Investigation of the Effects of Amlodipine on Paracetamol- Induced Acute Kidney Toxicity in Rats

Investigation of the Effects of Amlodipine on Paracetamol- Induced Acute Kidney Toxicity in Rats

Objective: Paracetamol is an analgesic and antipyretic agent that widely used throughout the world. The increase of the usage and its easy accessibility brings along the toxicity risk. Paracetamol toxicity may result in drug induced hepatotoxicity and nephrotoxicity. Anti-inflammatory and antioxidant effects of amlodipine which creates vasodilatation by blocking L-type calcium channels and its usage in elderly for renoprotective purposes, ponders that it might be favorable in cases with inflammation such renal damage inducted with paracetamol. Thus, aim of our study is to analyze effects of amlodipine, one of L-type calcium channel blockers, in acute renal damage inducted with paracetamol. Methods: 30 male rats consisting of 5 groups were used in our study. Groups; I: Health Control group. 2 ml Phosphate-buffered saline (PBS) oral was administered. II: 10 mg/kg Amlodipine III: Paracetamol (2g/kg) IV: 5 mg/kg Amlodipine + paracetamol V: 10 mg/kg Amlodipine + paracetamol. Rats were sacrificed after 24 hours following paracetamol administration. Results: Serum levels of creatinine and blood urea nitrogen (BUN) were increased in paracetamol group, those parameters improved in amlodipine groups. While superoxide dismutase (SOD) activity and glutathione (GSH) levels measured in kidney decreased in paracetamol group, amlodipine has significantly corrected these parameters. Meanwhile malondialdehyde (MDA) quantities increased in paracetamol group, it has been seen that in the amlodipine administered groups quantities of increased MDA have statistically significantly decreased Conclusion: This study showed that amlodipine has protective effects against paracetamol toxicity in kidney. Amlodipine revealed its protective effects by suppressing the oxidative damage and improving antioxidant activity. Amlodipine can be drug of choice in hypertensive patients with analgesic nephropathies.

