Potential role of angiotensin converting enzyme/neprilysin pathway and protective effects of omapatrilat for paracetamol‑induced acute liver injury

Aksakalli-Magden,Zeynep Berna; Ugan,Rustem Anil; Toktay,Erdem; Halici,Zekai; Cadirci,Elif

doi:10.3892/etm.2022.11765

Potential role of angiotensin converting enzyme/neprilysin pathway and protective effects of omapatrilat for paracetamol‑induced acute liver injury

Authors:
- Zeynep Berna Aksakalli-Magden
- Rustem Anil Ugan
- Erdem Toktay
- Zekai Halici
- Elif Cadirci
View Affiliations

Affiliations: Department of Pharmacology, Faculty of Medicine, Ataturk University, 25240 Erzurum, Turkey, Department of Pharmacology, Faculty of Pharmacy, Ataturk University, 25240 Erzurum, Turkey, Department of Histology and Embryology, Faculty of Medicine, Kafkas University, 36100 Kars, Turkey
Published online on: December 12, 2022 https://doi.org/10.3892/etm.2022.11765
Article Number: 66

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The renin‑angiotensin‑aldosterone system (RAAS) is an important pathway that contributes to the pathophysiology of acute liver injury due to paracetamol toxicity. Omapatrilat, a RAAS‑acting agent, inhibits both angiotensin converting enzyme (ACE) and neprilysin/neutral endopeptidase (NEP). The aim of the present study was to investigate the hepatoprotective effects of omapatrilat and examine the role of ACE/NEP pathway on the physiopathology of paracetamol toxicity. A total of 56 BALB/c mice were separated into seven groups: Control, 40 mg/kg omapatrilat only, 400 mg/kg paracetamol only, paracetamol and 140 mg/kg N‑acetylcysteine and three groups with paracetamol and 10‑40 mg/kg omapatrilat. Blood and liver tissue samples were studied through histopathological imaging, alanine transaminase (ALT) and aspartate transaminase (AST) liver function tests and oxidant/antioxidant biomarker measurements including superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA). ACE and NEP activities were also measured. Histopathological analysis revealed that paracetamol toxicity resulted in a number of apoptotic and necrotic cells in liver tissue samples. By contrast, with 40 mg/kg omapatrilat administration in toxicity‑induced mice, hepatocytes were significantly improved and exhibited similar appearance to the control group. Biochemical measurements also supported these histopathological results. Omapatrilat pretreatment provided a dose‑dependent reduction in oxidative stress and reversed paracetamol toxicity indications by reducing ALT and AST activities, increasing SOD activity and GSH levels and reducing MDA levels. Dose‑dependent increase of ACE and NEP enzymes in omapatrilat groups was also observed. The results demonstrated promotion of antioxidant activity by omapatrilat and suppression of oxidative stress associated with acute liver injury. These findings revealed the potential role of ACE/NEP pathway in paracetamol toxicity and hepatoprotective effects of omapatrilat against oxidative stress.

