Cardiovascular Toxicology

, Volume 13, Issue 3, pp 208–219 | Cite as

Cardiovascular Toxicity of Citrus aurantium in Exercised Rats

  • Deborah K. Hansen
  • Nysia I. George
  • Gene E. White
  • Ali Abdel-Rahman
  • Linda S. Pellicore
  • Daniel Fabricant
Article

Abstract

When safety concerns forced the removal of ephedra from the market, other botanicals, including Citrus aurantium or bitter orange (BO) were used as replacements. A major component of the BO extract is synephrine, a chemical that is structurally similar to ephedrine. Because ephedrine has cardiovascular effects that may be exacerbated during physical exercise, the purpose of this study was to determine whether extracts containing synephrine produced adverse effects on the cardiovascular system in exercising rats. Sprague–Dawley rats were dosed daily by gavage for 28 days with 10 or 50 mg of synephrine/kg body weight from one of two different extracts; caffeine was added to some doses. The rats ran on a treadmill for 30 min/day, 3 days/week. Heart rate, blood pressure, body temperature, and QT interval were monitored. Both doses of both extracts significantly increased systolic and diastolic blood pressure for up to 8 h after dosing. Effects on heart rate and body temperature appeared to be due primarily to the effects of caffeine. These data suggest that the combination of synephrine, caffeine, and exercise can have significant effects on blood pressure and do not appear to be effective in decreasing food consumption or body weight.

Keywords

Bitter orange Citrus aurantium Cardiotoxicology Blood pressure Heart rate Weight loss 

