Skip to main content
SpringerLink
Log in

Protective Effect of Neferine Against Isoproterenol-Induced Cardiac Toxicity

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

The present study was designed to investigate the cardioprotective effect of neferine against isoproterenol-induced myocardial infarction. Neferine was given orally for 30 days, and isoproterenol was injected subcutaneously for 2 days. Histopathological examination of heart tissue of isoproterenol-treated rats showed myocardial necrosis. Biochemical analysis of isoproterenol-treated rats showed significant increase in the serum marker enzymes—creatine kinase, lactate dehydrogenase, and aspartate transaminase and increased serum glycoprotein components with a concomitant decrease in the heart tissue homogenate when compared to control. Increased lipid peroxidation and decreased antioxidants reduced glutathione, superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase and altered lipid profile in serum and tissue was also recorded in the isoproterenol-treated rats, whereas the rats which received neferine pre-treatment followed by isoproterenol injection showed minimal histological changes, absence of inflammation, and a significant decrease in the serum marker enzymes and serum glycoprotein components with a concomitant increase in the heart tissue homogenate when compared to isoproterenol group. Neferine pre-treatment restored the altered biochemical parameters and lipid profile to near normal. The results of the present study showed that neferine exerts strong antioxidant property against isoproterenol-induced oxidative stress and can be used as a potent cardioprotective agent against isoproterenol-induced myocardial infarction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CVD:

Cardiovascular diseases

MI:

Myocardial infarction

MN:

Myocardial necrosis

CK:

Creatine kinase

LDH:

Lactate dehydrogenase

AST:

Aspartate transaminase

HDL:

High-density lipoprotein

LDL:

Low-density lipoprotein

VLDL:

Very low-density lipoprotein

SOD:

Superoxide dismutase

CAT:

Catalase

GSH:

Reduced glutathione

GST:

Glutathione-S-transferase

GPx:

Glutathione peroxidase

References

  1. Agarwal, V. K., Basannan, D. R., Sinh, R. P., Dutt, M., Abraham, D., & Mustafa, M. S. (2006). Coronary risk factors in a rural community. Indian Journal of Public Health, 50, 19–23.

    Google Scholar 

  2. Smith, S. C., Jackson, R., Pearson, T. A., Fuster, V., Yusuf, S., Faergeman, O., et al. (2004). Principles for national and regional guidelines on cardiovascular disease prevention. Circulation, 109, 3112–3121.

    Article  PubMed  Google Scholar 

  3. Sushamakumari, S., Jayadeep, A., Kumar, J. S., & Menon, V. P. (1989). Effect of carnitine on malondialdehyde, taurine and glutathione levels in heart of rats subjected to myocardial stress by isoproterenol. Indian Journal of Experimental Biology, 27, 134–137.

    CAS  PubMed  Google Scholar 

  4. Nirmala, C., & Puvanakrishnan, R. (1996). Protective role of curcumin against isoproterenol induced myocardial infarction in rats. Molecular and Cellular Biochemistry, 159, 85–93.

    Article  CAS  PubMed  Google Scholar 

  5. De Biase, L., Pignatelli, P., Lenti, L., Tocci, G., Piccioni, F., Riondino, S., et al. (2003). Enhanced TNF alpha and oxidative stress in patients with heart failure: Effect of TNF alpha on platelet O2-production. Thrombosis and Haemostasis, 90, 317–325.

    PubMed  Google Scholar 

  6. Rajadurai, M., & Stanely Mainzen Prince, P. (2007). Preventive effect of naringin on cardiac markers, electrocardiographic patterns and lysosomal hydrolases in normal and isoproterenol-induced myocardial infarction in Wistar rats. Toxicology, 230, 178–188.

    Article  CAS  PubMed  Google Scholar 

  7. Rajadurai, M., & Stanely Mainzen Prince, P. (2007). Preventive effect of naringin on isoproterenol-induced cardiotoxicity in Wistar rats: An in vivo and in vitro study. Toxicology, 232, 216–225.

