Skip to main content

Advertisement

Log in

The Effects of Lipid Emulsion, Magnesium Sulphate and Metoprolol in Amitriptyline-Induced Cardiovascular Toxicity in Rats

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

The aim of this study was to evaluate the effects of metoprolol, lipid emulsion and MgSO4 which can be recommended for prevention of long QT that is one of the lethal consequences of amitriptyline intoxication. Thirty Sprague–Dawley male rats were included. Five groups respectively received the following: saline intraperitoneally (i.p.); amitriptyline (AMT) 100 mg/kg per os (p.o.) and saline i.p.; AMT 100 mg/kg p.o. and 5 mg/kg metoprolol i.p.; AMT 100 mg/kg p.o. and 20 ml/kg lipid emulsion i.p.; AMT 100 mg/kg p.o. and 75 mg/kg MgSO4 i.p. After 1 h, all groups were analysed by ECG recordings in DII lead; their blood was taken for biochemical examination and euthanasia was performed. For histological examination, cardiac tissues were removed and sections were prepared. QTc was significantly reduced in treatment groups compared to the AMT+saline group. When compared with the AMT+saline, lipid emulsion did not affect pro-BNP and troponin levels in biochemical analysis, but it significantly reduced Caspase 3 expression in histological examination. In the group treated with AMT and metoprolol, there was no significant effect on Caspase 3 expression. In MgSO4-treated group, there was a significant decrease in troponin, pro-BNP and urea levels biochemically and significant decrease in Caspase 3 expression histologically when compared with the control group. With further studies including clinical studies, MgSO4, lipid emulsion or metoprolol may be used to improve AMT-induced cardiotoxicity. They can possibly become alternative approaches in the future for suicidal or accidental intoxication of tricyclic antidepressant in emergency departments.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Akgun, A., Kalkan, S., Hocaoglu, N., Gidener, S., & Tuncok, Y. (2008). Effects of adenosine receptor antagonists on amitriptyline-induced QRS prolongation in isolated rat hearts. Clinical Toxicology (Philadelphia), 46(7), 677–685.

    Article  CAS  Google Scholar 

  2. Akman, T., Erbas, O., Akman, L., & Yilmaz, A. U. (2014). Prevention of pazopanib-prevention induced prolonged cardiac repolarization and proarrhytmic effects. Arquivos Brasileiros de Cardiologia, 103(5), 403–409.

    PubMed  PubMed Central  Google Scholar 

  3. Alvarez, P. A., & Pahissa, J. (2010). QT alterations in psychopharmacology: Proven candidates and suspects. Current Drug Safety, 5(1), 97–104.

    Article  CAS  PubMed  Google Scholar 

  4. Balasubramaniyam, N., Palaniswamy, C., Aronow, W. S., Khera, S., Balasubramanian, G., Harikrishnan, P., et al. (2013). Association of corrected QT interval with long-term mortality in patients with syncope. Archives of Medical Science, 9(6), 1049–1054.

    Article  PubMed  Google Scholar 

  5. Barber, M. J., Starmer, C. F., & Grant, A. O. (1991). Blockade of cardiac sodium channels by amitriptyline and diphenylhydantoin. Evidence for two use-dependent binding sites. Circulation Research, 69(3), 677–696.

    Article  CAS  PubMed  Google Scholar 

  6. Barrington, P. L., & Ten Eick, R. E. (1990). Characterization of the electrophysiological effects of metoprolol on isolated feline ventricular myocytes. Journal of Pharmacology and Experimental Therapeutics, 252(3), 1043–1052.

    CAS  PubMed  Google Scholar 

  7. Basol, N., & Erbas, O. (2016). The effects of diltiazem and metoprolol in QTc prolongation due to amitriptyline intoxication. Human & Experimental Toxicology, 35(1), 29–34.

