title: Two drugs with paradoxical effects on liver regeneration through antiangiogenesis and antifibrosis: Losartan and Spironolactone: a pharmacologic dilemma on hepatocyte proliferation.
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.
  
  
  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.
authors.affiliation: Department of General Surgery, Adana Teaching and Research Center, Baskent University School of Medicine, Ankara, Turkey. aparlakgumus@yahoo.com
authors.forename: Alper
authors.initials: A
authors.lastname: Parlakgumus
authors.forename: Tamer
authors.initials: T
authors.lastname: Colakoglu
authors.forename: Fazilet
authors.initials: F
authors.lastname: Kayaselcuk
authors.forename: Sule
authors.initials: S
authors.lastname: Colakoglu
authors.forename: Ali
authors.initials: A
authors.lastname: Ezer
authors.forename: Kenan
authors.initials: K
authors.lastname: Calıskan
authors.forename: Jale
authors.initials: J
authors.lastname: Karakaya
authors.forename: Sedat
authors.initials: S
authors.lastname: Yildirim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005355:Fibrosis; D006498:Hepatectomy; D022781:Hepatocytes / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D019808:Losartan / Q000494:pharmacology*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051899:Smad2 Protein / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D047228:Angiotensin II Type 1 Receptor Blockers; D000893:Anti-Inflammatory Agents; D000451:Mineralocorticoid Receptor Antagonists; D018809:Proliferating Cell Nuclear Antigen; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D013148:Spironolactone; D019808:Losartan