    Article  CAS  PubMed  Google Scholar 

  8. Chatelain, P., Gremel, M., & Brotelle, R. (1987). Prevention by amiodarone of phospholipid depletion in isoproterenol-induced ischemia in rats. European Journal of Pharmacology, 144, 83–90.

    Article  CAS  PubMed  Google Scholar 

  9. Wexler, B. C. (1978). Myocardial infarction in young vs old male rats: Pathophysiologic changes. American Heart Journal, 96, 70–80.

    Article  CAS  PubMed  Google Scholar 

  10. Rathore, N., John, S., Kale, M., & Bhatnagar, D. (1998). Lipid peroxidation and antioxidant enzymes in isoproterenol induced oxidative stress in rat tissues. Pharmacological Research, 38, 297–303.

    Article  CAS  PubMed  Google Scholar 

  11. Pauletti, P. M., Castro-Gamboa, I., Siqueira Silva, D. H., Young, M. C. M., Tomazela, D. M., Eberlin, M. N., et al. (2003). New antioxidant C-glucosylxanthones from the stems of Arrabidaea samydoides. Journal of Natural Products, 66, 1384–1387.

    Article  CAS  PubMed  Google Scholar 

  12. Sridhar, K. R., & Bhat, R. (2007). Lotus—a potential nutraceutical source. Journal of Agricultural Technology, 3, 143–155.

    Google Scholar 

  13. Tomita, M., Watanabe, Y., & Furukawa, H. (1961). On the alkaloids of Nelumbo nucifera Gaertn. IV. Isolation of dl-armepavine. Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 81, 1644–1647.

    CAS  PubMed  Google Scholar 

  14. Furukawa, T. (1965). Use of diuretics based on their mechanism of action. 9. Effect of diuretics on the renal regulation of water balance and its application to the treatment of diabetes insipidus. Saishin igaku. Modern Medicine, 20, 2609–2621.

    CAS  PubMed  Google Scholar 

  15. Liu, S., Wang, B., Li, X. Z., Qi, L. F., & Liang, Y. Z. (2009). Preparative separation and purification of liensinine, isoliensinine and neferine from seed embryo of Nelumbo nucifera GAERTN using high-speed counter-current chromatography. Journal of Separation Science, 32, 2476–2481.

    Article  CAS  PubMed  Google Scholar 

  16. Gu, D., Li, D., Qi, Z., Shi, S., Hu, M., Liu, D., et al. (2009). Blockade of HERG K+ channel by isoquinoline alkaloid neferine in the stable transfected HEK293 cells. Naunyn-Schmiedeberg’s Archives of Pharmacology, 380, 143–151.

    Article  CAS  PubMed  Google Scholar 

  17. Chen, Y., Fan, G., Wu, H., Wu, Y., & Mitchell, A. (2007). Separation, identification and rapid determination of liensine, isoliensinine and neferine from embryo of the seed of Nelumbo nucifera GAERTN. By liquid chromatography coupled to diode array detector and tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis, 43, 99–104.

    Article  PubMed  Google Scholar 

  18. Chen, J., Liu, J.-H., Wang, T., Xiao, H.-J., Yin, C.-P., & Yang, J. (2008). Effects of plant extract neferine on cyclic adenosine monophosphate and cyclic guanosine monophosphate levels in rabbit corpus cavernosum in vitro. Asian Journal of Andrology, 10, 307–312.

    Article  CAS  PubMed  Google Scholar 

  19. Pan, Y., Cai, B., Wang, K., Wang, S., Zhou, S., Yu, X., et al. (2009). Neferine enhances insulin sensitivity in insulin resistant rats. Journal of Ethnopharmacology, 124, 98–102.

    Article  CAS  PubMed  Google Scholar 

  20. Xiong, Y. Q., & Zeng, F. D. (2003). Effect of neferine on toxicodynamics of dichlorvos for inhibiting rabbit cholinesterase. Acta Pharmacologica Sinica, 24, 332–336.