    Article  CAS  Google Scholar 

  8. Bateman, D. N., Chick, J., Good, A. M., Kelly, C. A., & Masterton, G. (2004). Are selective serotonin re-uptake inhibitors associated with an increased risk of self-harm by antidepressant overdose? European Journal of Clinical Pharmacology, 60, 2214.

    Google Scholar 

  9. Baysal, T., Oran, B., Doğan, M., Cimen, D., Elmas, S., & Karaaslan, S. (2007). Beta-blocker treatment in an adolescent with amitriptyline intoxication. The Anatolian Journal of Cardiology, 7(3), 324–325.

    PubMed  Google Scholar 

  10. Beach, S. R., Celano, C. M., Noseworthy, P. A., Januzzi, J. L., & Huffman, J. C. (2013). QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics, 54(1), 1–13.

    Article  PubMed  Google Scholar 

  11. Blaber, M. S., Khan, J. N., Nrebner, J. A., & McColm, R. (2012). “Lipid rescue” for tricyclic antidepressant cardiotoxicity. The Journal of Emergency Medicine, 43(3), 465–467.

    Article  PubMed  Google Scholar 

  12. Carreiro, S., Blum, J., & Hack, J. B. (2014). Pretreatment with intravenous lipid emulsion reduces mortality from cocaine toxicity in a rat model. Annals of Emergency Medicine, 64(1), 32–37.

    Article  PubMed  Google Scholar 

  13. Celebi, O., Diker, E., & Aydogdu, S. (2008). Clinical importance of cardiac troponins. Archives of the Turkish Society of Cardiology, 36(4), 269–277.

    PubMed  Google Scholar 

  14. Cotton, D. B., Gonik, B., & Dorman, K. F. (1984). Cardiovascular alterations in severe pregnancy-induced hypertension: Acute effects of intravenous magnesium sulphate. American Journal of Obstetrics and Gynecology, 148, 162–165.

    Article  CAS  PubMed  Google Scholar 

  15. Critelli, G., Ferro, G., Peschle, C., Perticone, F. R., Rengo, F. R., & Condorelli, M. (1977). Myocardial contractility after injection or prolonged infusion of magnesium sulphate. Acta Cardiologica, 32, 65–73.

    CAS  PubMed  Google Scholar 

  16. Dandavino, A., Woods, J. R., Murayama, K., Brinkman, C. R., & Assali, N. S. (1977). Circulatory effects of magnesium sulphate in normotensive and renal hypertensive pregnant sheep. American Journal of Obstetrics and Gynecology, 127, 769–774.

    Article  CAS  PubMed  Google Scholar 

  17. Demircan, C., Cikriklar, H. I., Engindeniz, Z., Cebicci, H., Atar, N., Guler, V., et al. (2005). Comparison of the effectiveness of intravenous diltiazem and metoprolol in the management of rapid ventricular rate in atrial fibrillation. Emergency Medicine Journal, 22(6), 411–414.

    Article  CAS  PubMed  Google Scholar 

  18. Dianat, S., Zarei, M. R., Hassanian-Moghaddam, H., Rashidi-Ranjbar, N., Rahimian, R., & Rasouli, M. R. (2011). Tricyclic antidepressants intoxication in Tehran, Iran: Epidemiology and associated factors. Human & Experimental Toxicology, 30(4), 283–288.

    Article  Google Scholar 

  19. Dinleyici, E. C., Kilic, Z., Sahin, S., Tutuncu-Toker, R., Eren, M., Yargic, Z. A., et al. (2013). Heart rate variability in children with tricyclic antidepressant intoxication. Cardiology Research and Practice, 2013, 196506.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Erbas, O., & Yilmaz, M. (2015). Metoprolol and diltiazem ameliorate ziprasidone-induced prolonged corrected QT interval in rats. Toxicology and Industrial Health, 31(12), 1152–1157.

    Article  CAS  PubMed  Google Scholar 

  21. Foianini, A., Joseph Wiegand, T., & Benowitz, N. (2010). What is the role of lidocaine or phenytoin in tricyclic antidepressant-induced cardiotoxicity? Clinical Toxicology, 48(4), 325–330.

