Endoteli Sağlam ve Hasarlı Aort Dokusunda Paroksetin ve Sitalopram Kasılma Kuvvetini Nasıl Etkiler?

Öz

Amaç: Depresyon kardiyovasküler hastalığı olanlarda yaygın olarak görülmektedir. En sık kullanılan antidepresan ilaçlar olan serotonin geri alım inhibitörlerinin (SSRI'lar) potansiyel kardiyovasküler etkilerine ilişkin klinik veriler tartışmalıdır. Mevcut çalışmada sitalopram ve paroksetinin sıçanların endotel sağlam ve hasarlı aort dokularındaki kas kontraksiyonuna etkilerinin karşılaştırılması hedeflenmiştir. Materyal ve Metod: Endotel Sağlam Aort Paroksetin (HEParox), Endotel Hasarlı Aort Paroksetin (DEParox), Endotel Sağlam Aort Sitalopram (HECital), Endotel Hasarlı Aort Sitalopram (DECital) grubu olarak ayrılan 12 adet erkek Wistar Albino cinsi sıçandan torasik aort doku kesitleri çıkarıldı. Dokular izole organ banyosu sistemine yerleştirildi. Endotel sağlam gruplara 10-6 M fenilefrin (PE) uygulanarak maksimum kasılma elde edildi. Endotel hasarlı gruplardaki aort kesitlerine endotel hasarı oluşturulup 10-6 M PE verildi. 10-6 M asetilkolin (Ach) uygulanarak endotel hasarı kontrol edildikten sonra ikinci doz PE uygulanarak maksi-mum kasılmalar kaydedildi. Kasılmalar plato çizince ilgili gruplara 10-8 – 10-3 M paroksetin ve sitalopram dozları kümülatif olarak uygulandı. PE verilmeden önceki 10. dakika ile verildikten sonraki 10. dakika ve her ilaç dozu uygulamasından sonraki 5 dakika-lık sürede meydana gelen kas gerim parametreleri değerlendirildi. Çalışmanın istatistiksel analizleri R 4.3.1 programıyla gerçek-leştirildi. Bulgular: Paroksetin ve sitalopram aort kasılmasında zamana bağlı önemli ölçüde farklı değişikliklere neden oldu; sitalopram, hem sağlıklı hem de hasarlı endotelde paroksetinden daha güçlü bir inhibitör etki gösterdi (p < .001). Gerim değerlerinin zamana göre değişimi grup içinde ikişerli karşılaştırıldığında anlamlı farklılıklar saptandı (p < .05). Zaman içi gerim değerleri gruplar arasında karşılaştırıldığında anlamlı farklılıklar tespit edildi (p < .001). Sonuç: Paroksetin ve sitalopram endoteli sağlam aort dokusunda doza bağlı baskılanmış bir kontraktil yanıt meydana getirmiş-tir. Endoteli hasarlı aort dokusunda ise yalnız sitalopram baskılanmış bir kontraktil yanıt meydana getirmiştir. Bu sonuç sitalop-ramın endotelden bağımsız, paroksetinin ise endotele bağımlı bir şekilde etkinlik gösterdiğini ortaya koymaktadır. Paroksetin ve sitalopram gibi sık tercih edilen SSRI türü antidepresan ilaçların kardiyovasküler hastalık durumlarındaki kullanımlarının güvenli-ği ve etkinliği hakkında daha fazla araştırmaya ihtiyaç bulunmaktadır.

Anahtar Kelimeler

• Aort
• Kardiyovasküler
• Kasılma
• Paroksetin
• Sitalopram.

How Do Paroxetine and Citalopram Affect the Force of Contraction in Endothelially Investigated and Damaged Aortic Tissue?

