Advertisement

Cardiovascular Toxicology

, Volume 17, Issue 4, pp 405–416 | Cite as

Hyperthermia Severely Affects the Vascular Effects of MDMA and Metabolites in the Human Internal Mammary Artery In Vitro

  • D. A. FonsecaEmail author
  • A. F. Guerra
  • F. Carvalho
  • E. Fernandes
  • L. M. Ferreira
  • P. S. Branco
  • P. E. Antunes
  • M. J. Antunes
  • M. D. Cotrim
Original Paper

Abstract

3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a recreational drug used worldwide for its distinctive psychotropic effects. Although important cardiovascular effects, such as increased blood pressure and heart rate, have also been described, the vascular effects of MDMA and metabolites and their correlation with hyperthermia (major side effect of MDMA) are not yet fully understood and have not been previously reported. This study aimed at evaluating the effects of MDMA and its main catechol metabolites, alpha-methyldopamine (α-MeDA), N-methyl-alpha-methyldopamine (N-Me-α-MeDA), 5-(glutathion-S-yl)-alpha-methyldopamine [5-(GSH)-α-MeDA] and 5-(glutathion-S-yl)-N-methyl-alpha-methyldopamine [5-(GSH)-N-Me-α-MeDA], on the 5-HT-dependent vasoactivity in normothermia (37 °C) and hyperthermia (40 °C) of the human internal mammary artery (IMA) in vitro. The results showed the ability of MDMA, α-MeDA and N-Me-α-MeDA to exert vasoconstriction of the IMA which was considerably higher in hyperthermic conditions (about fourfold for MDMA and α-MeDA and twofold for N-Me-α-MeDA). The results also showed that all the compounds may influence the 5-HT-mediated concentration-dependent response of IMA, as MDMA, α-MeDA and N-Me-α-MeDA behaved as partial agonists and 5-(GSH)-α-MeDA and 5-(GSH)-N-Me-α-MeDA as antagonists. In conclusion, MDMA abuse may imply a higher cardiovascular risk associated both to MDMA and its metabolites that might be relevant in patients with underlying cardiovascular diseases, particularly in hyperthermia.

Keywords

3,4-Methylenedioxymethamphetamine MDMA Catecholic metabolites of MDMA 5-Hydroxytryptamine Vascular effects Hyperthermia Human internal mammary artery 

Notes

Acknowledgements

The authors acknowledge all the support and help in the collection of samples from the nurses of Cardiothoracic Surgery, University Hospital of Coimbra.

Compliance with ethical standards

Conflicts of interest

The authors report no conflicts of interest.