View Figures

View References

1	Penna A and Buchanan N: Paracetamol poisoning in children and hepatotoxicity. Br J Clin Pharmacol. 32:143–149. 1991.PubMed/NCBI View Article : Google Scholar
2	Kurtovic J and Riordan S: Paracetamol-induced hepatotoxicity at recommended dosage. J Intern Med. 253:240–243. 2003.PubMed/NCBI View Article : Google Scholar
3	Morthorst BR, Erlangsen A, Nordentoft M, Hawton K, Hoegberg LCG and Dalhoff KP: Availability of paracetamol sold over the counter in Europe: A descriptive cross-sectional international survey of pack size restriction. Basic Clin Pharmacol Toxicol. 122:643–649. 2018.PubMed/NCBI View Article : Google Scholar
4	Steventon GB, Mitchell SC and Waring RH: Human metabolism of paracetamol (acetaminophen) at different dose levels. Drug Metabol Drug Interact. 13:111–117. 1996.PubMed/NCBI View Article : Google Scholar
5	Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR and Brodie BB: Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther. 187:195–202. 1973.PubMed/NCBI
6	Nilsson JLÅ, Blomgren A, Nilsson UJ, Högestätt ED and Grundemar L: N,N'-Bis(2-mercaptoethyl)isophthalamide binds electrophilic paracetamol metabolites and prevents paracetamol-induced liver toxicity. Basic Clin Pharmacol Toxicol. 123:589–593. 2018.PubMed/NCBI View Article : Google Scholar
7	Yayla M, Halici Z, Unal B, Bayir Y, Akpinar E and Gocer F: Protective effect of Et-1 receptor antagonist bosentan on paracetamol induced acute liver toxicity in rats. Eur J Pharmacol. 726:87–95. 2014.PubMed/NCBI View Article : Google Scholar
8	El-Demerdash E, Salam OM, El-Batran SA, Abdallah HM and Shaffie NM: Inhibition of the renin-angiotensin system attenuates the development of liver fibrosis and oxidative stress in rats. Clin Exp Pharmacol Physiol. 35:159–167. 2008.PubMed/NCBI View Article : Google Scholar
9	Stokkeland K, Lageborn CT, Ekbom A, Höijer J, Bottai M, Stål P and Söderberg-Löfdal K: Statins and angiotensin-converting enzyme inhibitors are associated with reduced mortality and morbidity in chronic liver disease. Basic Clin Pharmacol Toxicol. 122:104–110. 2018.PubMed/NCBI View Article : Google Scholar
10	Aroor AR, Demarco VG, Jia G, Sun Z, Nistala R, Meininger GA and Sowers JR: The role of tissue renin-angiotensin-aldosterone system in the development of endothelial dysfunction and arterial stiffness. Front Endocrinol (Lausanne). 4(161)2013.PubMed/NCBI View Article : Google Scholar
11	Bataller R, Gäbele E, Schoonhoven R, Morris T, Lehnert M, Yang L, Brenner DA and Rippe RA: Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver. Am J Physiol. 285:G642–G651. 2003.PubMed/NCBI View Article : Google Scholar
12	Bataller R, Gäbele E, Parsons CJ, Morris T, Yang L, Schoonhoven R, Brenner DA and Rippe RA: Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct-ligated rats. Hepatology. 41:1046–1055. 2005.PubMed/NCBI View Article : Google Scholar
13	Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology. 134:1655–1669. 2008.PubMed/NCBI View Article : Google Scholar
14	Mollnau H, Wendt M, Szöcs K, Lassègue B, Schulz E, Oelze M, Li H, Bodenschatz M, August M, Kleschyov AL, et al: Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res. 90:E58–E65. 2002.PubMed/NCBI View Article : Google Scholar
15	Landmesser U, Spiekermann S, Preuss C, Sorrentino S, Fischer D, Manes C, Mueller M and Drexler H: Angiotensin II induces endothelial xanthine oxidase activation: Role for endothelial dysfunction in patients with coronary disease. Arterioscler Thromb Vasc Biol. 27:943–948. 2007.PubMed/NCBI View Article : Google Scholar
16	Bataller R, Ginès P, Nicolás JM, Görbig MN, Garcia-Ramallo E, Gasull X, Bosch J, Arroyo V and Rodés J: Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology. 118:1149–1156. 2000.PubMed/NCBI View Article : Google Scholar
17	Hitomi H, Kiyomoto H and Nishiyama A: Angiotensin II and oxidative stress. Curr Opin Cardiol. 22:311–315. 2007.PubMed/NCBI View Article : Google Scholar
18	Yeung JH: Effect of sulphydryl drugs on paracetamol-induced hepatotoxicity in mice. Drug Metabol Drug Interact. 6:295–301. 1988.PubMed/NCBI View Article : Google Scholar
