title: Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction.
abstract: BACKGROUND
  Splanchnic vasodilation triggers the development of the hyperdynamic circulatory syndrome in portal hypertension. Neuropeptide Y (NPY), a sympathetic co-transmitter of norepinephrine, improves contractility in mesenteric arteries of pre-hepatic portal hypertensive rats. Therefore, we investigated the effect of NPY on mesenteric arterial contractility in vitro and in vivo in cirrhotic ascitic rats, as well as the vasoactive pathways involved.
  
  
  METHODS
  All experiments were performed in CCl₄-induced cirrhotic rats with ascites and compared to controls. In vivo haemodynamic characterisation was assessed before and after cumulative application of NPY i.v. using the microspheres technique. In vitro mesenteric arterial perfusion was used to analyse the effect of NPY on the response to α₁-adrenergic, as well as nitrergic stimulation. The NPY effects on vasoactive pathways (RhoA/Rho-kinase and NOS/NO) were analysed by western blot in mesenteric arteries.
  
  
  RESULTS
  NPY decreased portal-venous blood flow and reduced portal pressure in cirrhotic rats, without changes in mean arterial pressure. This was accompanied by decreased cardiac output and normalised systemic vascular resistance in cirrhotic rats. By contrast, no significant splanchnic or systemic haemodynamic effect of NPY was seen in controls. NPY enhanced arterial contractility in cirrhotic but not in control rats. Furthermore, NO-mediated vasodilation was reduced to a greater extent than in controls. These findings were paralleled by an increased expression and activity of the constrictive Rho-kinase pathway and decreased activation of vasodilating NOS/NO signalling after NPY administration in mesenteric arteries.
  
  
  CONCLUSIONS
  NPY exerts marked portal hypotensive effects and ameliorates the hyperdynamic circulation in cirrhotic ascitic rats. This is mediated mainly by a pronounced splanchnic vasoconstriction and reduction in splanchnic blood flow due to enhanced Rho-kinase expression and activity, as well as reduced NOS activation and NO effect.
authors.affiliation: Department of Internal Medicine, University Medical Center, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Moleda
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
authors.forename: Peter
authors.initials: P
authors.lastname: Dietrich
authors.forename: Erwin
authors.initials: E
authors.lastname: Gäbele
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Straub
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Juergen
authors.initials: J
authors.lastname: Schoelmerich
authors.forename: Reiner
authors.initials: R
authors.lastname: Wiest
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007262:Infusions, Intravenous; D008106:Liver Cirrhosis, Experimental / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D009478:Neuropeptide Y / Q000008:administration & dosage / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010477:Perfusion / Q000379:methods; D017082:Portal Pressure / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology*; D013577:Syndrome; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D009478:Neuropeptide Y; D019001:Nitric Oxide Synthase; D020742:rhoA GTP-Binding Protein