    Article  CAS  PubMed  Google Scholar 

  22. Fossa, A. A., Zhou, M., Brennan, N., Round, P., & Ford, J. (2014). Use of continuous ECG for improvements in assessing the standing response as a positive control for QT prolongation. Annals of Noninvasive Electrocardiology, 19(1), 82–89.

    Article  PubMed  Google Scholar 

  23. Harvey, M., & Cave, G. (2007). Intralipid outperforms sodium bicarbonate in a rabbit model of clomipramine toxicity. Annals of Emergency Medicine, 49(2), 178–185.

    Article  PubMed  Google Scholar 

  24. Harvey, M., & Cave, G. (2012). Case report: Successful lipid resuscitation in multi-drug overdose with predominant tricyclic antidepressant toxidrome. International Journal of Emergency Medicine, 5(1), 8.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Holly, T. A., Drincic, A., Byun, Y., Nakamura, S., Harris, K., Klocke, F. J., et al. (1999). Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo. Journal of Molecular and Cellular Cardiology, 31, 1709–1715.

    Article  CAS  PubMed  Google Scholar 

  26. Hussain, A., Gharanei, A. M., Nagra, A. S., & Maddock, H. L. (2014). Caspase inhibition Via A3 adenosine receptors: A new cardioprotective mechanism against myocardial infarction. Cardiovascular Drugs and Therapy, 28, 19–32.

    Article  CAS  PubMed  Google Scholar 

  27. Jalal, A. N., Yasseri, K., & Kadhim, H. A. (2009). Histopathological monitorring of cardioprotective effects of MgSO4, pioglitazone and omega-3 fatty acids in rabbits induced with myocardial infarction. Kufa Medical Journal, 12(1), 476–481.

    Google Scholar 

  28. James, M. F. M., Cork, R. C., & Dennett, J. E. (1987). Cardiovascular effects of magnesium sulphate in the baboon. Magnesium, 6, 314–324.

    CAS  PubMed  Google Scholar 

  29. Kalkan, S., Hocaoglu, N., Oransay, K., Buyukdeligoz, M., & Tuncok, Y. (2012). Adenosine mediated cardiovascular toxicity in amitriptyline poisoned rats. Drug and Chemical Toxicology, 35(4), 423–431.

    Article  CAS  PubMed  Google Scholar 

  30. Kaplan, Y. C., Hocaoglu, N., Oransay, K., Kalkan, S., & Tuncok, Y. (2008). Effect of glucagon on amitriptyline-induced cardiovascular toxicity in rats. Human & Experimental Toxicology, 27(4), 321–325.

    Article  CAS  Google Scholar 

  31. Karmakar, S., Padman, A., Mane, N. S., & Sen, T. (2013). Hypokalemia: A potent risk for QTc prolongation in clarithromycin treated rats. European Journal of Pharmacology, 709(1–3), 80–84.

    Article  CAS  PubMed  Google Scholar 

  32. Kemp, P. A., Gardiner, S. M., March, J. E., Bennett, T., & Rubin, P. C. (1994). Effects of NG-nitro-L-arginine methyl ester on regional hemomodynamic responses to MgSO4 in conscious rats. British Journal of Pharmacology, 111(1), 325–331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kerr, G. W., McGuffie, A. C., & Wilkie, S. (2001). Tricyclic antidepressant overdose: A review. Emergency Medicine Journal, 18(4), 236–241.

    Article  CAS  PubMed  Google Scholar 

  34. Kharb, S., & Singh, V. (2000). Magnesium deficiency potentiates free radical production associated with myocardial infarction. The Journal of the Association of Physicians of India, 48, 484–485.

    CAS  PubMed  Google Scholar 

  35. Kiyan, S., Aksay, E., Yanturali, S., Atilla, R., & Ersel, M. (2006). Acute myocardial infarction associated with amitripthyline overdose. Basic & Clinical Pharmacology & Toxicology, 98, 462–466.