    CAS  PubMed  Google Scholar 

  21. Sugimoto, Y., Furutani, S., Itoh, A., Tanahashi, T., Nakajima, H., Oshiro, H., et al. (2008). Effects of extracts and neferine from the embryo of Nelumbo nucifera seeds on the central nervous system. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 15, 1117–1124.

    Article  CAS  Google Scholar 

  22. Poornima, P., Quency, R. S., & Padma, V. V. (2013). Neferine induces reactive oxygen species mediated intrinsic pathway of apoptosis in HepG2 cells. Food Chemistry, 136, 659–667.

    Article  CAS  PubMed  Google Scholar 

  23. Cao, J. G., Tang, X. Q., & Shi, S. H. (2004). Multidrug resistance reversal in human gastric carcinoma cells by neferine. World Journal of Gastroenterology: WJG, 10, 3062–3064.

    CAS  PubMed  Google Scholar 

  24. Li, G. R., Qian, J. Q., & Lu, F. H. (1990). Effects of neferine on heart electromechanical activity in anaesthetized cats. Zhongguo yao li xue bao = Acta Pharmacologica Sinica, 11, 158–161.

    CAS  PubMed  Google Scholar 

  25. Yu, J., & Hu, W. S. (1997). [Effects of neferine on platelet aggregation in rabbits]. Yao xue xue bao = Acta pharmaceutica Sinica, 32, 1–4.

    CAS  PubMed  Google Scholar 

  26. Feng, Y., Wu, J., Cong, R., Wang, C., Zong, Y., & Feng, Z. (1998). The effect of neferine on foam cell formation by anti-low density lipoprotein oxidation. Journal of Tongji Medical University = Tong ji yi ke da xue xue bao, 18, 134–136.

    CAS  PubMed  Google Scholar 

  27. Wu, S., Sun, C., Cao, X., Zhou, H., Hong, Z., & Pan, Y. (2004). Preparative counter-current chromatography isolation of liensinine and its analogues from embryo of the seed of Nelumbo nucifera GAERTN. Using upright coil planet centrifuge with four multilayer coils connected in series. Journal of Chromatography A, 1041, 153–162.

    Article  CAS  PubMed  Google Scholar 

  28. Zhou, R., Xu, Q., Zheng, P., Yan, L., Zheng, J., & Dai, G. (2008). Cardioprotective effect of fluvastatin on isoproterenol-induced myocardial infarction in rat. European Journal of Pharmacology, 586, 244–250.

    Article  CAS  PubMed  Google Scholar 

  29. Okinaka, S., Kumagai, H., Ebashi, S., Sugita, H., Momoi, H., Toyokura, Y., et al. (1961). Serum creatine phosphokinase. Activity in progressive muscular dystrophy and neuromuscular diseases. Archives of Neurology, 4, 520–525.

    Article  CAS  PubMed  Google Scholar 

  30. King, J., (1965). The dehydrogenase of oxidoreductase–lactate dehydrogenase. Van, D. Nostrand Company, London.

  31. Bergmeyer, H. U., Bernt, E., Mollering, H., & Fleiderer, G. (1974). l-Aspartate and l-asparagine in methods of enzymatic analysis. Journal of Biochemistry, 4, 1696–1700.

    Google Scholar 

  32. Parekh, A. C., & Jung, D. H. (1970). Cholesterol determination with ferric acetate-uranium acetate and sulfuric acid-ferrous sulfate reagents. Analytical Chemistry, 42, 1423–1427.

    Article  CAS  Google Scholar 

  33. Rouser, G., Fleischer, S., & Yamamoto, A. (1970). Two dimensional thin layer chromatographic separation of polar lipids and determination of phospholipids by phosphorus analysis of spots. Lipids, 5, 494–496.

    Article  CAS  PubMed  Google Scholar 

  34. Rice, E. W. (1970). Standard method of clinical chemistry. New York: Academic Press.

    Google Scholar 

  35. Burstein, M., & Scholnick, H. R. (1973). Lipoprotein-polyanion-metal interactions. Advances in Lipid Research, 11, 67–108.

