title: Role of angiotensin-1 receptor blockade in cirrhotic liver resection.
abstract: BACKGROUND
  The regeneration capacity of cirrhotic livers might be affected by angiotensin-1 (AT1) receptors located on hepatic stellate cells (HSC). The effect of AT1 receptor blockade on microcirculation, fibrosis and liver regeneration was investigated.
  
  
  METHODS
  In 112 Lewis rats, cirrhosis was induced by repetitive intraperitoneal injections of CCl(4) . Six hours, 3, 7 and 14 days after partial hepatectomy or sham operation, rats were sacrificed for analysis. Animals were treated with either vehicle or 5 mg/kg body weight losartan pre-operatively and once daily after surgery by gavage. Microcirculation and portal vein flow were investigated at 6 h. The degree of cirrhosis was assessed by Azan Heidenhein staining, activation of HSC by desmin staining, apoptosis by ssDNA detection and liver regeneration by Ki-67 staining. Changes in expression of various genes important for liver regeneration and fibrosis were analysed at 6 h and 3 days. Haemodynamic parameters and liver enzymes were monitored.
  
  
  RESULTS
  Losartan treatment increased sinusoidal diameter, sinusoidal blood flow and portal vein flow after partial hepatectomy (P<0.05), but not after sham operation. AT1 receptor blockade resulted in increased apoptosis early after resection. HSC activation was reduced and after 7 days, a significantly lower degree of cirrhosis in resected animals was observed. Losartan increased the proliferation of hepatocytes at late time-points and of non-parenchymal cells early after partial hepatectomy (P<0.05). Tumour necrosis factor (TNF)-α was significantly upregulated at 6 h and stem cell growth factor (SCF) was downregulated at 3 days (P<0.05).
  
  
  CONCLUSIONS
  Losartan increased hepatic blood flow, reduced HSC activation and liver fibrosis, but interfered with hepatocyte proliferation after partial hepatectomy in cirrhotic livers.
authors: Department of General and Visceral Surgery, Division of Surgical Research, Muenster University Hospital, Muenster, Germany.
authors: Ralf
authors: R
authors: Bahde
authors: Linus
authors: L
authors: Kebschull
authors: Sandra
authors: S
authors: Stöppeler
authors: Andree
authors: A
authors: Zibert
authors: Ramsi
authors: R
authors: Siaj
authors: Jens P
authors: JP
authors: Hölzen
authors: Evgeny
authors: E
authors: Minin
authors: Hartmut H-J
authors: HH
authors: Schmidt
authors: Hans-Ullrich
authors: HU
authors: Spiegel
authors: Daniel
authors: D
authors: Palmes
mesh_terms: D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D002251:Carbon Tetrachloride; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation; D006498:Hepatectomy; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery; D008102:Liver Circulation / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D044140:Receptor, Angiotensin, Type 1; D002251:Carbon Tetrachloride; D019808:Losartan