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Beneficial effects of edaravone in experimental model of amitriptyline-induced cardiotoxicity in rats

  • Nursah Basol
  • Hatice AygunEmail author
  • Serdar Savas Gul
Original Article
  • 9 Downloads

Abstract

Amitriptyline (AMT) cardiotoxicity is commonly seen with high morbidity and mortality rates in emergency departments. Nevertheless, there are still no effective treatment options for amitriptyline-induced cardiotoxicity. The aim of the present study was to evaluate the effects of edaravone, a potent antioxidant and free radical scavenger, in rats by electrocardiographic (ECG), biochemical, and scintigraphic methods. Twenty-eight male Wistar rats were randomly divided into four groups as untreated control (CON), amitriptyline-induced cardiotoxicity (AMT), edaravone treatment (EDO), and amitriptyline + edaravone treatment (AMT+EDO). Cardiotoxicity was induced by intraperitoneal (i.p.) injection of a single-dose amitriptyline (100 mg/kg). Edaravone was administered at a dose of 30 mg/kg (i.p.) after amitriptyline injection. ECG, biochemical, and scintigraphic changes due to edaravone were analyzed. AMT cardiotoxicity was characterized with conduction abnormalities (increased QRS complex, T wave, and duration of QT interval and elevation of ST segment amplitude), elevated 99mTechnetium Pyrophosphate (99mTc-PYP) uptake level, and increased cardiac troponin T level (cTnT). Edaravone treatment significantly decreased all amitriptyline-associated conduction abnormalities in ECG (p < 0.001), 99mTc-PYP uptake (p < 0.001), and serum cTnT level (p < 0.001). 99mTc-PYP scintigraphy can show amitriptyline cardiotoxicity as well as ECG abnormalities and increased values of cTnT. According to the results of the present study, edaravone has strong beneficial effects on amitriptyline-induced cardiotoxicity.

Keywords

Amitriptyline Cardiotoxicity ECG Edaravone Rat 99mTc-PYP 

Notes

Author’s contributions

HA: Research concept and design. HA, NB, SSG: Conducting experiments, data collecting, analysis and interpretation of data. HA: Preparation of article and revisions. All authors read and approved the final version of the manuscript.

Compliance with ethical standards

The experimental protocol of this study was approved by the Tokat Gaziosmanpasa University Local Ethical Committee for Animal Experiments (HADYEK-2017/26).

Conflict of interests

The authors declare that they have no conflict of interest.

