Deneysel Olarak İntraabdominal Sepsis Oluşturulan Ratlarda Amiodaronun Böbrekler Üzerindeki Koruyucu Etkilerinin Değerlendirilmesi

Öz

Amaç: Bu çalışmada, sıçanlarda intraabdominal sepsis deney modelinde amiodaronun böbrek koruyucu potansiyeli araştırılmıştır.

Gereç ve Yöntemler: Toplam 100 erkek Wistar sıçanı beş gruba ayrılmıştır: sham cerrahi uygulanan bir kontrol grubu; sham cerrahi uygulanan ve 50 mg/kg dozunda amiodaron verilen bir kontrol grubu; çekal ligasyon ve perforasyon (CLP) uygulanan bir grup; CLP uygulanan ve 25 mg/kg dozunda amiodaron verilen bir grup; ve CLP uygulanan ve 50 mg/kg dozunda amiodaron verilen bir grup. Sepsis modelini oluşturmak için CLP tekniği kullanılmış ve amiodaron, ameliyat sırasında bir tüp aracılığıyla ağız yoluyla verilmiştir.

Bulgular: CLP ile indüklenen sepsis, kreatinin, üre, malondialdehit, IL-1β mRNA ve TNF-α mRNA düzeylerinde anlamlı bir artışa neden olmuştur; buna paralel olarak, süperoksit dismutaz ve glutatyon düzeylerinde anlamlı bir azalma gözlenmiştir. Amiodaron, bu değişiklikleri doza bağlı bir şekilde tersine çevirdi. 50 mg/kg'lık doz, tüm biyokimyasal, moleküler ve histolojik parametrelerde en kapsamlı iyileşmeye yol açtı.

Sonuç: Sonuçlar, amiodaronun sepsisle ilişkili akut böbrek hasarını hafifletebileceğini göstermektedir. Bu etki muhtemelen ilacın antioksidan ve antienflamatuar özelliklerinin birleşimi yoluyla ortaya çıkmaktadır.

Anahtar Kelimeler

• sepsis
• akut böbrek yetmezliği
• amiodaron
• aksidatif stres
• inflamasyon
• hayvan

Destekleyen Kurum

Bu çalışma Atatürk Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi tarafından desteklenmiştir.

Etik Beyan

Bu çalışma için Atatürk Üniversitesi Tıp Fakültesi Yerel Hayvan Etik Kurulu'ndan 31.05.2013 tarihli ve 1/16 sayılı etik onay alınmış ve çalışma Helsinki Bildirgesi kurallarına uygun olarak yürütülmüştür.

Evaluation of the Protective Effects of Amiodarone on the Kidneys in Rats with Experimentally Induced Intra-Abdominal Sepsis

Öz

Objective: This study examined the renoprotective potential of amiodarone in an experimental rat model of intra-abdominal sepsis.

Materials and Methods: A total of 100 male Wistar rats were distributed into five groups: sham-operated controls, sham controls receiving amiodarone 50 mg/kg, cecal ligation and puncture (CLP), CLP with amiodarone 25 mg/kg, and CLP with amiodarone 50 mg/kg. The CLP technique was employed to establish the sepsis model, and amiodarone was delivered orally via gavage at the time of surgery.

Results: Sepsis induction via CLP caused significant increases in creatinine, urea, malondialdehyde, IL-1β mRNA, and TNF-α mRNA, accompanied by significant decreases in superoxide dismutase and glutathione. Amiodarone reversed these alterations in a dose-dependent manner, with the 50 mg/kg dose producing the most comprehensive improvements across all biochemical, molecular, and histological measures.

Conclusion: The results suggest that amiodarone may mitigate sepsis-associated acute kidney injury, an effect likely mediated through its combined antioxidant and anti-inflammatory properties.

Anahtar Kelimeler

• sepsis
• acute kidney injury
• amiodarone
• oxidative stress
• inflammation
• animal

Destekleyen Kurum

This study was supported by Atatürk University Scientific Research Projects Coordination Unit

Etik Beyan

Ethical permission was obtained from the Atatürk University, Medical Faculty Local Animal Ethics Committee for this study with date 31.05.2013 and number 1/16 and Helsinki Declaration rules were followed to conduct this study.