Öz

Background: Depression is common in patients with cardiovascular disease. Clinical data on the potential cardiovascular effects of the most commonly used antidepressant drugs, serotonin reuptake inhibitors (SSRI), are controversial. The present study aimed to compare the effects of citalopram and paroxetine on muscle contraction in endothelial intact and damaged aortic tissues of rats. Materials and Methods: Thoracic aortic tissue sections were removed from 12 male Wistar Albino rats divided into Healthy Endothelium Aorta Paroxetine (HEParox), Damaged Endothelium Aorta Paroxetine (DEParox), Healthy Endothelium Aorta Citalopram (HECital), Damaged Endothelium Aorta Citalopram (DECital) groups. The tissues were placed in the isolated organ bath system. Maximum contraction was obtained by adding 10-6 M phenylephrine (PE) to the endothelium intact groups. Endot-helial damage was created in the aorta sections in the endothelium damaged groups and 10-6 M PE was given. After controlling the endothelial damage by adding 10-6 M acetylcholine (Ach), a second dose of PE was added and maximum contractions were recorded. When the contractions reached a plateau, cumulative doses of 10-8 – 10-3 M paroxetine and citalopram were added to the relevant groups. Muscle tension parameters occurring 10 minutes before PE addition, 10 minutes after addition, and 5 minutes after each drug dose were evaluated. Statistical analyses of the study were performed with the R 4.3.1 program. Results: Paroxetine and citalopram caused significantly different time-dependent changes in aortic contraction, with citalopram exerting a stronger inhibitory effect than paroxetine in both healthy and damaged endothelium (p < .001). When the change in tension values over time was compared in pairs within the group, significant differences were detected (p < .05). When the tension values over time were compared between the groups, significant differences were detected (p < .001). Conclusions: Paroxetine and citalopram produced a dose-dependent suppressed contractile response in endothelial-intact aortic tissue. In endothelial-damaged aortic tissue, only citalopram produced a suppressed contractile response. This result demonst-rates that citalopram is endothelium-independent, whereas paroxetine is endothelium-dependent. More research is needed on the safety and efficacy of frequently preferred SSRI antidepressant drugs such as paroxetine and citalopram in cardiovascular disease conditions

Anahtar Kelimeler

• Aorta
• Cardiovascular
• Contraction
• Paroxetine
• Citalopram.

Kaynakça

1. 1. Galiuto L, Locorotondo G. Cardiovascular Aging. Integr Cardiol. Springer; Cham, Switzerland: 2017; (9):109–120. doi: 10.1007/978-3-319-40010-5_9.
2. 2. Steeman M, Lande G. Cardiac aging and heart disease in hu-mans. Biophys Rev. 2017;9:131–137. doi: 10.1007/s12551-017-0255-9
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. Fan H, Yu W, Zhang Q, Cao H, Li J, Wang J, et al. Depression after heart failure and risk of cardiovascular and all-cause mor-tality: a meta-analysis. Prev Med. 2014 Jun;63:36-42. doi: 10.1016/j.ypmed.2014.03.007.
5. 5. Ramamurthy G, Trejo E, Faraone SV. Depression treatment in patients with coronary artery disease: a systematic review. Prim Care Companion CNS Disord. 2013;15(5):PCC.13r01509. doi: 10.4088/PCC.13r01509.
6. 6. Shanmugasegaram S, Russell KL, Kovacs AH, Stewart DE, Grace SL. Gender and sex differences in prevalence of major depres-sion in coronary artery disease patients: a meta-analysis. Matu-ritas. 2012; 73(4): 305-11. doi: 10.1016/j.maturitas.2012.09.005.
7. 7. Meijer A, Conradi HJ, Bos EH, Thombs BD, van Melle JP, de Jonge P. Prognostic association of depression following myo-cardial infarction with mortality and cardiovascular events: a meta-analysis of 25 years of research. Gen Hosp Psychiatry. 2011;33(3):203-216. doi:10.1016/j.genhosppsych.2011.02.007
8. 8. Gan Y, Gong Y, Tong X, Sun H, Cong Y, Dong X, et al. Depression and the risk of coronary heart disease: a meta-analysis of pros-pective cohort studies. BMC Psychiatry. 2014; 14:371. doi: 10.1186/s12888-014-0371-z.