References

  1. Acosta D, Ramos K (1984) Cardiotoxicity of tricyclic antidepressants in primary cultures of rat myocardial cells. J Toxicol Environ Health 14(2–3):137–143CrossRefGoogle Scholar
  2. Aksar AT, Yuksel N, Gok M, Cekmen M, Caglar Y (2015) Neuroprotective effect of edaravone in experimental glaucoma model in rats: a immunofluorescence and biochemical analysis. Int J Ophthalmol 8(2):239Google Scholar
  3. Alzoubi KH, Shatnawi A, Al-Qudah MA, Alfaqih MA (2019) Edaravone prevents memory impairment in an animal model of post-traumatic distress. Behav Pharmacol 30(2):201–207CrossRefGoogle Scholar
  4. Arıcı MA, Buyukdeligoz M, Kalkan S, Tuncok Y (2013) Effects of BQ-788 on amitriptyline-induced cardiovascular toxicity. Hum Exp Toxicol 32(3):316–322CrossRefGoogle Scholar
  5. Aygun H, Gül SS (2019) Protective effect of edaravone on adriamycin-induced cardiotoxicity in rats. Cumhuriyet Med J 41:10–18Google Scholar
  6. Bakshi TK, Choo MK, Edwards CC, Scott AG, Hart HH, Armstrong GP (2002) Causes of elevated troponin I with a normal coronary angiogram. Intern Med J 32(11):520–525CrossRefGoogle Scholar
  7. Basol N, Erbas O (2016) The effects of diltiazem and metoprolol in QTc prolongation due to amitriptyline intoxication. Hum Exp Toxicol 35(1):29–34CrossRefGoogle Scholar
  8. Clark S, Catt JW, Caffery T (2015) Rapid diagnosis and treatment of severe tricyclic antidepressant toxicity. BMJ Case Rep 2015:bcr2015211428CrossRefGoogle Scholar
  9. Diener HC, Holle D, Dresler T, Gaul C (2018) Chronic headache due to overuse of analgesics and anti-migraine agents. Dtsch Arztebl Int 115(22):365–370Google Scholar
  10. Einstein AJ, Shuryak I, Castano A, Mintz A, Maurer MS, Bokhari S (2018) Estimating cancer risk from 99mTc pyrophosphate imaging for transthyretin cardiac amyloidosis. J Nucl Cardiol:1–10.  https://doi.org/10.1007/s12350-018-1307-7
  11. Elbaradey GF, Elshmaa NS, Hodeib H (2016) Role of edaravone in managemant of septic peritonitis. J Anaesthesiol Clin Pharmacol 32(4):465CrossRefGoogle Scholar
  12. Emekli-Alturfan E, Alev B, Tunali S, Oktay S, Tunali-Akbay T, Ozturk LK, Yanardag R, Yarat A (2015) Effects of edaravone on cardiac damage in valproic acid induced toxicity. Ann Clin Lab Sci 45(2):166–172Google Scholar
  13. Foster HE Jr, Hanno PM, Nickel JC et al (2010) Effect of amitriptyline on symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. J Urol 183:1853–1858CrossRefGoogle Scholar
  14. Giwa A, Oey E (2018) The return of an old nemesis: survival after severe tricyclic antidepressant toxicity, a case report. Toxicol Rep 10(5):357–362CrossRefGoogle Scholar
  15. Gul SS, Aygun H (2018) Cardioprotective effect of vitamin D and melatonin on doxorubicin-induced cardiotoxicity in rat model: an electrocardiographic, scintigraphic and biochemical study. European Res J.  https://doi.org/10.18621/eurj.410029
  16. Hassan MQ, Akhtar MS, Akhtar M, Ali J, Haque SE, Najmi AK (2015) Edaravone protects rats against oxidative stress and apoptosis in experimentally induced myocardial infarction: biochemical and ultrastructural evidence. Redox Rep 20(6):275–281CrossRefGoogle Scholar
  17. Hassan MQ, Akhtar MS, Akhtar M, Ali J, Haque SE, Najmi AK (2016) Edaravone, a potent free radical scavenger and a calcium channel blocker attenuate isoproterenol induced myocardial infarction by suppressing oxidative stress, apoptotic signaling and ultrastructural damage. Ther Adv Cardiovasc Dis 10(4):214–223CrossRefGoogle Scholar
  18. Häuser W, Wolfe F, Tölle T, Uçeyler N, Sommer C (2012) The role of antidepressants in the management of fibromyalgia syndrome: a systematic review and meta-analysis. CNS Drugs 26:297–307CrossRefGoogle Scholar
  19. He C, Zhang W, Li S, Ruan W, Xu J, Xiao F (2018) Edaravone improves septic cardiac function by inducing an HIF-1α/HO-1 pathway. Oxidative Med Cell Longev 2018:5216383Google Scholar
  20. Higgins JP, Higgins JA (2003) Elevation of cardiac troponin I indicates more than myocardial ischemia. Clin Invest Med 26:133–147Google Scholar
  21. Ikegami E, Fukazawa R, Kanbe M, Watanabe M, Abe M, Watanabe M, Ogawa S (2007) Edaravone, a potent free radical scavenger, prevent santhracycline-induced myocardial cell death. Circ J 71(11):1815–1820CrossRefGoogle Scholar
  22. Isoda H, Itagaki Y, Nomura N et al (1999) Usefulness of dual SPECT with Tc-99m pyrophosphate and Tl-201 to predict further events after acute myocardial infarction with single-vessel coronary artery disease. Clin Nucl Med 24(4):227–231CrossRefGoogle Scholar
  23. Kassim T, Mahfood Haddad T, Rakhra A et al (2018) A case of amitriptyline-induced myocarditis. Cureus 10(6):e2840Google Scholar
  24. Kerr GW, McGuffie AC, Wilkie S (2001) Tricyclic antidepressant overdose: a review. Emerg Med J 18(4):236–241CrossRefGoogle Scholar
  25. Kikuchi K, Tancharoen S, Takeshige N, Yoshitomi M, Morioka M, Murai Y, Tanaka E (2013) The efficacy of edaravone (radicut), a free radical scavenger, for cardiovascular disease. Int J Mol Sci 14(7):13909–13930CrossRefGoogle Scholar
  26. Kiyan S, Aksay E, Yanturali S, Atilla R, Ersel M (2006) Acute myocardial infarction associated with amitriptyline overdose. Basic Clin Pharmacol Toxicol 98(5):462–466CrossRefGoogle Scholar
  27. Mochizuki T, Murase K, Higashino H, Miyagawa M, Sugawara Y, Kikuchi T, Ikezoe J (2002) Ischemic “memory image” in acute myocardial infarction of 123I-BMIPP after reperfusion therapy: a comparison with 99mTc-pyrophosphate and 201Tl dual-isotope SPECT. Ann Nucl Med 16(8):563–568CrossRefGoogle Scholar
  28. Olgun H, Yildirim ZK, Karacan M, Ceviz N (2009) Clinical, electrocardiographic, and laboratory findings in children with amitriptyline intoxication. Pediatr Emerg Care 25(3):170–173CrossRefGoogle Scholar
  29. Sorodoc V, Sorodoc L, Ungureanu D, Sava A, Jaba IM (2013) Cardiac troponin T and NT-proBNP as biomarkers of early myocardial damage in amitriptyline-induced cardiovascular toxicity in rats. Int J Toxicol 32(5):351–357CrossRefGoogle Scholar
  30. Tokumaru O, Shuto Y, Ogata K, Kamibayashi M, Bacal K, Takei H, Yokoi I, Kitano T (2018) Dose-dependency of multiple free radical-scavenging activity of edaravone. J Surg Res 228:147–153CrossRefGoogle Scholar
  31. Xin Y, Zhang S, Gu L, Liu S, Gao H, You Z, Xuan Y (2011) Electrocardiographic and biochemical evidence for the cardioprotective effect of antioxidants in acute doxorubicin-induced cardiotoxicity in the beagle dogs. Biol Pharm Bull 34(10):1523–1526CrossRefGoogle Scholar
  32. Yamawaki M, Sasaki N, Shimoyama M, Miake J, Ogino K, Igawa O, Hisatome I (2004) Protective effect of edaravone against hypoxia-reoxygenation injury in rabbit cardiomyocytes. British J Pharm 142(3):618–626CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Emergency MedicineFaculty of Medicine, Tokat Gaziosmanpasa UniversityTokatTurkey
  2. 2.Department of PhysiologyFaculty of Medicine, Tokat Gaziosmanpasa UniversityTokatTurkey
  3. 3.Department of Nuclear MedicineFaculty of Medicine, Tokat Gaziosmanpasa UniversityTokatTurkey

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