Kaynakça

1. Caltekin I, Koksal A, Aygun A, Saribas MS, Tomakin M. Prognostic Value of a Novel Lactate-shock Index for 28-day Mortality in Adult Sepsis Patients. The Medical Bulletin of Haseki. 2025;63(2):55-61. https://doi.org/10.4274/haseki.galenos.2025.10042
2. Rudd KE, Johnson SC, Agesa KM, M., Shackelford K. A., Tsoi D., Kievlan D. R, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. The Lancet. 2020;395(10219):200-11. https://doi.org/10.1016/S0140-6736(19)32989-7
3. Cao C, Yu M, Chai Y. Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis. Cell death & disease. 2019;10(10):782. https://doi.org/10.1038/s41419-019-2015-1
4. Husabø G, Nilsen RM, Flaatten H, Solligård E., Frich J. C., Bondevik G. T., et al. Early diagnosis of sepsis in emergency departments, time to treatment, and association with mortality: an observational study. PloS one. 2020;15(1):e0227652. https://doi.org/10.1371/journal.pone.0227652
5. Jarczak D, Kluge S, Nierhaus A. Sepsis-pathophysiology and therapeutic concepts. Frontiers in medicine. 2021;8:628302. https://doi.org/10.3389/fmed.2021.628302
6. Dubois-Deruy E, Peugnet V, Turkieh A, Pinet F. Oxidative stress in cardiovascular diseases. Antioxidants. 2020;9(9):864. https://doi.org/10.3390/antiox9090864
7. Ow CPC, Trask-Marino A, Betrie AH, Evans RG, May CN, Lankadeva YR. Targeting Oxidative Stress in Septic Acute Kidney Injury: From Theory to Practice. Journal of Clinical Medicine. 2021;10(17):3798. https://doi.org/10.3390/jcm10173798
8. Jian Z, Guo H, Liu H, Cui H., Fang J., Zuo Z et al. Oxidative stress, apoptosis and inflammatory responses involved in copper-induced pulmonary toxicity in mice. Aging (Albany NY). 2020;12(17):16867. https://doi.org/10.18632/aging.103585

