Two drugs with paradoxical effects on liver regeneration through antiangiogenesis and antifibrosis: Losartan and Spironolactone: A pharmacologic dilemma on hepatocyte proliferation

• Published in: The Journal of surgical research Vol. 179; no. 1; pp. 60 - 65
• Main Authors: Parlakgumus, Alper, MD, Colakoglu, Tamer, MD, Kayaselcuk, Fazilet, MD, Colakoglu, Sule, MD, Ezer, Ali, MD, Calskan, Kenan, MD, Karakaya, Jale, PhD, Yildirim, Sedat, MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2013
• Subjects: Aldosterone antagonist; Angiogenesis; Angiogenesis Inhibitors - pharmacology; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin receptor antagonist; Animals; Anti-Inflammatory Agents - pharmacology; Cell Proliferation - drug effects; Female; Fibrosis; Hepatectomy; Hepatocytes - pathology; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver regeneration; Liver Regeneration - drug effects; Liver Regeneration - physiology; Losartan - pharmacology; Mineralocorticoid Receptor Antagonists - pharmacology; Models, Animal; Neovascularization, Physiologic - drug effects; Proliferating Cell Nuclear Antigen - metabolism; Rats; Rats, Wistar; Smad2 Protein - metabolism; Spironolactone - pharmacology; Surgery; Transforming Growth Factor beta1 - metabolism; Vascular Endothelial Growth Factor A - metabolism; Angiogenesis; Aldosterone antagonist; Liver regeneration; Angiotensin receptor antagonist
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2012.08.046

Abstract Background There is a strong relationship between liver regeneration and angiogenesis and fibrosis. It is known that Spironolactone, an aldosterone antagonist, acting on rennin–aldosterone axis, and Losartan, an angiotensin II type I antagonist, have both antifibrotic and antiangiogenic effects. Theoretically, the end result of these mechanisms with contradictory influences on liver regeneration is not known well. In this study, we aimed to reveal the effects on liver regeneration of administration of Spironolactone and Losartan, having contradicting effects on regeneration through antiangiogenesis and antifibrosis. Materials and methods A total of 72 Wistar albino rats were divided into control, Spironolactone, and Losartan groups and subdivided to conduct examinations on days 1, 3, 5, and 7. The specimens were treated with proliferating cell nuclear antigen to evaluate the characteristics of liver regeneration; with phosphorylated Smad2 (phospho-Smad2), serum transforming growth factor beta (TGF-B) 1, and tissue TGF-B1 to evaluate the termination of regeneration and with vascular endothelial growth factor receptor 2, Flk-1/KDR, to evaluate angiogenesis. Results The proliferating cell nuclear antigen–labeling index was found to be significantly higher in Spironolactone and Losartan groups than in the control group on days 1, 3, and 5 ( P = 0.031, 0.0023, and 0.032, respectively). Vascular endothelial growth factor receptor 2, Flk-1/KDR, expression was significantly lower in Spironolactone and Losartan groups than in the control group on days 3, 5, and 7 ( P = 0.032, 0.0024, and 0.007, respectively). Phospho-Smad2 was significantly lower on days 1, 3, and 5 in Spironolactone and Losartan groups than in the control group ( P = 0.011, 0.0020, and 0.05, respectively). Tissue TGF-B1 levels were significantly lower in Spironolactone and Losartan groups than in the control group only on day 3 ( P = 0039). Serum TGF-B1 levels in Losartan groups were significantly different from those of control and Spironolactone groups only on day 1 ( P < 0.05). Conclusions Liver regeneration, expected to decrease on day 3, was prolonged and increased even on day 5 despite antiangiogenic effects of Losartan and Spironolactone, which in fact inhibit fibrosis through phospho-Smad2 and increase regeneration. In addition, serum and tissue TGF-B1 levels are not sensitive enough to show active TGF-B1 for the evaluation of regeneration.