9. 9. Behlke LM, Lenze EJ, Carney RM. The Cardiovascular Effects of Newer Antidepressants in Older Adults and Those With or At High Risk for Cardiovascular Diseases. CNS Drugs. 2020 Nov;34(11):1133-1147. doi: 10.1007/s40263-020-00763-z.
10. 10. 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
11. 11. Işık B, Ozen Koca R, Solak Gormus ZI, Solak H, Özdemir A, Emek-siz A. “Vasoactive Effects of Fluoxetine in Rat Thoracic Aorta Smooth Muscle”. Cukurova Med J. vol. 47, no. 2, 2022, pp. 729-37, doi:10.17826/cumj.1085783.
12. 12. Calvi A, Fischetti I, Verzicco I, Belvederi Murri M, Zanetidou S, Volpi R, et al. Antidepressant Drugs Effects on Blood Pressure. Front Cardiovasc Med. 2021 Aug 3;8:704281. doi: 10.3389/fcvm.2021.704281.
13. 13. Hofferer A, Dolladille C, Chretien B, Sassier M, Laugier D, At-zenhoffer M, et al. Antidépresseurs et hypertension artérielle: étude cas /non-cas dans la base nationale de pharmacovigilance (Antidepressive agents and hypertension: A case/no-case study in French pharmacovigilance database). Encephale. 2022 Aug;48(4):404-408. French. doi: 10.1016/j.encep.2021.04.009.
14. 14. Rami M, Guillamat-Prats R, Rinne P, Salvermoser M, Ring L, Bianchini M, et al. Chronic Intake of the Selective Serotonin Reuptake Inhibitor Fluoxetine Enhances Atherosclerosis. Arte-rioscler Thromb Vasc Biol. 2018 May;38(5):1007-1019. doi: 10.1161/ATVBAHA.117.310536.
15. 15. de Oliveira CM, Raimundo RD, de Souza IS, Dos Santos Chagas A, Folegatti DRMA, Dos Santos GC, et al. The effect of paroxetine on heart rate variability in patients with major depressive di-sorder: A systematic review and meta-analysis. J Affect Disord. 2024 Jun 15;355:200-209. doi: 10.1016/j.jad.2024.03.071..
16. 16. Sun X, Zhou M, Wen G, Huang Y, Wu J, Peng L, et al. Paroxetine Attenuates Cardiac Hypertrophy Via Blocking GRK2 and ADRB1 Interaction in Hypertension. J Am Heart Assoc. 2021 Jan 5;10(1):e016364. doi: 10.1161/JAHA.120.016364.
17. 17. Alonazi AS, Almodawah S, Aldigi R, Bin Dayel A, Alamin M, Almo-tairi AR, et al. Potential cardioprotective effect of paroxetine against ventricular remodeling in an animal model of myocar-dial infarction: a comparative study. BMC Pharmacol Toxicol. 2024 Dec 18;25(1):99. doi: 10.1186/s40360-024-00824-9.
18. 18. Waddingham MT, Tsuchimochi H, Sonobe T, Sequeira V, Na-yeem MJ, Shirai M, et al. The selective serotonin reuptake in-hibitor paroxetine improves right ventricular systolic function in experimental pulmonary hypertension. J Mol Cell Cardiol Plus. 2024 Mar 26;8:100072. doi: 10.1016/j.jmccpl.2024.100072.
19. 19. Unis A, Abdelbary A, Hamza M. Comparison of the effects of HECitalopram and atorvastatin on diet-induced atherosclerosis in rats. Can J Physiol Pharmacol. 2014 Mar;92(3):226-33. doi: 10.1139/cjpp-2013-0168.
20. 20. Wanstall JC, Fiore SA, Gambino A, Chess-Williams R. Potentia-tion of 5-hydroxytryptamine (5-HT) responses by a 5-HT uptake inhibitor in pulmonary and systemic vessels: effects of exposing rats to hypoxia. Naunyn Schmiedebergs Arch Pharmacol. 2003 Dec;368(6):520-7. doi: 10.1007/s00210-003-0823-3.
