title: A distinct nitric oxide and adenosine A1 receptor dependent hepatic artery vasodilatatory response in the CCl-cirrhotic liver.
abstract: Increase of portal venous vascular resistance is counteracted by decrease of hepatic arterial vascular resistance (hepatic arterial buffer response). This process is mediated by adenosine in normal livers. In cirrhosis, hepatic arterial vascular resistance is decreased but the involvement of adenosine in this process is unknown. The aim of our study was to identify the signalling pathway responsible for the decreased hepatic arterial resistance in cirrhotic livers.
  
  
  METHODS
  Cirrhosis was induced by CCl(4). Using a bivascular liver perfusion dose-response curves to adenosine of the HA were performed in the presence and the absence of pan-adenosine blocker (8-SPT), A1 blocker (caffeine) or nitric oxide synthase-blocker (l-NMMA) after preconstriction with an alpha1-agonist (methoxamine). Western blot of the HA were used to measure the density of the A1 and A2a receptors.
  
  
  RESULTS
  Adenosine caused a dose dependent relaxation of the hepatic artery of both cirrhotic and control animals that were blocked in both groups by 8-SPT (P<0.02). The response to adenosine was greater in cirrhotic rats (P=0.016). Both l-NMMA (P=0.003) and caffeine reduced the response to adenosine in cirrhotic but not in control animals. Western blot analysis showed a higher density of A1 and a lower density of A2a receptor in cirrhotic animals (P<0.05).
  
  
  CONCLUSIONS
  The adenosine-induced vasodilatation of the HA is increased in cirrhotic rats suggesting a role for adenosine-NO in the decreased hepatic arterial vascular resistance found in cirrhosis. This significantly greater response in cirrhosis by the A1 receptor follows the same pathway that is seen in hypoxic conditions in extra-hepatic tissues.
authors.affiliation: Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA. alexander.zipprich@medizin.uni-halle.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Zipprich
authors.forename: Wajahat Z
authors.initials: WZ
authors.lastname: Mehal
authors.forename: Cristina
authors.initials: C
authors.lastname: Ripoll
authors.forename: Roberto J
authors.initials: RJ
authors.lastname: Groszmann
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D015153:Blotting, Western; D002110:Caffeine / Q000494:pharmacology; D002251:Carbon Tetrachloride; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006499:Hepatic Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010477:Perfusion; D011169:Portal Vein / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014655:Vascular Resistance; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D004791:Enzyme Inhibitors; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D002110:Caffeine; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D002251:Carbon Tetrachloride; D019001:Nitric Oxide Synthase; D000241:Adenosine