    CAS  PubMed  Google Scholar 

  36. DuBois, M., Gilles, K. A., Hamilton, J. K., Rebers, P. A., & Smith, F. (1956). Colorimetric method for determination of sugars and related substances. Analytical Chemistry, 28, 350–356.

    Article  CAS  Google Scholar 

  37. William, D. W. (1979). A more sensitive assay discriminating galactosamine and glucosamine in mixtures. Analytical Biochemistry, 94, 394–396.

    Article  Google Scholar 

  38. Dische, Z., & Shettles, L. B. (1948). A specific color reaction of methylpentoses and a spectrophotometric micromethod for their determination. Journal of Biological Chemistry, 175, 595–603.

    CAS  PubMed  Google Scholar 

  39. Warren, L. (1959). The thiobarbituric acid assay of sialic acids. The Journal of biological chemistry, 234, 1971–1975.

    CAS  PubMed  Google Scholar 

  40. Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95, 351–358.

    Article  CAS  PubMed  Google Scholar 

  41. Marklund, S., & Marklund, G. (1974). Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. European Journal of Biochemistry/FEBS, 47, 469–474.

    Article  CAS  PubMed  Google Scholar 

  42. Takahara, S., Hamilton, H. B., Neel, J. V., Kobara, T. Y., Ogura, Y., & Nishimura, E. T. (1960). Hypocatalasemia: A new genetic carrier state. The Journal of Clinical Investigation, 39, 610–619.

    Article  CAS  PubMed  Google Scholar 

  43. Moron, M.S., Depierre, J.W. and Mannervik, B. (1979). Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochimica et Biophysica Acta (BBA)-General Subjects 582:67–78.

    Google Scholar 

  44. Tietze, F. (1969). Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissues. Analytical Biochemistry, 27, 502–522.

    Article  CAS  PubMed  Google Scholar 

  45. Rotruck, J. T., Pope, A. L., Ganther, H. E., Swanson, A. B., Hafeman, D. G., & Hoekstra, W. G. (1973). Selenium: Biochemical role as a component of glutathione peroxidase. Science, 179, 588–590.

    Article  CAS  PubMed  Google Scholar 

  46. Habig, W. H., Pabst, M. J., & Jakoby, W. B. (1974). Glutathione S-transferases. Journal of Biological Chemistry, 249, 7130–7139.

    CAS  PubMed  Google Scholar 

  47. Folch, J., Lees, M., & Stanley, G. H. S. (1957). A simple method for the isolation and purification of total lipids from animal tissues. Journal of Biological Chemistry, 226, 497–509.

    CAS  PubMed  Google Scholar 

  48. Haenen, G. R. M. M., Veerman, M., & Bast, A. (1990). Reduction of β-adrenoceptor function by oxidative stress in the heart. Free Radical Biology and Medicine, 9, 279–288.

    Article  CAS  PubMed  Google Scholar 

  49. Upaganlawar, A., Gandhi, C., & Balaraman, R. (2009). Effect of green tea and vitamin E combination in isoproterenol induced myocardial infarction in rats. Plant Foods for Human Nutrition, 64, 75–80.

    Article  CAS  PubMed  Google Scholar 

  50. Judd, J. T., & Wexler, B. C. (1974). Myocardial glycoprotein changes with isoproterenol-induced necrosis and repair in the rat. American Journal of Physiology, 226, 597–602.

    CAS  PubMed  Google Scholar 

  51. Patel, V., Upaganlawar, A., Zalawadia, R., & Balaraman, R. (2010). Cardioprotective effect of melatonin against isoproterenol induced myocardial infarction in rats: A biochemical, electrocardiographic and histoarchitectural evaluation. European Journal of Pharmacology, 644, 160–168.