21. 21. Ng QX, Venkatanarayanan N, Ho CYX, Sim WS, Lim DY, Yeo WS. Selective Serotonin Reuptake Inhibitors and Persistent Pulmo-nary Hypertension of the Newborn: An Update Meta-Analysis. J Womens Health (Larchmt). 2019 Mar;28(3):331-338. doi: 10.1089/jwh.2018.7319.
22. 22. Morecroft I, Loughlin L, Nilsen M, Colston J, Dempsie Y, Sheward J, et al. Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries. J Pharmacol Exp Ther. 2005 May;313(2):539-48. doi: 10.1124/jpet.104.081182.
23. 23. Lekakis J, Ikonomidis I, Papoutsi Z, Moutsatsou P, Nikolaou M, Parissis J, et al. Selective serotonin re-uptake inhibitors decrea-se the cytokine-induced endothelial adhesion molecule expression, the endothelial adhesiveness to monocytes and the circulating levels of vascular adhesion molecules. Int J Cardiol. 2010 Mar 4;139(2):150-8. doi: 10.1016/j.ijcard.2008.10.010.
24. 24. Kokras N, Papadopoulou E, Georgiopoulos G, Dalla C, Petropou-los I, Kontogiannis C, et al. The effect of treatment response on endothelial function and arterial stiffness in depression. A prospective study. J Affect Disord. 2019;252:190-200. doi:10.1016/j.jad.2019.04.024
25. 25. Namdar H, Khani E, Khiali S, Safaie N, Ameli H, Rahbari Banaeian G, et al. Effects of citalopram on blood pressure control in dep-ressive patients with hypertension: A randomized clinical trial. J Cardiovasc Thorac Res. 2024;16(1):49-54. doi: 10.34172/jcvtr.31849.
26. 26. Kacar E, Tan F, Sahinturk S, Zorlu G, Serhatlioglu I, Bulmus O, et al. Modulation of melatonin receptors regulates reproductive physiology: the ımpact of agomelatine on the estrus cycle, ges-tation, offspring, and uterine contractions in rats. Physiol Res. 2023 Dec 31;72(6):793-807. doi: 10.33549/physiolres.935064.
27. 27. Akkoca A, Sen A, Kutlu S. The Dose-Dependent Effects of Du-loxetine on the Mechanical Muscle Activities of Rat Diaph-ragms. Selcuk Med J 2024;40(3):19-23. doi: 10.30733/std.2024.01753
28. 28. Gerö D, Szoleczky P, Suzuki K, Módis K, Oláh G, Coletta C, et al. Cell-based screening identifies paroxetine as an inhibitor of di-abetic endothelial dysfunction. Diabetes. 2013;62(3):953-964. doi:10.2337/db12-0789
29. 29. Higashi CM, Sartoretto SM, Echem C, Lucchetti BFC, Carvalho MHC, Pelosi GG, et al. Intrauterine and lactational exposure to fluoxetine enhances endothelial modulation of aortic contracti-le response in adult female rats. Vascul Pharmacol. 2018;108:67-73. doi:10.1016/j.vph.2018.04.004
30. 30. Nurullahoglu-Atalık KE, Kutlu S, Solak H, Ozen Koca R. Agomela-tine-induced responses in rat aorta. Int J of Basic Med Sci Pharm. 2017;7(1):7-10.
31. 31. Ribback S, Pavlovic D, Herbst D, Nedeljkov-Jancic R, Wendt M, Nedeljkov V, et al. Effects of amitriptyline, fluoxetine, tranylcypromine and venlafaxine on rat vascular smooth muscle in vitro--the role of the endothelium. J Physiol Pharmacol. 2012;63(2):119-125.
32. 32. Chrapko W, Jurasz P, Radomski MW, Archer SL, Newman SC, Baker G, et al. Alteration of decreased plasma NO metabolites and platelet NO synthase activity by paroxetine in depressed patients. Neuropsychopharmacology. 2006;31(6):1286-1293. doi:10.1038/sj.npp.1300961.