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  • [1] Canayakin D, Bayir Y, Kilic Baygutalp N, Sezen Karaoglan E, Atmaca HT, Kocak Ozgeris FB, et al. Paracetamol-induced nephrotoxicity and oxidative stress in rats: the protective role of Nigella sativa. Pharm Biol. 2016;54(10):2082-2091.
  • [2] Agrawal S, Khazaeni B. Acetaminophen Toxicity. StatPearls. Treasure Island (FL)2021.
  • [3] Davidson DG, Eastham WN. Acute liver necrosis following overdose of paracetamol. Br Med J. 1966;2(5512):497-499.
  • [4] Bessems JG, Vermeulen NP. Paracetamol (acetaminophen)- induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol. 2001;31(1):55-138.
  • [5] Corcoran GB, Mitchell JR, Vaishnav YN, Horning EC. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-parabenzoquinoneimine. Mol Pharmacol. 1980;18(3):536-542.
  • [6] Nguyen NU, Stamper BD. Polyphenols reported to shift APAPinduced changes in MAPK signaling and toxicity outcomes. Chem Biol Interact. 2017;277:129-136.
  • [7] Kayaalp SO. Akılcı tedavi yönünden tıbbi farmakoloji: Pelikan Yayıncılık; 2012 (Turkish).
  • [8] Bulsara KG, Cassagnol M. Amlodipine. StatPearls. Treasure Island (FL)2021.
  • [9] Schrier RW, Arnold PE, Van Putten VJ, Burke TJ. Cellular calcium in ischemic acute renal failure: role of calcium entry blockers. Kidney Int. 1987;32(3):313-321.
  • [10] Albayrak A, Bayir Y, Halici Z, Karakus E, Oral A, Keles MS. The biochemical and histopathological investigation of amlodipine in ethylene glycol-induced urolithiasis rat model. Ren Fail. 2013;35(1):126-131.
  • [11] Coskun AK, Gunal A, Halici Z, Oral A, Seyrek M, Bayir Y. The effects of amlodipine on the biochemical and histopathological changes in the rabbit ileum subjected to ischemia-reperfusion. Eurasian J Med. 2011;43(1):33-38.
  • [12] Halici Z, Karaca M, Keles ON, Borekci B, Odabasoglu F, Suleyman H. Protective effects of amlodipine on ischemia-reperfusion injury of rat ovary: biochemical and histopathologic evaluation. Fertil Steril. 2008;90(6):2408-2415.
  • [13] Suleyman H, Halici Z, Hacimuftuoglu A, Gocer F. Role of adrenal gland hormones in antiinflammatory effect of calcium channel blockers. Pharmacol Rep. 2006;58(5):692-699.
  • [14] Chattopadhyay RR. Possible mechanism of hepatoprotective activity of Azadirachta indica leaf extract: part II. J Ethnopharmacol. 2003;89(2-3):217-219.
  • [15] Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clinical Chemistry 1988;34(3):497-500.
  • [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.
  • [17] Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry 1979;95(2):351-358.
  • [18] Bayir Y, Un H, Cadirci E, Akpinar E, Diyarbakir B, Calik I. Effects of Aliskiren, an RAAS inhibitor, on a carrageenan-induced pleurisy model of rats. Anais da Academia Brasileira de Ciências 2019;91(1): e20180106.
  • [19] Karaoglan ES, Bayir Y, Albayrak A, Toktay E, Ozgen U, Kazaz C. Isolation of Major Compounds and Gastroprotective Activity of Alchemilla Caucasica on Indomethacin Induced Gastric Ulcers in Rats. Eurasian J Med. 2020;52(3):249-253.
  • [20] Un H, Ugan RA, Kose D, Bayir Y, Cadirci E, Selli J. A novel effect of Aprepitant: Protection for cisplatin-induced nephrotoxicity and hepatotoxicity. Eur J Pharmacol. 2020;880:173168.
  • [21] Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman’s the pharmacological basis of therapeutics: McGraw- Hill Education New York; 2018.
  • [22] Ozkaya O, Genc G, Bek K, Sullu Y. A case of acetaminophen (paracetamol) causing renal failure without liver damage in a child and review of literature. Renal Failure 2010;32(9):1125- 1127.
  • [23] Prescott LF. Paracetamol overdosage-Pharmacological considerations and clinical management. Drugs 1983;25(3):290-314.
  • [24] Mazer M, Perrone J. Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management. J Med Toxicol. 2008;4(1):2-6.
  • [25] El-Sayed EM, Abd-Allah AR, Mansour AM, El-Arabey AA. Thymol and carvacrol prevent cisplatin-induced nephrotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats. J Biochem Mol Toxicol. 2015;29(4):165-172.
  • [26] Somchit MN, Sanat F, Hui GE, Wahab SI, Ahmad Z. Mefenamic Acid induced nephrotoxicity: an animal model. Adv Pharm Bull. 2014;4(4):401-404.
  • [27] Naguib YM, Azmy RM, Samaka RM, Salem MF. Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen-induced hepato-renal injury. BMC Complement Altern Med. 2014;14:494.
  • [28] Das J, Ghosh J, Manna P, Sil PC. Taurine protects acetaminophen-induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation. Toxicology. 2010;269(1):24-34.
  • [29] Li J, Tie CR, Li QX, Zheng F. Amlodipine prevents adriamycininduced toxicity in cultured rat mesangial cells by upregulation of Smad6, Smad7 expression. Environ Toxicol Phar. 2014;38(1):251-256.
  • [30] Tan H, Gepdiremen A, Halici Z. Effect of lithium and valproic acid on kainate-induced neurotoxicity in cerebral cortical cell. Asian J Chem. 2009;21(3):1769-1774.
  • [31] Albayrak A, Bayir Y, Halici Z, Karakus E, Oral A, Keles MS. The biochemical and histopathological investigation of amlodipine in ethylene glycol-induced urolithiasis rat model. Febs J. 2013;280(S1):336-337.
  • [32] Abdul Hamid Z, Budin SB, Wen Jie N, Hamid A, Husain K, Mohamed J. Nephroprotective effects of Zingiber zerumbet Smith ethyl acetate extract against paracetamol-induced nephrotoxicity and oxidative stress in rats. J Zhejiang Univ Sci B. 2012;13(3):176-785.
  • [33] Cominacini L, Fratta Pasini A, Garbin U, Pastorino AM, Davoli A, Nava C, et al. Antioxidant activity of different dihydropyridines. Biochem Biophys Res Commun. 2003;302(4):679-84. 176-185.
  • [34] Liu LL, Li QX, Xia L, Li J, Shao L. Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats. Toxicology. 2007;231(1):81-90.
  • [35] Nielsen F, Mikkelsen BB, Nielsen JB, Andersen HR, Grandjean P. Plasma malondialdehyde as biomarker for oxidative stress: Reference interval and effects of life-style factors. Clin Chem. 1997;43(7):1209-1214.
  • [36] Aycan IO, Tokgoz O, Tufek A, Alabalik U, Evliyaoglu O, Turgut H. The use of thymoquinone in nephrotoxicity related to acetaminophen. Int J Surg. 2015;13:33-37.
  • [37] Palabiyik SS, Karakus E, Halici Z, Cadirci E, Bayir Y, Ayaz G. The protective effects of carvacrol and thymol against paracetamolinduced toxicity on human hepatocellular carcinoma cell lines (HepG2). Hum Exp Toxicol. 2016;35(12):1252-1263.