19	Karcioglu SS, Palabiyik SS, Bayir Y, Karakus E, Mercantepe T, Halici Z and Albayrak A: The role of RAAS inhibition by aliskiren on paracetamol-induced hepatotoxicity model in rats. J Cell Biochem. 117:638–646. 2016.PubMed/NCBI View Article : Google Scholar
20	McDowell G, Coutie W, Shaw C, Buchanan KD, Struthers AD and Nicholls DP: The effect of the neutral endopeptidase inhibitor drug, candoxatril, on circulating levels of two of the most potent vasoactive peptides. Br J Clin Pharmacol. 43:329–332. 1997.PubMed/NCBI View Article : Google Scholar
21	Mangiafico S, Costello-Boerrigter LC, Andersen IA, Cataliotti A and Burnett JC Jr: Neutral endopeptidase inhibition and the natriuretic peptide system: An evolving strategy in cardiovascular therapeutics. Eur Heart J. 34:886–893c. 2013.PubMed/NCBI View Article : Google Scholar
22	Gerwig T, Meissner H, Bilzer M, Kiemer AK, Arnholdt H, Vollmar AM and Gerbes AL: Atrial natriuretic peptide preconditioning protects against hepatic preservation injury by attenuating necrotic and apoptotic cell death. J Hepatol. 39:341–348. 2003.PubMed/NCBI View Article : Google Scholar
23	Kiemer AK, Gerbes AL, Bilzer M and Vollmar AM: The atrial natriuretic peptide and cGMP: Novel activators of the heat shock response in rat livers. Hepatology. 35:88–94. 2002.PubMed/NCBI View Article : Google Scholar
24	Sekino M, Makita T, Ureshino H, Sungsam C and Sumikawa K: Synthetic atrial natriuretic peptide improves systemic and splanchnic circulation and has a lung-protective effect during endotoxemia in pigs. Anesth Analg. 110:141–147. 2010.PubMed/NCBI View Article : Google Scholar
25	Kostis JB, Packer M, Black HR, Schmieder R, Henry D and Levy E: Omapatrilat and enalapril in patients with hypertension: The omapatrilat cardiovascular treatment vs enalapril (OCTAVE) trial. Am J Hypertens. 17:103–111. 2004.PubMed/NCBI View Article : Google Scholar
26	Quaschning T, d'Uscio LV, Shaw S and Lüscher TF: Vasopeptidase inhibition exhibits endothelial protection in salt-induced hypertension. Hypertension. 37:1108–1113. 2001.PubMed/NCBI View Article : Google Scholar
27	Dong Y, Zhou H, Shaffer E, Atamas N, Liao WC and Wei C: The cardiovascular actions of omapatrilat in spontaneously hypertensive rats. Curr Hypertens Rep. 3 (Suppl 2):S1–S5. 2001.PubMed/NCBI View Article : Google Scholar
28	Taal MW, Nenov VD, Wong W, Satyal SR, Sakharova O, Choi JH, Troy JL and Brenner BM: Vasopeptidase inhibition affords greater renoprotection than angiotensin-converting enzyme inhibition alone. J Am Soc Nephrol. 12:2051–2059. 2001.PubMed/NCBI View Article : Google Scholar
29	Song Z, Cui Y, Ding MZ, Jin HX and Gao Y: Protective effects of recombinant human brain natriuretic peptide against LPS-Induced acute lung injury in dogs. Int Immunopharmacol. 17:508–512. 2013.PubMed/NCBI View Article : Google Scholar
30	Kostakoglu U, Topcu A, Atak M, Tumkaya L, Mercantepe T and Uydu HA: The protective effects of angiotensin-converting enzyme inhibitor against cecal ligation and puncture-induced sepsis via oxidative stress and inflammation. Life Sci. 241(117051)2020.PubMed/NCBI View Article : Google Scholar
31	Ugan RA, Un H, Gurbuz MA, Kaya G, Kahramanlar A, Aksakalli-Magden ZB, Halici Z and Cadirci E: Possible contribution of the neprilysin/ACE pathway to sepsis in mice. Life Sci. 258(118177)2020.PubMed/NCBI View Article : Google Scholar
32	Hayek T, Hamoud S, Keidar S, Pavlotzky E, Coleman R, Aviram M and Kaplan M: Omapatrilat decreased macrophage oxidative status and atherosclerosis progression in atherosclerotic apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 43:140–147. 2004.PubMed/NCBI View Article : Google Scholar
33	Lapointe N, Nguyen QT, Desjardins JF, Marcotte F, Pourdjabbar A, Moe G, Calderone A and Rouleau JL: Effects of pre-, peri-, and postmyocardial infarction treatment with omapatrilat in rats: Survival, arrhythmias, ventricular function, and remodeling. Am J Physiol Heart Circ Physiol. 285:H398–H405. 2003.PubMed/NCBI View Article : Google Scholar
