Flavonoids as Inhibitors of Tyrosine Protein Kinases and Seine/Threonine Protein Kinases,” Biochemical Pharmcology, Vol. 37, No. 15, 1988, pp. 2987-2992. doi:10.1016/0006-2952(88)90286-9
[25]	A. Beretz, J. Stoclet and R. Anton, “Inhibition of Isolated Rat Aorta Contraction by Flavonoids: Possible Correlation with Cyclic AMP-Phosphodiesterase Inhibition,” Planta Medica, Vol. 39, 1980, pp. 236-242.
[26]	T. Nikaido, T. Ohmoto, U. Sankawa, T. Hamanaka and K. Totsuka, “Inhibition of Cyclic AMP Phosphodiesterase by Flavonoids,” Planta Medica, Vol. 46, No. 11, 1982, pp. 162-166. doi:10.1055/s-2007-970043
[27]	W.-C. Ko, C.-M. Shih, Y.-H. Lai, J.-H. Chen and H.-L. Huang, “Inhibitory Effects of Flavonoids on Phosphodiesterase Isozymes from Guinea Pig and Their StructureActivity Relationships,” Biochemical Pharmacology, Vol. 68, No. 10, 2004, pp. 2087-2094. doi:10.1016/j.bcp.2004.06.030
[28]	D. P. Westfall, W. T. Gerthoffer and R. C. Webb, “Vasodilators and Nitric Oxide Synthase,” In: T. M. Brody, J. Larner and K. P. Minnerman, Eds., Human Pharmacology Molecular to Clinical, Mosby, Saint Louis, 1998, pp 239-247.
[29]	C. Manach, C. Morand, V. Crespy, C. Demigné, O. Texier, F. Régérat and C. Rémésy, “Quercetin is Recovered in Human Plasma as Conjugated Derivatives Which Retain Antioxidant Properties,” FEBS Letters, Vol. 426, No. 3, 1998, pp. 331-336. doi:10.1016/S0014-5793(98)00367-6
[30]	J. Lee, Z. Y. Wang, H. Li, L. Chen, Y. Sun, S. Gobbo, D. A. Balentine and C. S. Yang, “Analysis of Plasma and Urinary Tea Polyphenols in Human Subjects,” Cancer Epidemiol, Biomarkers & Prevention, Vol. 4, No. 4, 1995, pp. 393-399.
[31]	D. Rein, S. Lotito, R. R. Holt, C. L. Keen, H. H. Schmitz and C. G. Fraga, “Epicatechin in Human Plasma: In Vivo Determination and Effect of Chocolate Consumption on Plasma Oxidation Status,” Journal of Nutrition, Vol. 130, No. 8, 2000, pp. 2109S-2114S.
[32]	E. U. Graefe, J. Wittiig, S. Mueller, A. K. Riethling, B Uehleke, B. Drewelow, H. Pforte, G. Jacobash, H. Derendorf and M. Veit, “Pharmacokinetics and Bioavailability of Quercetin Glycosides in Humans,” Journal of Clinical Pharmacology, Vol. 41, No. 5, 2001, pp. 492-499. doi:10.1177/00912700122010366
[33]	W. Wa?tjen, G. Michels, B. Steffan, P. Niering, Y. Chovolou, A. Kampk?tter, Q.-H. Tran-Thi, P. Proksch and R. Kahl, “Low Concentrations of Flavonoids are Protective in Rat H4IIE Cells Whereas High Concentrations Cause DNA Damage and Apoptosis,” Journal of Nutrition, Vol. 135, No. 3, 2005, pp. 525-531.
[34]	P. C. Hollman, J. H. de Vries, S. D. van Leeuwen, M. J. Mengelers and M. B. Katan, “Absorption of Dietary Quercetin Glycosides and Quercetin in Healthy Ileostomy Volunteers,” The American Journal of Clinical Nutrition, Vol. 62, No. 6, 1995, pp. 1276-1282.