Effect of Lisinopril, an Angiotensin-Converting Enzyme Inhibitor, on Fibrotic Liver Regeneration
[1]
Aysha Ambreen, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
[2]
Samina Jalali, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
[3]
Sarwat Jahan, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
[4]
Naushaba Memom, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
[5]
Riffat Gilani, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
Hepatic fibrosis resulted in defective liver regeneration following partial hepatectomy. Angiotensin converting enzyme (ACE) inhibitor, lisinopril enhances liver regeneration and reduces fibrosis. Present study is conducted to evaluate the efficacy of ACE inhibitor, lisinopril on the fibrotic liver regeneration. Six weeks old female Sprague-Dawley rats were made fibrotic by intraperitoneal administration of carbon tetrachloride at the dose of 1.5 ml/kg for seven weeks while vehicle received olive oil at the same dose for the same duration. Vehicle and fibrotic control group was given saline (1ml) while treated group received lisinopril (2.5mg/kg) orally for one week followed by two-third partial hepatectomy. Liver regeneration rate, serum functional markers, alanine aminotransferase (ALT), asparate aminotransferase (AST) and bilirubin levels were determined 24 hours post-surgery. The result indicated that lisinopril administration increased liver regeneration rate and reduced ALT, AST and bilirubin levels of fibrotic rats following partial hepatectomy. Histopathological liver evaluation showed that hepatic cell plate width was decreased, sinusoids were widened, and fibrosis was reduced by lisinopril treatment in regenerating fibrotic livers. In conclusion ACE-Inhibitor, lisinopril affected the regeneration of fibrotic liver with improved functional capability after partial hepatectomy.
Partial Hepatectomy, Hepatic Fibrosis, Alanine Aminotransferase, Asparate Aminotransferase, Bilirubin
[1]
Michalopoulos GK, DeFrances MC. Liver Regeneration. Science 1997; 276: 60-66.
[2]
Andiran F, Ayhan A, Tanyel FC, Abbasoğlu O, Sayek I. Regenerative capacities of normal and cirrhotic livers following 70% hepatectomy in rats and the effect of α-tocopherol on cirrhotic regeneration. J. Surg. Res. 2000; 89: 184-188.
[3]
Hashimoto M, Watanabe G. Functional capacity of the cirrhotic liver after partial hepatectomy in the rat. Surgery 1999; 126: 541-547.
[4]
Belghiti J, Hiramatsu K, Benoist S, Massault P, Sauvanet A, Farges O. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg. 2000; 191: 38-46.
[5]
Ramalho FS, Ramalho LNZ, Castro-e-Silva Júnior O, Zucoloto S, Corrêa FMA. Angiotensin-converting enzyme inhibition by lisinopril enhances liver regeneration in rats. Brazilian Journal of Medical and Biological Research 2001; 34: 125-127.
[6]
Yayama K, Sugiyama K, Miyagi R, Okamoto H. Angiotensin-converting enzyme inhibitor enhances liver regeneration following partial hepatectomy: involvement of bradykinin B2 and angiotensin AT1 receptors. Biological and Pharmaceutical Bulletin 2007; 30: 591-594.
[7]
Koh SL, Ager E, Malcontenti-Wilson C, Muralidharan V, Christophi C. Blockade of the renin–angiotensin system improves the early stages of liver regeneration and liver function. Journal of Surgical Research 2013; 179: 66-71.
[8]
Tuncer I, Ozbek H, Ugras H, Ugras S, Bayram I. Anti-fibrogenic effects of captopril and candesartan cilexetil on the hepatic fibrosis development in rat: The effect of AT1-R blocker on the hepatic fibrosis. Experimental and Toxicologic Pathology 2003; 55: 159-166.
[9]
Toblli JE, Muñoz MC, Cao G, Mella J, Pereyra L, Mastai R. ACE inhibition and AT1 receptor blockade prevent fatty liver and fibrosis in obese Zucker rats. Obesity 2008; 16: 770-776.
[10]
Huang ML, Li X, Meng Y, Xiao B, Ma Q, Ying SS, Wu PS, Zhang ZS. Upregulation of angiotensin-converting enzyme (ACE) 2 in hepatic fibrosis by ACE inhibitors. Clinical and Experimental Pharmacology and Physiology 2010; 37: e1-e6.
