title: Droxidopa, an oral norepinephrine precursor, improves hemodynamic and renal alterations of portal hypertensive rats.
abstract: We aimed to evaluate the effects of droxidopa (an oral synthetic precursor of norepinephrine) on the hemodynamic and renal alterations of portal hypertensive rats. Sham, portal vein-ligated (PVL), and 4-week biliary duct-ligated (BDL) rats received a single oral dose of droxidopa (25-50 mg/kg) or vehicle and hemodynamic parameters were monitored for 2 hours. Two groups of BDL and cirrhotic rats induced by carbon tetrachloride (CCl(4) ) were treated for 5 days with droxidopa (15 mg/kg, twice daily, orally); hemodynamic parameters and blood and urinary parameters were assessed. The droxidopa effect on the Rho kinase (RhoK) / protein kinase B (AKT) / endothelial nitric oxide synthase (eNOS) pathways was analyzed by western blot in superior mesenteric artery (SMA). The acute administration of droxidopa in PVL and BDL rats caused a significant and maintained increase in arterial pressure and mesenteric arterial resistance, with a significant decrease of mesenteric arterial and portal blood flow, without changing portal pressure and renal blood flow. Two-hour diuresis greatly increased. Carbidopa (DOPA decarboxylase inhibitor) blunted all effects of droxidopa. Chronic droxidopa therapy in BDL rats produced the same beneficial hemodynamic effects observed in the acute study, did not alter liver function parameters, and caused a 50% increase in 24-hour diuresis volume (7.4 ± 0.9 mL/100g in BDL vehicle versus 11.8 ± 2.5 mL/100g in BDL droxidopa; P = 0.01). Droxidopa-treated rats also showed a decreased ratio of p-eNOS/eNOS and p-AKT/AKT and increased activity of RhoK in SMA. The same chronic treatment in CCl(4) rats caused similar hemodynamic effects and produced significant increases in diuresis volume and 24-hour natriuresis (0.08 ± 0.02 mmol/100g in CCl(4) vehicle versus 0.23 ± 0.03 mmol/100g in CCl(4) droxidopa; P = 0.014).
  
  
  CONCLUSIONS
  Droxidopa might be an effective therapeutic agent for hemodynamic and renal alterations of liver cirrhosis and should be tested in cirrhosis patients.
authors.affiliation: Department of Internal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Coll
authors.forename: Sarai
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Imma
authors.initials: I
authors.lastname: Raurell
authors.forename: Nahia
authors.initials: N
authors.lastname: Ezkurdia
authors.forename: Astrid
authors.initials: A
authors.lastname: Brull
authors.forename: Salvador
authors.initials: S
authors.lastname: Augustin
authors.forename: Jaime
authors.initials: J
authors.lastname: Guardia
authors.forename: Rafael
authors.initials: R
authors.lastname: Esteban
authors.forename: María
authors.initials: M
authors.lastname: Martell
authors.forename: Joan
authors.initials: J
authors.lastname: Genescà
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001652:Bile Ducts; D001794:Blood Pressure / Q000187:drug effects; D002230:Carbidopa / Q000494:pharmacology; D002251:Carbon Tetrachloride; D004195:Disease Models, Animal; D004231:Diuresis / Q000187:drug effects; D015103:Droxidopa / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D006975:Hypertension, Portal / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology*; D008026:Ligation; D008103:Liver Cirrhosis / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011169:Portal Vein / Q000503:physiopathology; D011433:Propranolol / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D012079:Renal Circulation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014563:Urodynamics / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D054460:rho-Associated Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D004791:Enzyme Inhibitors; D011433:Propranolol; D002251:Carbon Tetrachloride; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D015103:Droxidopa; D002230:Carbidopa