title: Diabetes enhances the intrahepatic vascular response to endothelin-1 in cirrhotic rats: association with the ETA receptor and pERK up-regulation.
abstract: OBJECTIVE
  Cirrhosis is characterized by increased intrahepatic vascular resistance and enhanced vasocontractile responsiveness that impedes portal inflow and elevates portal pressure, in which endothelin-1 (ET-1) plays a role. Diabetes and glucose influence vasoresponsiveness but their impact on the intrahepatic vascular bed in cirrhosis is unknown. To investigate intrahepatic ET-1 vasoresponsiveness in cirrhotic rats with and without diabetes and to explore the underlying mechanisms.
  
  
  METHODS
  Spraque-Dawley rats received common bile-duct ligation (BDL) to induce cirrhosis. Streptozotocin was injected to induce diabetes in the BDL rats (BDL/STZ). In situ liver perfusion was performed to obtain the ET-1 concentration-response curves. The basic hemodynamics and hepatic protein expressions of ET-1 receptors, pERK, ERK, pAkt, Akt, iNOS, eNOS, peNOS and calmodulin were evaluated. The circulating concentrations of N-terminal pro-brain natriuretic peptide (NT-ProBNP), blood urea nitrogen (BUN) and creatinine were also determined.
  
  
  RESULTS
  Body weight, mean arterial pressure, heart rate and survival rate were significantly decreased in the BDL/STZ rats. The perfusion pressure changes in response to ET-1 were higher in the BDL/STZ group for all perfusates. ETA receptor and pERK expressions were enhanced in the BDL/STZ group. The circulating concentrations of NT-ProBNP, BUN and creatinine, as well as SMA flow, were not significantly different between the BDL and BDL/STZ groups.
  
  
  CONCLUSIONS
  Cirrhotic rats with diabetes showed higher intrahepatic ET-1 vasoresponsiveness than normoglycemic cirrhotic rats. This effect is not affected by changes in perfused glucose concentration and may be related, at least in part, to intrahepatic ETA R receptor and pERK over-expression.
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Lee
authors.forename: Fa-Yauh
authors.initials: FY
authors.lastname: Lee
authors.forename: Teh-Ia
authors.initials: TI
authors.lastname: Huo
authors.forename: Sun-Sang
authors.initials: SS
authors.lastname: Wang
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Huang
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.forename: Chiao-Lin
authors.initials: CL
authors.lastname: Chuang
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006975:Hypertension, Portal / Q000150:complications; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000503:physiopathology*; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D010477:Perfusion; D017082:Portal Pressure / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D003404:Creatinine; D019332:Endothelin-1; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D044022:Receptor, Endothelin A; D019892:eIF-2 Kinase; C109794:pro-brain natriuretic peptide (1-76)
keywords: diabetes mellitus; endothelin-1; intrahepatic vascular response; liver cirrhosis