    Article  CAS  Google Scholar 

  36. Kline, J. A., DeStefano, A. A., Schroeder, J. D., & Raymond, R. M. (1994). Magnesium potantiates imipramine toxicity in the isolated rat heart. Annals of Emergency Medicine, 24, 224–232.

    Article  CAS  PubMed  Google Scholar 

  37. Legome, E. (2006). Toxicity, antidepressant. Emergency medicine online textbook. Retrieved September 26, from http://www.emedicine.com.

  38. Levine, M., Brooks, D. E., Franken, A., & Graham, R. (2012). Delayed-onset seizure and cardiac arrest after amitriptyline overdose, treated with intravenous lipid emulsion therapy. Pediatrics, 130(2), E432–E438.

    Article  Google Scholar 

  39. Li, J., Iorga, A., Sharma, S., Youn, J. Y., Partow-Navid, R., Umar, S., et al. (2012). Intralipid, a clinically safe compound, protects the heart against ischemia-reperfusion injury more efficiently than cyclosporine-A. Anesthesiology: The Journal of the American Society of Anesthesiologists, 117(4), 836–846.

    Article  CAS  Google Scholar 

  40. Liebelt, E. L. (2011). Cyclic antidepressants. In L. S. Nelson, N. A. Lewin, M. A. Howland, R. S. Hoffman, L. R. Goldfrank, & N. E. Flomenbaum (Eds.), Goldfrank’s toxicologic emergencies (9th ed., pp. 1049–1057). New York: Mcgraw Hill Companies.

    Google Scholar 

  41. Lou, P., Lucchinetti, E., Zhang, L., Affolter, A., Schaub, M. C., Gandhi, M., et al. (2014). The mechanism of intralipid®-mediated cardioprotection complex IV inhibition by the active metabolite, palmitoylcarnitine, generates reactive oxygen species and activates reperfusion injury salvage kinases. PLoS ONE. https://doi.org/10.1371/journal.pone.0087205.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Martin, B. J., Black, J., & McLelland, A. S. (1991). Hipomagnesemi in elderly hospital admissions: A study of clinical significance. QJM: An International Journal of Medicine, 78, 177–184.

    CAS  Google Scholar 

  43. Mazoit, J. X., Le Guen, R., Beloeil, H., & Benhamou, D. (2009). Binding of long-lasting local anesthetics to lipid emulsions. Anesthesiology, 110, 380–386.

    PubMed  Google Scholar 

  44. Mroczek, W. J., Lee, W. R., & Davidov, M. E. (1970). Effect of magnesium sulphate on cardiovascular hemomodynamics. Angiology, 10, 720–724.

    Google Scholar 

  45. Nose`, M., & Barbui, C. (2014). Do antidepressants prolong the QT interval? Epidemiology and Psychiatric Sciences, 23(1), 19–20.

    Article  CAS  Google Scholar 

  46. Olgun, H., Yildirim, Z. K., Karacan, M., & Ceviz, N. (2009). Clinical, electrocardiographic, and laboratory findings in children with amitriptyline intoxication. Pediatric Emergency Care, 25(3), 170–173.

    Article  PubMed  Google Scholar 

  47. Oransay, K., Kalkan, S., Hocaoglu, N., Arici, A., & Tuncok, Y. (2011). An alternative antidote therapy in amitriptyline-induced rat toxicity model: Theophylline. Drug and Chemical Toxicology, 34(1), 53–60.

    Article  CAS  PubMed  Google Scholar 

  48. Potter, W. Z., & Hollister, L. E. (2004). Antidepressant agents. In B. G. Katzung (Ed.), Basic and clinical pharmacology. A LANGE medical book (pp. 482–496). New York: McGraw-Hill.

    Google Scholar 

  49. Pritchard, J. A., & Pritchard, S. A. (1975). Standardized treatment of 154 consecutive cases of eclampsia. American Journal of Obstetrics and Gynecology, 123, 543–552.