34	Canayakin D, Bayir Y, Baygutalp NK, Karaoglan ES, Atmaca HT, Ozgeris FBK, Keles MS and Halici Z: Paracetamol-induced nephrotoxicity and oxidative stress in rats: The protective role of Nigella sativa. Pharm Biol. 54:2082–2091. 2016.PubMed/NCBI View Article : Google Scholar
35	Randle LE, Sathish JG, Kitteringham NR, Macdonald I, Williams DP and Park BK: alpha(1)-Adrenoceptor antagonists prevent paracetamol-induced hepatotoxicity in mice. Br J Pharmacol. 153:820–830. 2008.PubMed/NCBI View Article : Google Scholar
36	Patterson AD, Shah YM, Matsubara T, Krausz KW and Gonzalez FJ: Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity. Hepatology. 56:281–290. 2012.PubMed/NCBI View Article : Google Scholar
37	Scialis RJ, Ghanem CI and Manautou JE: The modulation of transcriptional expression and inhibition of multidrug resistance associated protein 4 (MRP4) by analgesics and their primary metabolites. Curr Res Toxicol. 1:34–41. 2020.PubMed/NCBI View Article : Google Scholar
38	Palabiyik SS, Karakus E, Akpinar E, Halici Z, Bayir Y, Yayla M and Kose D: The role of urotensin receptors in the paracetamol-induced hepatotoxicity model in mice: Ameliorative potential of urotensin II antagonist. Basic Clin Pharmacol Toxicol. 118:150–159. 2016.PubMed/NCBI View Article : Google Scholar
39	Ferah I, Halici Z, Bayir Y, Demirci E, Unal B and Cadirci E: The role of infliximab on paracetamol-induced hepatotoxicity in rats. Immunopharmacol Immunotoxicol. 35:373–381. 2013.PubMed/NCBI View Article : Google Scholar
40	Sun Y, Oberley LW and Li Y: A simple method for clinical assay of superoxide dismutase. Clin Chem. 34:497–500. 1988.PubMed/NCBI
41	Ohkawa H, Ohishi N and Yagi K: Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 95:351–358. 1979.PubMed/NCBI View Article : Google Scholar
42	Ugan RA, Cadirci E, Halici Z, Toktay E and Cinar I: The role of urotensin-II and its receptors in sepsis-induced lung injury under diabetic conditions. Eur J Pharmacol. 818:457–469. 2018.PubMed/NCBI View Article : Google Scholar
43	Cigremis Y, Turel H, Adiguzel K, Akgoz M, Kart A, Karaman M and Ozen H: The effects of acute acetaminophen toxicity on hepatic mRNA expression of SOD, CAT, GSH-Px, and levels of peroxynitrite, nitric oxide, reduced glutathione, and malondialdehyde in rabbit. Mol Cell Biochem. 323:31–38. 2009.PubMed/NCBI View Article : Google Scholar
44	Betto MRB, Lazarotto LF, Watanabe TT, Driemeier D, Leite CE and Campos MM: Effects of treatment with enalapril on hepatotoxicity induced by acetaminophen in mice. Naunyn Schmiedebergs Arch Pharmacol. 385:933–943. 2012.PubMed/NCBI View Article : Google Scholar
45	Bessems JG and Vermeulen NP: Paracetamol (acetaminophen)-induced toxicity: Molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol. 31:55–138. 2001.PubMed/NCBI View Article : Google Scholar
46	Karatas E, Bayraktutan Z and Cadirci E: Investigation of the effects of amlodipine on paracetamol-induced acute kidney toxicity in rats. Clin Exp Health Sci. 12:155–161. 2022.
47	Kalsi SS, Dargan PI, Waring WS and Wood DM: A review of the evidence concerning hepatic glutathione depletion and susceptibility to hepatotoxicity after paracetamol overdose. Open Access Emerg Med. 3:87–96. 2011.PubMed/NCBI View Article : Google Scholar
48	Castañeda-Arriaga R, Pérez-González A and Galano A: Chemical protectors against the toxic effects of paracetamol (acetaminophen) and its meta analogue: Preventing protein arylation. ACS Omega. 3:18582–18591. 2018.
49	Ip SP, Kwan PC, Williams CH, Pang S, Hooper NM and Leung PS: Changes of angiotensin-converting enzyme activity in the pancreas of chronic hypoxia and acute pancreatitis. Int J Biochem Cell Biol. 35:944–954. 2003.PubMed/NCBI View Article : Google Scholar
50	Hoshida S, Kato J, Nishino M, Egami Y, Takeda T, Kawabata M, Tanouchi J, Yamada Y and Kamada T: Increased angiotensin-converting enzyme activity in coronary artery specimens from patients with acute coronary syndrome. Circulation. 103:630–633. 2001.PubMed/NCBI View Article : Google Scholar