References

  1. 1.
    Green, A. R., Mechan, A. O., Elliott, J. M., O’Shea, E., & Colado, M. I. (2003). The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacological Reviews, 55(3), 463–508. doi: 10.1124/pr.55.3.3.CrossRefPubMedGoogle Scholar
  2. 2.
    Capela, J. P., Carmo, H., Remião, F., Bastos, M. L., Meisel, A., & Carvalho, F. (2009). Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: An overview. Molecular Neurobiology, 39(3), 210–271. doi: 10.1007/s12035-009-8064-1.CrossRefPubMedGoogle Scholar
  3. 3.
    Carvalho, M., Carmo, H., Costa, V. M., Capela, J. P., Pontes, H., Remião, F., et al. (2012). Toxicity of amphetamines: An update. Archives of Toxicology, 86(8), 1167–1231. doi: 10.1007/s00204-012-0815-5.CrossRefPubMedGoogle Scholar
  4. 4.
    Vollenweider, F. X., Gamma, A., Liechti, M., & Huber, T. (1998). Psychological and cardiovascular effects and short-term sequelae of MDMA (“ecstasy”) in MDMA-naïve healthy volunteers. Neuropsychopharmacology, 19(4), 241–251. doi: 10.1016/S0893-133X(98)00013-X.CrossRefPubMedGoogle Scholar
  5. 5.
    Mas, M., Farré, M., de la Torre, R., Roset, P. N., Ortuño, J., Segura, J., et al. (1999). Cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4-methylenedioxymethamphetamine in humans. Journal of Pharmacology and Experimental Therapeutics, 290(1), 136–145.PubMedGoogle Scholar
  6. 6.
    Ducros, A., Boukobza, M., Porcher, R., Sarov, M., Valade, D., & Bousser, M.-G. (2007). The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain, 130(12), 3091–3101. doi: 10.1093/brain/awm256.CrossRefPubMedGoogle Scholar
  7. 7.
    Milroy, C. M., & Parai, J. L. (2011). The histopathology of drugs of abuse. Histopathology, 59(4), 579–593. doi: 10.1111/j.1365-2559.2010.03728.x.CrossRefPubMedGoogle Scholar
  8. 8.
    Cole, J. C., & Sumnall, H. R. (2003). Altered states: The clinical effects of ecstasy. Pharmacology and Therapeutics, 98(1), 35–58.CrossRefPubMedGoogle Scholar
  9. 9.
    Silva, S., Carvalho, F., Fernandes, E., Antunes, M. J., & Cotrim, M. D. (2016). Contractile effects of 3,4-methylenedioxymethamphetamine on the human internal mammary artery. Toxicology in Vitro, 34, 187–193. doi: 10.1016/j.tiv.2016.04.002.CrossRefPubMedGoogle Scholar
  10. 10.
    Carvalho, M., Carvalho, F., Remião, F., de Lourdes Pereira, M., Pires-das-Neves, R., & de Lourdes Bastos, M. (2002). Effect of 3,4-methylenedioxymethamphetamine (“ecstasy”) on body temperature and liver antioxidant status in mice: Influence of ambient temperature. Archives of Toxicology, 76(3), 166–172. doi: 10.1007/s00204-002-0324-z.CrossRefPubMedGoogle Scholar
  11. 11.
    Green, A. R., O’Shea, E., Saadat, K. S., Elliott, J. M., & Colado, M. I. (2005). Studies on the effect of MDMA (“ecstasy”) on the body temperature of rats housed at different ambient room temperatures. British Journal of Pharmacology, 146(2), 306–312. doi: 10.1038/sj.bjp.0706318.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Blessing, W. W., Seaman, B., Pedersen, N. P., & Ootsuka, Y. (2003). Clozapine reverses hyperthermia and sympathetically mediated cutaneous vasoconstriction induced by 3,4-methylenedioxymethamphetamine (ecstasy) in rabbits and rats. Journal of Neuroscience, 23(15), 6385–6391.PubMedGoogle Scholar
  13. 13.
    Saadat, K. S., Elliott, J. M., Colado, M. I., & Green, A. R. (2004). Hyperthermic and neurotoxic effect of 3,4-methylenedioxymethamphetamine (MDMA) in guinea pigs. Psychopharmacology (Berl), 173(3–4), 452–453. doi: 10.1007/s00213-003-1653-1.Google Scholar
  14. 14.
    Fiege, M., Wappler, F., Weisshorn, R., Gerbershagen, M. U., Menge, M., & Schulte Am Esch, J. (2003). Induction of malignant hyperthermia in susceptible swine by 3,4-methylenedioxymethamphetamine (“ecstasy”). Anesthesiology, 99(5), 1132–1136.CrossRefPubMedGoogle Scholar
  15. 15.
    Taffe, M. A., Lay, C. C., Von Huben, S. N., Davis, S. A., Crean, R. D., & Katner, S. N. (2006). Hyperthermia induced by 3,4-methylenedioxymethamphetamine in unrestrained rhesus monkeys. Drug and Alcohol Dependence, 82(3), 276–281. doi: 10.1016/j.drugalcdep.2005.09.013.CrossRefPubMedGoogle Scholar
  16. 16.