    Article  CAS  PubMed  Google Scholar 

  52. Sabeena Farvin, K. H., Anandan, R., Senthil Kumar, S. H., Shiny, K. S., Sankar, T. V., & Thankappan, T. K. (2004). Effect of squalene on tissue defense system in isoproterenol-induced myocardial infarction in rats. Pharmacological Research, 50, 231–236.

    Article  CAS  PubMed  Google Scholar 

  53. Gürgün, C., Ildızlı, M., Yavuzgil, O., Sin, A., Apaydın, A., Çınar, C., et al. (2008). The effects of short term statin treatment on left ventricular function and inflammatory markers in patients with chronic heart failure. International Journal of Cardiology, 123, 102–107.

    Article  PubMed  Google Scholar 

  54. Prabhu, S., Jainu, M., Sabitha, K. E., & Devi, C. S. (2006). Cardioprotective effect of mangiferin on isoproterenol induced myocardial infarction in rats. Indian Journal of Experimental Biology, 44, 209–215.

    CAS  PubMed  Google Scholar 

  55. Yang, Y., Shui, Q. L., Zeng, X. R., Liu, Z. F., Zhou, W., & Li, M. L. (2000). Effects of neferine on potassium channels in guinea pig ventricular cells and porcine coronary artery smooth muscle cells. Chinese Journal of Pharmacology and Toxicology, 14, 405–410.

    CAS  Google Scholar 

  56. Tang, X., & Cao, J. G. (2004). Review on the pharmacological research of neferine. Chinese Pharmacology Bulletin, 20, 8–10.

    CAS  Google Scholar 

  57. Singal, P. K., Kapur, N., Dhillon, K. S., Beamish, R. E., & Dhalla, N. S. (1982). Role of free radicals in catecholamine-induced cardiomyopathy. Canadian Journal of Physiology and Pharmacology, 60, 1390–1397.

    Article  CAS  PubMed  Google Scholar 

  58. Sevanian, A., & Hochstein, P. (1985). Mechanisms and consequences of lipid peroxidation in biological systems. Annual Review of Nutrition, 5, 365–390.

    Article  CAS  PubMed  Google Scholar 

  59. Hari Senthil Kumar, S., Anandan, R., Devaki, T., & Santhosh Kumar, M. (2001). Cardioprotective effects of Picrorhiza kurroa against isoproterenol-induced myocardial stress in rats. Fitoterapia, 72, 402–405.

    Article  Google Scholar 

  60. Jayalakshmi, R., & Niranjali Devaraj, S. (2004). Cardioprotective effect of tincture of crataegus on isoproterenol-induced myocardial infarction in rats. The Journal of Pharmacy and Pharmacology, 56, 921–926.

    Article  CAS  PubMed  Google Scholar 

  61. Rai, S., Wahile, A., Mukherjee, K., Saha, B. P., & Mukherjee, P. K. (2006). Antioxidant activity of Nelumbo nucifera (sacred lotus) seeds. Journal of Ethnopharmacology, 104, 322–327.

    Article  PubMed  Google Scholar 

  62. Jayalakshmi, R., Thirupurasundari, C., & Devaraj, S. (2006). Pretreatment with alcoholic extract of shape Crataegus oxycantha (AEC) activates mitochondrial protection during isoproterenol-induced myocardial infarction in rats. Molecular and Cellular Biochemistry, 292, 59–67.

    Article  CAS  PubMed  Google Scholar 

  63. Ithayarasi, A. P., & Devi, C. S. (1997). Effect of alpha-tocopherol on lipid peroxidation in isoproterenol induced myocardial infarction in rats. Indian Journal of Physiology and Pharmacology, 41, 369–376.

    CAS  PubMed  Google Scholar 

  64. Ji, L. L., Stratman, F. W., & Lardy, H. A. (1988). Antioxidant enzyme systems in rat liver and skeletal muscle: Influences of selenium deficiency, chronic training, and acute exercise. Archives of Biochemistry and Biophysics, 263, 150–160.

