Correlation between Amitriptyline-Induced Cardiotoxic Effects and Cardiac S100b Protein in Isolated Rat Hearts

Abstract

Background: Amitriptyline is an important cause of mortality due to its cardiovascular toxicity. Aims: To investigate the changes in levels of cardiac S100b protein on amitriptyline-induced cardiotoxicity and also to examine the correlation between amitriptyline-induced cardiotoxic effects and cardiac S100b protein in an isolated rat heart model. Study Design: Animal experimentation, isolated heart model. Methods: After a stabilization period, isolated hearts were randomized to two groups (n=5 and n=7). In the control group, isolated hearts were subjected to an infusion of 5% dextrose for 60 minutes. In the amitriptyline group, 5.5×10-5 M amitriptyline was infused for 60 minutes to achieve amitriptyline toxicity. After the infusion period, heart tissues were removed for histological examination. Results: In comparison to control treatment, amitriptyline infusion decreased left ventricular developed pressure (LVDP), dp/dtmax and heart rate (HR) and significantly prolonged QRS duration (p<0.05). The semiquantitative scores for S100b protein levels in amitriptyline-infused hearts were higher than in the control group (p<0.01). At the end of the experiment, in the amitriptyline-infused group, significant correlations were found between LVDP and S100b protein scores (r=-0.807, p=0.003) and between QRS duration and S100b protein scores (r=0.859, p=0.001). Conclusion: Our results indicate that the S100b protein may be a helpful indicator or biomarker in studying the cardiotoxic effects of amitriptyline.

Keywords

• S100b protein, amitriptyline, toxicity, isolated heart, rat

References

1. 1. Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol Rev 2005;24:205-14. [CrossRef]
2. 2. Pimentel L, Trommer L. Cyclic antidepressant overdoses. Emerg Med Clin North Am 1994;12:533-47.
3. 3. Shannon M, Liebelt EL. Toxicology reviews: Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: The pivotal role for alkalinization and sodium loading. Pediatr Emerg Care 1998;14:293-8. [CrossRef]
4. 4. Gürsoy M, Büyükuysal RL. Mechanism of S100b release from rat cortical slices determined under basal and stimulated conditions. Neurochem Res 2010;35:429-36. [CrossRef]
5. 5. Donato R. S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol 2001;33:637-68. [CrossRef]
6. 6. Kahn HJ, Baumal R, Van Eldik LJ, Dunn RJ, Marks A. Immunoreactivity of S100 beta in heart, skeletal muscle, and kidney in chronic lung disease: possible induction by cAMP. Mod Pathol 1991;4:698-701.
7. 7. Tsoporis JN, Marks A, Kahn HJ, Butany JW, Liu PP, O’Hanlon D, et al. Inhibition of norepinephrine-induced cardiac hypertrophy in S100beta transgenic mice. J Clin Invest 1998;102:1609- 16. [CrossRef]
8. 8. Rothermundt M, Arolt V, Wiesmann M, Missler U, Peters M, Rudolf S, et al. S-100B is increased in melancholic but not in non-melancholic major depression. J Affect Disord 2001;66:89- 93. [CrossRef]

9. 9. Tsoporis JN, Mohammadzadeh F, Parker TG. S100B: a multifunctional role in cardiovascular pathophysiology. Amino Acids 2011;41:843-7. [CrossRef]
10. 10. Mazzini GS, Schaf DV, Oliveira AR, Gonçalves CA, BellóKlein A, Bordignon S, et al. The ischemic rat heart releases S100B. Life Sci 2005;77:882-9. [CrossRef]
11. 11. Haring JH, Hagan A, Olson J, Rodgers B. Hippocampal serotonin levels influence the expression of S100 beta detected by immunocytochemistry. Brain Res 1993;631:119-23. [CrossRef]
12. 12. Manev R, Uz T, Manev H. Fluoxetine increases the content of neurotrophic protein S100b in the rat hippocampus. Eur J Pharmacol 2001;420:R1-2. [CrossRef]
13. 13. Manev H, Uz T, Manev R. Glia as a putative target for antidepressant treatments. J Affect Disord 2003;75:59-64. [CrossRef]
14. 14. Akhisaroglu M, Manev R, Akhisaroglu E, Uz T, Manev H. Both aging and chronic fluoxetine increase S100B content in the mouse hippocampus. Neuro Report 2003;14:1471-3. [CrossRef]
15. 15. Manev R, Manev H. Could treatment with arundic acid (ONO2506) increase vulnerability for depression? Med Hypotheses 2006;67:1170-2. [CrossRef]
16. 16. Manev H, Manev R. Olanzapine and S100 proteins. Neuropsychopharmacology 2006;31:2567. [CrossRef]
17. 17. Hocaoglu N, Kalkan S, Buyukdeligoz M, Oransay K, Tuncok Y. Is serum S100B protein a biomarker for amitriptyline-induced cardiovascular toxic effects? Cardiovasc Toxicol 2012;12:115- 22. [CrossRef]
18. 18. Akgun A, Kalkan S, Hocaoglu N, Gidener S, Tuncok Y. Effects of adenosine receptor antagonists on amitriptyline-induced QRS prolongation in isolated rat hearts. Clin Toxicol (Phila) 2008;46:677-85. [CrossRef]
19. 19. Akgun Arici MA, Kalkan S, Demir O, Hocaoglu Aksay N, Gidener S, Tuncok Y. Does adenosine A(1) receptor stimulation causes QRS prolongation by blocking beta adrenergic receptors in amitriptyline poisoning? Toxicol Lett 2009;186:130-8. [CrossRef]
20. 20. Micili SC, Goker A, Sayin O, Akokay P, Ergur BU. The effect of lipoic acid on wound healing in a full thickness uterine injury model in rats. J Mol Hist 2013;4:339-45. [CrossRef]
21. 21. Tuzun F, Gencpınar P, Ozbal S, Dilek M, Ergur BU, Duman N, et al. Neuroprotective effect of neotrofin in a neonatal rat model of periventricular leukomalacia. Neurosci Lett 2012;520:6-10. [CrossRef]
22. 22. Olgun H, Yildirim ZK, Karacan M, Ceviz N. Clinical, electrocardiographic, and laboratory findings in children with amitriptyline intoxication. Pediatr Emerg Care 2009;25:170-3. [CrossRef]
23. 23. Buckley NA, Chevalier S, Leditschke IA, O’Connell DL, Leitch J, Pond SM. The limited utility of electrocardiography variables used to predict arrhythmia in psychotropic drug overdose. Crit Care 2003;7:R101-7. [CrossRef]
24. 24. van Boven WJ, Morariu A, Salzberg SP, Gerritsen WB, Waanders FG, Korse TC, et al. Impact of different surgical strategies on perioperative protein S100β release in elderly patients undergoing coronary artery bypass grafting. Innovations (Phila) 2013;8:230-6. [CrossRef]
25. 25. Di Legge S, Di Piero V, Di Stani F, Perna R, Gattuso R, Reale MG, et al. Carotid endarterectomy and gliofibrillar S100b protein release. Neurol Sci 2003;24:351-6. [CrossRef]
26. 26. Tsoporis JN, Izhar S, Leong-Poi H, Desjardins JF, Huttunen HJ, Parker TG. S100B interaction with the receptor for advanced glycation end products (RAGE): a novel receptor-mediated mechanism for myocyte apoptosis postinfarction. Circ Res 2010;106:93-101. [CrossRef