References

  1. 1.
    Shekelle, P. G., Hardy, M. L., Morton, S. C., Maglione, M., Mojica, W. A., Suttorp, M. J., et al. (2003). Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance. Journal of the American Medical Association, 289, 1537–1545.PubMedGoogle Scholar
  2. 2.
    Fugh-Berman, A., & Myers, A. (2004). Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: Current status of clinical and basic research. Experimental Biology and Medicine, 229, 698–704.PubMedGoogle Scholar
  3. 3.
    Allison, D. B., Cutter, G., Poehlman, E. T., Moore, D. R., & Barnes, S. (2005). Exactly which synephrine alkaloids does Citrus aurantium (bitter orange) contain? International Journal of Obesity, 29, 443–446.PubMedCrossRefGoogle Scholar
  4. 4.
    Santana, J., Sharpless, K. E., & Nelson, B. C. (2008). Determination of para-synephrine and meta-synephrine positional isomers in bitter orange-containing dietary supplements by LC/UV and LC/MS/MS. Food Chemistry, 109, 675–682.CrossRefGoogle Scholar
  5. 5.
    Pellati, F., & Benvenuti, S. (2007). Chromatographic and electrophoretic methods for the analysis of phenethylamine alkaloids in Citrus aurantium. Journal of Chromatography A, 1161, 71–88.PubMedCrossRefGoogle Scholar
  6. 6.
    Stohs, S. J., Preuss, H. G., & Shara, M. (2011). The safety of Citrus aurantium (Bitter Orange) and its primary protoalkaloide p-synephrine. Phytotherapy Research, 25, 1421–1428.PubMedCrossRefGoogle Scholar
  7. 7.
    Stohs, S. J., Preuss, H. G., & Shara, M. (2011). A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxidative Medicine and Cellular Longevity,. doi:10.1155/2011/482973.PubMedGoogle Scholar
  8. 8.
    Brown, C. M., McGrath, J. C., Midgley, J. M., Muir, A. G. B., O’Brien, J. W., Thonoor, C. M., et al. (1988). Activities of octopamine and synephrine stereoisomers on α-adrenoceptors. British Journal of Pharmacology, 93, 417–429.PubMedCrossRefGoogle Scholar
  9. 9.
    Jordan, R., Midgley, J. M., Thonoor, C. M., & Williams, C. M. (1987). Beta-adrenergic activities of octopamine and synephrine stereoisomers on guinea-pig atria and trachea. Journal of Pharmacy and Pharmacology, 39, 752–754.PubMedCrossRefGoogle Scholar
  10. 10.
    Haaz, S., Fontaine, K. R., Cutter, G., Limdi, N., Perumean-Chaney, S., & Allison, D. B. (2006). Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: An update. Obesity Review, 7, 79–88.CrossRefGoogle Scholar
  11. 11.
    Carpene, C., Galitzky, J., Fontana, E., Atgie, C., Lafontan, M., & Berlan, M. (1999). Selective activation of β3-adrenoreceptors by octopamine: Comparative studies in mammalian fat cells. Naunyn Schmiedeberg’s Archives of Pharmacology, 359, 310–321.PubMedCrossRefGoogle Scholar
  12. 12.
    Fang, Y.-S., Shan, D.-M., Liu, J.-W., Xu, W., Li, C.-L., Wu, H.-Z., et al. (2009). Effect of constituents from Fructus aurantii immaturus and Radix Paeoniae Alba on gastrointestinal movement. Plant Medicine, 75, 24–31.CrossRefGoogle Scholar
  13. 13.
    Nasir, J. M., Durning, S. J., Ferguson, M., Barold, H. S., & Haigney, M. C. (2004). Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine. Mayo Clinic Proceedings, 79, 1059–1062.PubMedCrossRefGoogle Scholar
  14. 14.
    Nykamp, D. L., Fackih, M. N., & Compton, A. L. (2004). Possible association of acute later-wall myocardial infarction and bitter orange supplement. Annals of Pharmacotherapy, 38, 812–816.PubMedCrossRefGoogle Scholar
  15. 15.
    Thomas, J. E., Munir, J. A., McIntyre, P. Z., & Ferguson, M. A. (2009). STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement. A case report and review of the literature. Texas Heart Institute Journal, 36, 586–590.PubMedGoogle Scholar
  16. 16.
    Bouchard, N. C., Howland, M. A., Greller, H. A., Hoffman, R. S., & Nelson, L. S. (2005). Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine. Mayo Clinic Proceedings, 80, 541–545.PubMedCrossRefGoogle Scholar
  17. 17.
    Gange, C. A., Madias, C., Felix-Getzik, E. M., Weintraub, A. R., & Estes, N. A. M., I. I. I. (2006). Variant angina associated with bitter orange in a dietary supplement. Mayo Clinic Proceedings, 81, 545–548.PubMedCrossRefGoogle Scholar
  18. 18.
    Firenzuoli, F., Gori, L., & Galapai, C. (2005). Adverse reaction to an adrenergic herbal extract (Citrus aurantium). Phytomedicine, 12, 247–248.PubMedCrossRefGoogle Scholar
  19. 19.
    Gray, S., & Woolf, A. D. (2005). Citrus aurantium used for weight loss by an adolescent with anorexia nervosa. Journal of Adolescent Health, 37, 415–416.Google Scholar
  20. 20.
    Holmes, R. O., & Tavee, J. (2008). Vasospasm and stroke attributable to ephedra-fee Xendadrine: Case report. Military Medicine, 173, 708–710.PubMedGoogle Scholar
  21. 21.
    Stephensen, T. A., & Sarlay, R., Jr. (2009). Ventricular fibrillation associated with use of synephrine containing dietary supplement. Military Medicine, 174, 1313–1319.PubMedGoogle Scholar
  22. 22.
    Sultan, S., Spector, J., & Mitchell, R. M. (2006). Ischemic colitis associated with use of a bitter orange-containing dietary weight-loss supplement. Mayo Clinic Proceedings, 81, 1630–1631.PubMedCrossRefGoogle Scholar