    Article  CAS  PubMed  Google Scholar 

  65. Priscilla, D. H., & Prince, P. S. M. (2009). Cardioprotective effect of gallic acid on cardiac troponin-T, cardiac marker enzymes, lipid peroxidation products and antioxidants in experimentally induced myocardial infarction in Wistar rats. Chemico-Biological Interactions, 179, 118–124.

    Article  CAS  PubMed  Google Scholar 

  66. Zhao, L., Wang, X., Chang, Q., Xu, J., Huang, Y., Guo, Q., et al. (2010). Neferine, a bisbenzylisoquinoline alkaloid attenuates bleomycin-induced pulmonary fibrosis. European Journal of Pharmacology, 627, 304–312.

    Article  CAS  PubMed  Google Scholar 

  67. Mathew, S., Menon, P. V., & Kurup, P. A. (1981). Changes in myocardial & aortic lipids, lipolytic activity & fecal excretion of sterols & bile acids in isoproterenol-induced myocardial infarction in rats. Indian Journal of Biochemistry & Biophysics, 18, 131–133.

    CAS  Google Scholar 

  68. Sathish, V., Kumar Ebenezar, K., & Devaki, T. (2003). Synergistic effect of nicorandil and amlodipine on tissue defense system during experimental myocardial infarction in rats. Molecular and Cellular Biochemistry, 243, 133–138.

    Article  CAS  PubMed  Google Scholar 

  69. Jacksen, G. (1998). Metabolic agents for stable angina.

  70. Karthikeyan, K., Sarala Bai, B. R., & Niranjali Devaraj, S. (2007). Efficacy of grape seed proanthocyanidins on serum and heart tissue lipids in rats subjected to isoproterenol-induced myocardial injury. Vascular Pharmacology, 47, 295–301.

    Article  CAS  PubMed  Google Scholar 

  71. Manjula, T. S., Geetha, A., Ramesh, T. G., & Devi, C. S. (1992). Reversal of changes of myocardial lipids by chronic administration of aspirin in isoproterenol-induced myocardial damage in rats. Indian Journal of Physiology and Pharmacology, 36, 47–50.

    CAS  PubMed  Google Scholar 

  72. Yeagle, P. L. (1985). Cholesterol and the cell membrane. Biochimica et Biophysica Acta, 822, 267–287.

    Article  CAS  PubMed  Google Scholar 

  73. Zern, T. L., West, K. L., & Fernandez, M. L. (2003). Grape polyphenols decrease plasma triglycerides and cholesterol accumulation in the aorta of ovariectomized guinea pigs. The Journal of Nutrition, 133, 2268–2272.

    CAS  PubMed  Google Scholar 

  74. Punithavathi, V. R., & Prince, P. S. M. (2009). Combined effects of quercetin and α-tocopherol on lipids and glycoprotein components in isoproterenol induced myocardial infarcted Wistar rats. Chemico-Biological Interactions, 181, 322–327.

    Article  CAS  PubMed  Google Scholar 

  75. Judd, J. T., & Wexler, B. C. (1970). Myocardial connective tissue metabolism in response to injury: II. Investigation of the mucopolysaccharides involved in isoproterenol-induced necrosis and repair in rat hearts. Circulation Research, 26, 101–109.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors express their sincere gratitude to Mr. Kumaresh, Sanjeevini Herbals, Salem, India, for providing lotus seeds for the isolation of neferine.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Animal Tissue Culture Laboratory, Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore, 641046, Tamilnadu, India

    Gurusamy Lalitha, Paramasivan Poornima, Arjunan Archanah & Viswanadha Vijaya Padma

Authors
  1. Gurusamy Lalitha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paramasivan Poornima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arjunan Archanah
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Viswanadha Vijaya Padma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Viswanadha Vijaya Padma.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lalitha, G., Poornima, P., Archanah, A. et al. Protective Effect of Neferine Against Isoproterenol-Induced Cardiac Toxicity. Cardiovasc Toxicol 13, 168–179 (2013). https://doi.org/10.1007/s12012-012-9196-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-012-9196-5

Keywords

Search

Navigation