    He, G.-W. (2013). Arterial grafts: Clinical classification and pharmacological management. Annals of Cardiothoracic Surgery, 2(4), 507–518. doi: 10.3978/j.issn.2225-319X.2013.07.12.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Otsuka, F., Yahagi, K., Sakakura, K., & Virmani, R. (2013). Why is the mammary artery so special and what protects it from atherosclerosis? Annals of Cardiothoracic Surgery, 2(4), 519–526. doi: 10.3978/j.issn.2225-319x.2013.07.06.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Conti, A., Monopoli, A., Forlani, A., Ongini, E., Antona, C., & Biglioli, P. (1990). Role of 5-HT2 receptors in serotonin-induced contraction in the human mammary artery. European Journal of Pharmacology, 176(2), 207–212.CrossRefPubMedGoogle Scholar
  19. 19.
    Tanaka, N., Nakamura, E., Ohkura, M., Kuwabara, M., Yamashita, A., Onitsuka, T., et al. (2008). Both 5-hydroxytryptamine 5-HT2A and 5-HT1B receptors are involved in the vasoconstrictor response to 5-HT in the human isolated internal thoracic artery. Clinical and Experimental Pharmacology and Physiology, 35(7), 836–840. doi: 10.1111/j.1440-1681.2008.04933.x.CrossRefPubMedGoogle Scholar
  20. 20.
    Capela, J. P., Macedo, C., Branco, P. S., Ferreira, L. M., Lobo, A. M., Fernandes, E., et al. (2007). Neurotoxicity mechanisms of thioether ecstasy metabolites. Neuroscience, 146(4), 1743–1757. doi: 10.1016/j.neuroscience.2007.03.028.CrossRefPubMedGoogle Scholar
  21. 21.
    Capela, J. P., Meisel, A., Abreu, A. R., Branco, P. S., Ferreira, L. M., Lobo, A. M., et al. (2006). Neurotoxicity of ecstasy metabolites in rat cortical neurons, and influence of hyperthermia. Journal of Pharmacology and Experimental Therapeutics, 316(1), 53–61. doi: 10.1124/jpet.105.092577.CrossRefPubMedGoogle Scholar
  22. 22.
    Macedo, C., Branco, P. S., Ferreira, L. M., Lobo, A. M., Capela, J. P., Fernandes, E., et al. (2007). Synthesis and cyclic voltammetry studies of 3,4-methylenedioxymethamphetamine (MDMA) human metabolites. Journal of Health Science, 53(1), 31–42.CrossRefGoogle Scholar
  23. 23.
    Liechti, M. E., & Vollenweider, F. X. (2000). The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3,4-methylenedioxymethamphetamine (“Ecstasy”) in healthy volunteers. Journal of Psychopharmacology, 14(3), 269–274.CrossRefPubMedGoogle Scholar
  24. 24.
    Yildiz, O., Ciçek, S., Ay, I., Tatar, H., & Tuncer, M. (1996). 5-HT1-like receptor-mediated contraction in the human internal mammary artery. Journal of Cardiovascular Pharmacology, 28(1), 6–10.CrossRefPubMedGoogle Scholar
  25. 25.
    Bexis, S., & Docherty, J. R. (2006). Effects of MDMA, MDA and MDEA on blood pressure, heart rate, locomotor activity and body temperature in the rat involve alpha-adrenoceptors. British Journal of Pharmacology, 147(8), 926–934. doi: 10.1038/sj.bjp.0706688.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Liechti, M. E., Saur, M. R., Gamma, A., Hell, D., & Vollenweider, F. X. (2000). Psychological and physiological effects of MDMA (“Ecstasy”) after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans. Neuropsychopharmacology, 23(4), 396–404. doi: 10.1016/S0893-133X(00)00126-3.CrossRefPubMedGoogle Scholar
  27. 27.
    Parrott, A. C. (2012). MDMA and temperature: A review of the thermal effects of “Ecstasy” in humans. Drug and Alcohol Dependence, 121(1–2), 1–9. doi: 10.1016/j.drugalcdep.2011.08.012.CrossRefPubMedGoogle Scholar
  28. 28.
    Mallick, A., & Bodenham, A. R. (1997). MDMA induced hyperthermia: A survivor with an initial body temperature of 42.9 degrees C. Journal of Accident and Emergency Medicine, 14(5), 336–338.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Connolly, E., & O’Callaghan, G. (1999). MDMA toxicity presenting with severe hyperpyrexia: A case report. Critical Care and Resuscitation, 1(4), 368–370.PubMedGoogle Scholar
  30. 30.
    Freedman, R. R., Johanson, C.-E., & Tancer, M. E. (2005). Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl), 183(2), 248–256. doi: 10.1007/s00213-005-0149-6.CrossRefGoogle Scholar
  31. 31.
