How does agomelatine affect contraction in rat myocardial tissue?

Abstract

Objectives: Cardiovascular diseases and depression are frequently seen together. Despite the developments in the treatment efficacy of agomelatine, a widely used antidepressant, its safety profile on cardiac tissue has not been sufficiently investigated. The aim of this study was to evaluate effects of agomelatine on contraction in rat myocardial tissue in depression and anxiety conditions frequently encountered in cardiovascular diseases and after cardiac surgery.

Methods: Myocardial tissue sections were removed from 12 male Wistar Albino rats divided into control and agomelatine groups. The tissues were placed in the isolated organ bath system. Maximum contraction was achieved by applying 10^-1 M adrenaline to both groups. When the contraction plateaued, the same volume of vehicle as agomelatine were applied to the Control group. Agomelatine cumulative doses (10^-8 – 10^-4 M) were applied to the agomelatine group. The resulting isometric contraction forces were recorded by the isolated organ bath system. The statistical analyses of the study were performed with the R 4.3.1 program.

Results: A significant increase in the tension of the tissues was observed with adrenaline in both the Control and Agomelatine groups. In the Agomelatine group, the tension at 10^-8 agomelatine dose was significantly lower compared to 10^-1 M adrenaline dose (P<0.05), and tension at 10^-6 agomelatine dose was significantly lower compared to 10^-7 agomelatine dose (P<0.05).

Conclusions: Agomelatine produced a dose-dependent suppressed contractile response in myocardial tissue. This suggests that it may have positive effects on increased blood pressure, positive inotropic effect and hypertensive state, which can occur in cardiovascular diseases and are also common in depression. Agomelatine may have a more favorable side effect profile than other antidepressants in cardiovascular disease states.

Keywords

• Agomelatine
• antidepressant
• cardiovascular disease
• contraction
• myocardium

References

1. 1. Patterson SL, Marcus M, Goetz M, Vaccarino V, Gooding HC. Depression and anxiety are associated with cardiovascular health in young adults. J Am Heart Assoc. 2022;11(24):e027610. doi: 10.1161/JAHA.122.027610.
2. 2. Tully PJ, Harrison NJ, Cheung P, Cosh S. Anxiety and cardiovascular disease risk: a review. Curr Cardiol Rep. 2016;18(12):120. doi:10.1007/s11886-016-0800-3.
3. 3. Hare DL, Toukhsati SR, Johansson P, Jaarsma T. Depression and cardiovascular disease: a clinical review. Eur Heart J. 2014:35(21):1365-1372. doi: 10.1093/eurheartj/eht462.
4. 4. Gan Y, Gong Y, Tong X, et al. Depression and the risk of coronary heart disease: a meta-analysis of prospective cohort studies. BMC Psychiatry. 2014;14:371. doi: 10.1186/s12888-014-0371-z.
5. 5. Macchi MM, Bruce JN. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol. 2004;25(3-4):177-195. doi: 10.1016/j.yfrne.2004.08.001.
6. 6. Reiter RJ, Tan DX. Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res. 2003;58(1):10-19. doi: 10.1016/s0008-6363(02)00827-1.
7. 7. Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005;27(2):101-110. doi: 10.1385/ENDO:27:2:101.
8. 8. Yao K, Zhao YF, Zu HB. Melatonin receptor stimulation by agomelatine prevents Aβ-induced tau phosphorylation and oxidative damage in PC12 cells. Drug Des Devel Ther. 2019 21;13:387-396. doi: 10.2147/DDDT.S182684.

9. 9. Solak Gormus ZI, Eker CB, Solak H, Ozen Koca R, Ozdengul F. Does sertraline affect contraction in endothelium damaged aorta? Selcuk Med J. 2024;40(1):8-15. doi: 10.30733/std.2023.01688.
10. 10. Isık B, Ozen Koca R, Solak Gormus ZI, Solak H, Özdemir A, Emeksiz A. Vasoactive effects of fluoxetine in rat thoracic aorta smooth muscle. Cukurova Med J. 2022;47(2):729-737. doi:10.17826/cumj.1085783.
11. 11. de Bodinat C, Guardiola-Lemaitre B, Mocaër E, Renard P, Muñoz C, Millan MJ. Agomelatine, the first melatonergic antidepressant: discovery, characterization and development. Nat Rev Drug Discov. 2010;9(8):628-642. doi: 10.1038/nrd3140. Epub 2010 Jun 25.
12. 12. Sansone RA, Sansone LA. Agomelatine: a novel antidepressant. Innov Clin Neurosci. 2011;8(11):10-14.
13. 13. Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005;27(2):101-110. doi: 10.1385/ENDO:27:2:101.
14. 14. Asci H, Ozmen O, Erzurumlu Y, Sofu A, Icten P, Kaynak M. Agomelatine protects heart and aorta against lipopolysaccharide-induced cardiovascular toxicity via inhibition of NF-kβ phosphorylation. Drug Chem Toxicol. 2022;45(1):133-142. doi: 10.1080/01480545.2019.1663209.
15. 15. Singh P, Gupta S, Sharma B. Melatonin receptor and KATP channel modulation in experimental vascular dementia. Physiol Behav. 2015;142:66-78. doi: 10.1016/j.physbeh.2015.02.009.
16. 16. Kacar E, Tan F, Sahinturk S, et al. Modulation of melatonin receptors regulates reproductive physiology: the ımpact of agomelatine on the estrus cycle, gestation, offspring, and uterine contractions in rats. Physiol Res. 2023;72(6):793-807. doi: 10.33549/physiolres.935064.
17. 17. Nurullahoglu-Atalık KE, Kutlu S, Solak H, Ozen Koca R. Agomelatine-induced responses in rat aorta. IJBMSP. 2017;7(1):7-10.
18. 18. Jia P, Liu C, Wu N, Jia D, Sun Y. Agomelatine protects against myocardial ischemia reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Transl Res. 2018;10(5):1310-1323.
19. 19. Hafez HM, Waz S, El-Tahawy NFG, Mohamed MZ. Agomelatine ameliorates cadmium-induced toxicity through the modification of HMGB-1/TLR-4/NFκB pathway. Toxicol Appl Pharmacol. 2022;457:116313. doi: 10.1016/j.taap.2022.116313.
20. 20. Khalaf HM, Abdalla AM, Ahmed AF, Abdel-Aziz AM. Role of nitric oxide in mediating the cardioprotective effect of agomelatine against isoproterenol-induced myocardial injury in rats. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(10):1809-1823. doi: 10.1007/s00210-020-01860-y
21. 21. Aygun H, Gul SS. Cardioprotective effect of melatonin and agomelatine on doxorubicin-induced cardiotoxicity in a rat model: an electrocardiographic, scintigraphic and biochemical study. Bratisl Lek Listy. 2019;120(4):249-255. doi: 10.4149/BLL_2019_045.