title: Comparative portal hypotensive effects as propranolol of vitamin D₃ treatment by decreasing intrahepatic resistance in cirrhotic rats.
abstract: OBJECTIVE
  Vitamin D₃ improves portal hypertension (PH) through the activation of vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) in cirrhotic rats. Propranolol is a non-selective β-blocker that is recommended for the treatment of PH. The present study aims to investigate the detail systemic and hepatic mechanisms of vitamin D₃ and propranolol, alone or in combination, in cirrhotic rats.
  
  
  METHODS
  Common bile duct-ligated and thioacetamide cirrhotic rats were treated with vehicle, propranolol (30 mg/kg/day), vitamin D₃ (0.5 μg/100 g/day, twice weekly), or propranolol + vitamin D₃, separately.
  
  
  RESULTS
  Significantly, propranolol and vitamin D₃ produced a similar magnitude of reduction in portal venous pressure (PVP) in cirrhotic rats through different mechanisms: whereas propranolol decreased PVP by reducing splanchnic hyperemia and cardiac index, vitamin D₃ decreased PVP by decreasing intrahepatic resistance (IHR). However, propranolol + vitamin D₃ did not further decrease PVP in cirrhotic rats. Notably, a marked decrease in hepatic VDR and CaSR expressions was noted in cirrhotic human/rat livers compared with non-cirrhotic human/rat livers. In cirrhotic rats, vitamin D₃ administration decreasing IHR by inhibiting the renin-angiotensin system, hepatic oxidative stress, inflammation/fibrosis, angiotensin II (ANGII) production, CaSR-mediated ANGII hyperresponsiveness, ANGII-induced hepatic stellate cells contraction, and correcting hepatic endothelial dysfunction through upregulation of hepatic VDR, CaSR, and endothelial nitric oxide synthase expressions.
  
  
  CONCLUSIONS
  Chronic vitamin D₃ treatment alone results in comparative portal hypotensive effects as propranolol alone in cirrhotic rats with PH. Taken together, chronic vitamin D₃ administration was an ideal alternative strategy to effectively improve PH without unwanted systemic side-effects.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Pei-Chang
authors.initials: PC
authors.lastname: Lee
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Yang
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Lee
authors.forename: Kuei-Chuan
authors.initials: KC
authors.lastname: Lee
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Tzung-Yan
authors.initials: TY
authors.lastname: Lee
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
mesh_terms: D000319:Adrenergic beta-Antagonists; D000818:Animals; D002762:Cholecalciferol / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000209:etiology*; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D011433:Propranolol / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing; D002762:Cholecalciferol; D011433:Propranolol
keywords: Calcium-sensing receptor; hepatic endothelial dysfunction; intrahepatic resistance; propranolol; vitamin D receptor; vitamin D3