9. Mallat J, Rahman N, Hamed F, Hernandez G., Fischer M. O. Pathophysiology, mechanisms, and managements of tissue hypoxia. Anaesthesia Critical Care & Pain Medicine. 2022;41(4):101087. https://doi.org/10.1016/j.accpm.2022.101087
10. Liu J, Xie H, Ye Z, Li F, Wang L. Rates, predictors, and mortality of sepsis-associated acute kidney injury: a systematic review and meta-analysis. BMC Nephrology. 2020;21(1):318. https://doi.org/10.1186/s12882-020-01974-8
11. Mujović N, Dobrev D, Marinković M, Russo V, Potpara T. S. The role of amiodarone in contemporary management of complex cardiac arrhythmias. Pharmacological Research. 2020;151:104521. https://doi.org/10.1016/j.phrs.2019.104521
12. Medić F, Bakula M, Alfirević M, Bakula M., Mucić K., Marić N. Amiodarone and thyroid dysfunction. Acta clinica Croatica. 2022;61(2):327-41. https://doi.org/10.20471/acc.2022.61.02.20
13. Polat B, Cadirci E, Halici Z, Bayir Y., Unal D., Bilgin B. C., et al. The protective effect of amiodarone in lung tissue of cecal ligation and puncture-induced septic rats: a perspective from inflammatory cytokine release and oxidative stress. Naunyn-Schmiedeberg's archives of pharmacology. 2013;386(7):635-43. https://doi.org/10.1007/s00210-013-0862-3
14. Matsumori A, Ono K, Nishio R, Nose Y., Sasayama, S. Amiodarone inhibits production of tumor necrosis factor-alpha by human mononuclear cells: a possible mechanism for its effect in heart failure. Circulation. 1997;96(5):1386-9. https://doi.org/10.1161/01.CIR.96.5.1386
15. Halici Z, Dengiz GO, Odabasoglu F, Suleyman H, Cadirci E, Halici M. Amiodarone has anti-inflammatory and anti-oxidative properties: an experimental study in rats with carrageenan-induced paw edema. European Journal of Pharmacology. 2007;566(1-3):215-221. https://doi.org/10.1016/j.ejphar.2007.03.046
16. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Analytical Biochemistry. 1968;25(1):192-205. https://doi.org/10.1016/0003-2697(68)90092-4
17. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001 Dec;25(4):402-8. doi: 10.1006/meth.2001.1262.
18. Singer M, Deutschman CS, Seymour CW., Shankar-Hari M., Annane D., Bauer M., et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama. 2016;315(8):801-10. https://doi.org/10.1001/jama.2016.0287
19. Zarbock A, Nadim MK, Pickkers P, Gomez H., Bell S., Joannidis M., et al. Sepsis-associated acute kidney injury: consensus report of the 28th Acute Disease Quality Initiative workgroup. Nature reviews Nephrology. 2023;19(6):401-17. https://doi.org/10.1038/s41581-023-00683-3
20. Ide T, Tsutsui H, Kinugawa S, Utsumi H., Takeshita, A.. Amiodarone protects cardiac myocytes against oxidative injury by its free radical scavenging action. Circulation. 1999;100(7):690-2. https://doi.org/10.1161/01.CIR.100.7.690
21. Nicolescu AC, Ji Y, Comeau JL, Hill B. C., Takahashi T., Brien J., et al. Direct mitochondrial dysfunction precedes reactive oxygen species production in amiodarone-induced toxicity in human peripheral lung epithelial HPL1A cells. Toxicology and applied pharmacology. 2008;227(3):370-9. https://doi.org/10.1016/j.taap.2007.12.009
22. Doi K, Leelahavanichkul A, Yuen PS, Star RA. Animal models of sepsis and sepsis-induced kidney injury. The Journal of clinical investigation. 2009;119(10):2868-78. https://doi.org/10.1172/JCI39421
23. Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA. Immunodesign of experimental sepsis by cecal ligation and puncture. Nature protocols. 2009;4(1):31-6. https://doi.org/10.1038/nprot.2008.214
24. Zarbock A, Gomez H, Kellum JA. Sepsis-induced acute kidney injury revisited: pathophysiology, prevention and future therapies. Current opinion in critical care. 2014;20(6):588-95. https://doi.org/10.1097/MCC.0000000000000153
25. Morales AI, Barata JD, Bruges M, Arévalo M. A., González de Buitrago J. M., Palma P., et al. Acute renal toxic effect of amiodarone in rats. Pharmacology & toxicology. 2003;92(1):39-42. https://doi.org/10.1034/j.1600-0773.2003.920107.x
26. Macdonald J, Galley HF, Webster NR. Oxidative stress and gene expression in sepsis. British journal of anaesthesia. 2003;90(2):221-32. https://doi.org/10.1093/bja/aeg034
27. Haddad JJ. Antioxidant and prooxidant mechanisms in the regulation of redox(y)-sensitive transcription factors. Cellular signalling. 2002;14(11):879-97. https://doi.org/10.1016/S0898-6568(02)00053-0
28. Crimi E, Sica V, Williams-Ignarro S, Zhang H., Slutsky A. S., Ignarro L. J., et al. The role of oxidative stress in adult critical care. Free Radical Biology and Medicine. 2006;40(3):398-406. https://doi.org/10.1016/j.freeradbiomed.2005.10.054
29. Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4‐hydroxy‐2‐nonenal. Oxidative medicine and cellular longevity. 2014;2014(1):360438. https://doi.org/10.1155/2014/360438
30. Donnahoo KK, Shames BD, Harken AH, Meldrum DR. The role of tumor necrosis factor in renal ischemia-reperfusion injury. The Journal of urology. 1999;162(1):196-203. https://doi.org/10.1097/00005392-199907000-00068
31. Wang N, Mao L, Yang L, Zou J., Liu K., Liu M., et al. Resveratrol protects against early polymicrobial sepsis-induced acute kidney injury through inhibiting endoplasmic reticulum stress-activated NF-κB pathway. Oncotarget. 2017;8(22):36449. https://doi.org/10.18632/oncotarget.16860