[11]
Reese LJ, Tider DS, Stivala AC, Fishbein DA. Effects of Angiotensin Converting Enzyme Inhibitors on Liver Fibrosis in HIV and Hepatitis C Coinfection. AIDS research and treatment 2012; doi:10.1155/2012/978790.
[12]
Özbek H, Uğraş S, Dülger H, Bayram I, Tuncer I, Öztürk G, Öztürk A. Hepatoprotective effect of Foeniculum vulgare essential oil. Fitoterapia 2003; 74:317-319.
[13]
Higgins GM, Anderson RM. Experimental pathology of the liver-Restoration of the liver of the white rat following partial surgical removal. Arch. Pathol. 1931; 12: 186-202.
[14]
Fishback, FC. A morphologic study of regeneration of the liver after partial removal. Arch. Pathol. 1929; 7: 955-977.
[15]
Nakano N, Moriguchi A, Morishita R, Kida I, Tomita N, Matsumoto K, Nakamura T, Higaki J, Ogihara T. Role of angiotensin II in the regulation of a novel vascular modulator, hepatocyte growth factor (HGF), in experimental hypertensive rats. Hypertension 1997; 30: 1448-1454.
[16]
Matsumoto K, Morishita R, Moriguchi A, Tomita N, Yo Y, Nishii T, Matsumoto K, Nakamura T, Higaki J, Ogihara T. Prevention of renal damage by angiotensin II blockade accompanied by increased renal hepatocyte growth factor in experimental hypertensive rats. Hypertension 1999; 34: 279-284.
[17]
Day RM, Thiel G, Lum J, Chévere RD, Yang Y, Stevens J, Sibert L, Fanburg BL. Hepatocyte growth factor regulates angiotensin converting enzyme expression. Journal of Biological Chemistry 2004; 279: 8792-8801.
[18]
Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S. Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342: 440-443.
[19]
Aly HF, Mohamad HE, Soliman AM, Shams SGE. Role of melatonin in management of partially hepatectomized and/or propagated-cirrhotic livers of rats. Int. J. Pharm. Sci. Rev. Res. 2014; 26: 11-31.
[20]
Morsy MA. Protective Effect of Lisinopril on Hepatic Ischemia/reperfusion Injury in Rats. Indian Journal of Pharmacology 2011; 43: 652-655.
[21]
Wei HS, Lu HM, Li DG, Zhan YT, Wang ZR, Huang X, Cheng JL, Xu QF. The regulatory role of AT 1 receptor on activated HSCs in hepatic fibrogenesis: effects of RAS inhibitors on hepatic fibrosis induced by CCl4. World Journal of Gastroenterology 2000; 6: 824-828.
[22]
Abd-Allah OM, Sharaf EI, Din AA. Evaluation of antifibrotic and antioxidant effects of olmesartan medoximil, a new angiotensin II blocker, on experimentally-induced liver fibrosis in rats. Journal of the Egyptian Society of Pharmacology and Experimental therapeutics 2008; 29: 553-577.
[23]
Newberry EP, Kennedy SM, Xie Y, Luo J, Stanley SE, Semenkovich CF, Crooke RM, Graham MJ, Davidson NO. Altered hepatic triglyceride content after partial hepatectomy without impaired liver regeneration in multiple murine genetic models. Hepatology 2008; 48: 1097-1105.
[24]
Ohishi T, Saito H, Tsusaka K, Toda K, Inagaki H, Hamada Y, Kumagai N, Atsukawa K, Ishii, H. Anti-fibrogenic effect of an angiotensin converting enzyme inhibitor on chronic carbon tetrachloride-induced hepatic fibrosis in rats. Hepatology research 2001; 21: 147-158.
[25]
Auch-Schwelk W, Bossaller C, Claus M, Graf K, Gräfe M, Fleck E. Local potentiation of bradykinin-induced vasodilation by converting-enzyme inhibition in isolated coronary arteries. Journal of cardiovascular pharmacology 1992; 20: S62-S67.
[26]
Witherow FN, Helmy A, Webb DJ, Fox KA, Newby DE. Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure. Circulation 2001; 104: 2177-2181.