  23. 23.
    Hansen, D. K., George, N. I., White, G. E., Pellicore, L. S., Abdel-Rahman, A., & Fabricant, D. (2012). Physiological effects following administration of Citrus aurantium for 28 days in rats. Toxicology and Applied Pharmacology, 261, 236–247.PubMedCrossRefGoogle Scholar
  24. 24.
    NRC. (1996). Guide for the care and use of laboratory animals. Washington, DC: Institute for Laboratory Animal Resources.Google Scholar
  25. 25.
    Calapai, G., Firenzuoli, F., Saitta, A., Squadrito, F., Arlotta, M. R., Costantino, G., et al. (1999). Antiobesity and cardiovascular toxic effects of Citrus aurantium extracts in the rat: A preliminary report. Fitoterapia, 70, 586–592.CrossRefGoogle Scholar
  26. 26.
    Arbo, M. D., Larentis, E. R., Linck, V. M., Aboy, A. L., Pimentel, A. L., Henriques, A. T., et al. (2008). Concentrations of p-synephrine in fruits and leaves of Citrus species (Rutaceae) and the acute toxicity testing of Citrus aurantium extract and p-synephrine. Food and Chemical Toxicology, 46, 2770–2775.PubMedCrossRefGoogle Scholar
  27. 27.
    Arbo, M. D., Schmitt, G. C., Limberger, M. F., Charao, M. F., Moro, A. M., Ribeiro, G. L., et al. (2009). Subchronic toxicity of Citrus aurantium L. (Rutaceae) extract and p-synephrine in mice. Regulatory Toxicology and Pharmacology, 54, 114–117.PubMedCrossRefGoogle Scholar
  28. 28.
    Reagan-Shaw, S., Nihal, M., & Ahmad, N. (2008). Dose translation from animal to human studies revisited. FASEB Journal, 22, 659–661.PubMedCrossRefGoogle Scholar
  29. 29.
    Knight, C. A., Knight, I., Mitchell, D. C., & Zepp, J. E. (2004). Beverage caffeine intake in US consumers and subpopulations of interest: Estimates from the share of intake panel survey. Food and Chemical Toxicology, 42, 1923–1930.PubMedCrossRefGoogle Scholar
  30. 30.
    Frary, C. D., Johnson, R. K., & Wang, M. Q. (2005). Food sources and intakes of caffeine in the diets of persons in the United States. Journal of the American Dietetic Association, 105, 110–113.PubMedCrossRefGoogle Scholar
  31. 31.
    Andrews, K. W., Schweitzer, A., Zhao, C., Holden, J. M., Roseland, J. M., Brandt, M., et al. (2007). The caffeine contents of dietary supplements commonly purchased in the US: Analysis of 53 products with caffeine-containing ingredients. Analytical and Bioanalytical Chemistry, 389, 231–239.PubMedCrossRefGoogle Scholar
  32. 32.
    Werle, E. O., Strobel, G., & Weicker, H. (1990). Decrease I rat cardiac beta1- and beta2-adrenoceptors by training and endurance exercise. Life Sciences, 46, 9–17.PubMedCrossRefGoogle Scholar
  33. 33.
    Favret, F., Henderson, K. K., Clancy, R. L., Richalet, J.-P., & Gonzalez, N. C. (2001). Exercise training alters the effect of chronic hypoxia on myocardial adrenergic and muscarinic receptor number. Journal of Applied Physiology, 91, 1283–1288.PubMedGoogle Scholar
  34. 34.
    Barbier, J., Rannou-Bekono, F., Marchais, J., Berthon, P.-M., Delamarche, P., & Carre, F. (2004). Effect of training on β1β2 β3 adrenergic and M2 muscarinic receptors in rat heart. Medicine and Science in Sports and Exercise, 36, 949–954.PubMedCrossRefGoogle Scholar
  35. 35.
    Barbier, J., Reland, S., Ville, N., Rannou-Bekono, F., Wong, S., & Carre, F. (2006). The effects of exercise training on myocardial adrenergic and muscarinic receptors. Clinical Autonomic Research, 16, 61–65.PubMedCrossRefGoogle Scholar
  36. 36.
    Ohiwa, N., Saito, T., Chang, H., Omori, T., Fujikawa, T., Asada, T., et al. (2006). Activation of A1 and A2 noradrenergic neurons in response to running in the rat. Neuroscience Letters, 395, 46–50.PubMedCrossRefGoogle Scholar
  37. 37.
    Libonati, J. R., & MacDonnell, S. M. (2011). Cardiac β-adrenergic responsiveness with exercise. European Journal of Applied Physiology, 111, 2735–2741.PubMedCrossRefGoogle Scholar
  38. 38.
    Haller, C. A., Duan, M., Jacob, P., I. I. I., & Benowitz, N. (2008). Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions. British Journal of Clinical Pharmacology, 65, 33–840.CrossRefGoogle Scholar
  39. 39.
    Sale, C., Harris, R. C., Delves, S., & Corbett, J. (2006). Metabolic and physiological effects of ingesting extracts of bitter orange, green tea and guarana at rest and during treadmill walking in overweight males. International Journal of Obesity, 30, 764–773.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  • Deborah K. Hansen
    • 1
  • Nysia I. George
    • 2
  • Gene E. White
    • 3
  • Ali Abdel-Rahman
    • 4
  • Linda S. Pellicore
    • 5
  • Daniel Fabricant
    • 4
  1. 1.Division of Systems BiologyFood and Drug Administration (FDA)/NCTRJeffersonUSA
  2. 2.Division of Bioinformatics and BiostatisticsFood and Drug Administration (FDA)/NCTRJeffersonUSA
  3. 3.Toxicological Pathology AssociatesJeffersonUSA
  4. 4.Office of Nutrition, Labeling and Dietary SupplementsUS Food and Drug Administration (FDA)/Center for Food Safety and NutritionCollege ParkUSA
  5. 5.Office of New DrugsUS Food and Drug Administration (FDA)/Center for Drug Evaluation and ResearchSilver SpringUSA

Personalised recommendations