    Zhang, G., & Tao, R. (2011). Enhanced responsivity of 5-HT2A receptors at warm ambient temperatures is responsible for the augmentation of the 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia. Neuroscience Letters, 490(1), 68–71. doi: 10.1016/j.neulet.2010.12.028.CrossRefPubMedGoogle Scholar
  32. 32.
    Vanhoutte, P. M., Shimokawa, H., Tang, E. H. C., & Feletou, M. (2009). Endothelial dysfunction and vascular disease. Acta Physiologica, 196(2), 193–222. doi: 10.1111/j.1748-1716.2009.01964.x.CrossRefPubMedGoogle Scholar
  33. 33.
    Battaglia, G., Brooks, B. P., Kulsakdinun, C., & De Souza, E. B. (1988). Pharmacologic profile of MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites. European Journal of Pharmacology, 149(1–2), 159–163.CrossRefPubMedGoogle Scholar
  34. 34.
    Carvalho, M., Remião, F., Milhazes, N., Borges, F., Fernandes, E., Carvalho, F., et al. (2004). The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine. Toxicology, 200(2–3), 193–203. doi: 10.1016/j.tox.2004.03.016.CrossRefPubMedGoogle Scholar
  35. 35.
    Capela, J. P., Ruscher, K., Lautenschlager, M., Freyer, D., Dirnagl, U., Gaio, A. R., et al. (2006). Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia. Neuroscience, 139(3), 1069–1081. doi: 10.1016/j.neuroscience.2006.01.007.CrossRefPubMedGoogle Scholar
  36. 36.
    Parrott, A. C. (2005). Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy. Journal of Psychopharmacology, 19(1), 71–83. doi: 10.1177/0269881105048900.CrossRefPubMedGoogle Scholar
  37. 37.
    García-Repetto, R., Moreno, E., Soriano, T., Jurado, C., Giménez, M. P., & Menéndez, M. (2003). Tissue concentrations of MDMA and its metabolite MDA in three fatal cases of overdose. Forensic Science International, 135(2), 110–114.CrossRefPubMedGoogle Scholar
  38. 38.
    Segura, M., Ortuño, J., Farré, M., McLure, J. A., Pujadas, M., Pizarro, N., et al. (2001). 3,4-Dihydroxymethamphetamine (HHMA). A major in vivo 3,4-methylenedioxymethamphetamine (MDMA) metabolite in humans. Chemical Research in Toxicology, 14(9), 1203–1208.CrossRefPubMedGoogle Scholar
  39. 39.
    Chu, T., Kumagai, Y., DiStefano, E. W., & Cho, A. K. (1996). Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion. Biochemical Pharmacology, 51(6), 789–796.CrossRefPubMedGoogle Scholar
  40. 40.
    Jones, D. C., Duvauchelle, C., Ikegami, A., Olsen, C. M., Lau, S. S., de la Torre, R., et al. (2005). Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. Journal of Pharmacology and Experimental Therapeutics, 313(1), 422–431. doi: 10.1124/jpet.104.077628.CrossRefPubMedGoogle Scholar
  41. 41.
    Hysek, C., Schmid, Y., Rickli, A., Simmler, L. D., Donzelli, M., Grouzmann, E., et al. (2012). Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans. British Journal of Pharmacology, 166(8), 2277–2288. doi: 10.1111/j.1476-5381.2012.01936.x.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Hysek, C. M., Brugger, R., Simmler, L. D., Bruggisser, M., Donzelli, M., Grouzmann, E., et al. (2012). Effects of the α2-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers. Journal of Pharmacology and Experimental Therapeutics, 340(2), 286–294. doi: 10.1124/jpet.111.188425.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • D. A. Fonseca
    • 1
    • 2
    • 3
    Email author
  • A. F. Guerra
    • 1
  • F. Carvalho
    • 4
  • E. Fernandes
    • 5
  • L. M. Ferreira
    • 6
  • P. S. Branco
    • 6
  • P. E. Antunes
    • 7
  • M. J. Antunes
    • 7
  • M. D. Cotrim
    • 1
    • 2
    • 3
  1. 1.Pharmacology and Pharmaceutical Care Group, Faculty of PharmacyUniversity of CoimbraCoimbraPortugal
  2. 2.Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  3. 3.CNC.IBILIUniversity of CoimbraCoimbraPortugal
  4. 4.UCIBIO/REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of PharmacyUniversity of PortoPortoPortugal
  5. 5.UCIBIO/REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of PharmacyUniversity of PortoPortoPortugal
  6. 6.REQUIMTE/CQFB (Centro de Química Fina e Biotecnologia), Department of Chemistry, Faculty of Sciences and TechnologyUniversity Nova of LisbonCaparicaPortugal
  7. 7.Center of Cardiothoracic SurgeryCoimbra University HospitalsCoimbraPortugal

Personalised recommendations