    Article  CAS  PubMed  Google Scholar 

  50. Shantsila, E., Watson, T., & Lip, G. Y. (2007). Drug-induced QT-interval prolongation and proarrhythmic risk in the treatment of atrial arrhythmias. Europace, 9(Suppl 4), iv37–i44.

    PubMed  Google Scholar 

  51. Sorodoc, V., Sorodoc, L., Ungureanu, D., Sava, A., & Jaba, I. M. (2013). Troponin T and NT-proBNP as biomarkers of early myocardial damage amitriptyline-induced cardiovascular toxicity in rats. International Journal of Toxicology, 32(5), 351–357.

    Article  CAS  PubMed  Google Scholar 

  52. Su, Q., Li, L., Liu, Y. C., Zhou, Y., Lu, Y. G., & Wen, W. M. (2013). Effect of metoprolol on myocardial apoptosis and caspase-9 activation after coronary microembolization in rats. Experimental & Clinical Cardiology, 18(2), 161–165.

    Google Scholar 

  53. Thanacoody, H. K., & Thomas, S. H. (2005). Tricyclic antidepressant poisoning: Cardiovascular toxicity. Toxicological Reviews, 24(3), 205–214.

    Article  CAS  PubMed  Google Scholar 

  54. Trinkley, K. E., Lee Page, R., Lien, H., Yamanouye, K., & Tisdale, J. E. (2013). QT interval prolongation and the risk of torsades de pointes: Essentials for clinicians. Current Medical Research and Opinion, 29(12), 1719–1726.

    Article  PubMed  Google Scholar 

  55. Turlapaty, P. D. M. V., & Altura, B. M. (1980). Magnesium deficiency produces spasms of coronary arteries: Relationship to etiology of sudden death ischemic heart disease. Science, 208, 198–200.

    Article  CAS  PubMed  Google Scholar 

  56. Tzivoni, D., Banai, S., Schuger, C., Benhorin, J., Keren, A., Gottlieb, S., et al. (1988). Treatment of torsade de pointes with magnesium sulfate. Circulation, 77, 392–397.

    Article  CAS  PubMed  Google Scholar 

  57. Weinberg, G. L., Ripper, R., Murphy, P., Edelman, L. B., Hoffman, W., Strichartz, G., et al. (2006). Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Regional Anesthesia and Pain Medicine, 31, 296–303.

    Article  CAS  PubMed  Google Scholar 

  58. Weinberg, G. L., VadeBoncouer, T., Ramaraju, G. A., Garcia-Amaro, M. F., & Cwik, M. J. (1998). Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole. Anesthesiology, 88, 1071–1075.

    Article  CAS  PubMed  Google Scholar 

  59. Woolf, A. D., Erdman, A. R., Nelson, L. S., Caravati, E. M., Cobaugh, D. J., Booze, L. L., et al. (2007). Tricyclic antidepressant poisoning: An evidence-based consensus guideline for out-of-hospital management. Clinical Toxicology, 45(3), 203–233.

    Article  CAS  PubMed  Google Scholar 

  60. Yap, Y. G., & Camm, A. J. (2003). Drug induced QT prolongation and torsades de pointes. Heart, 89(11), 1363–1372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yoav, G., Odelia, G., & Shaltiel, C. (2002). A lipid emulsion reduces mortality from clomipramine overdose in rats. Veterinary and Human Toxicology, 44(1), 30–30.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Saylav Bora.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Handling Editor: Rajiv Janardhanan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bora, S., Erdoğan, M.A., Yiğittürk, G. et al. The Effects of Lipid Emulsion, Magnesium Sulphate and Metoprolol in Amitriptyline-Induced Cardiovascular Toxicity in Rats. Cardiovasc Toxicol 18, 547–556 (2018). https://doi.org/10.1007/s12012-018-9466-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-018-9466-y

Keywords

Navigation