title: Dose-dependent effects of a nitric oxide biosynthesis inhibitor on hyperdynamic circulation in two models of portal hypertension in conscious rats.
abstract: The role of nitric oxide (NO) in the hyperkinetic circulation in portal hypertension has not been clearly elucidated. Different doses of NO inhibitors, haemodynamic values and experimental conditions might explain the discrepant results. The aim of the present study was to investigate the acute effects of a specific biosynthesis inhibitor of NO, Nomega-nitro-L-arginine (L-NNA), on the systemic and splanchnic circulation in normal conscious rats and rats with portal hypertension due to either partial portal vein stenosis or secondary biliary cirrhosis. The administration of L-NNA (15 to 960 micrograms.kg-1.min-1) induced a significant dose dependent increase in arterial pressure which was not different among the three groups of rats. Following an acute and maximal vasopressive dose of L-NNA (1 mg.kg-1.min-1) cardiac index decreased more in portal vein stenosed and cirrhotic rats (-45 +/- 3% and -45 +/- 2%, respectively) than in normal rats (-31 +/- 2%), and systemic vascular resistance increased more in the two groups of portal hypertensive rats than in normals (+ 161 +/- 13% and + 154 +/- 10% vs + 85 +/- 6%, respectively). L-NNA caused a greater decrease in portal tributary blood flow in portal vein stenosed and cirrhotic rats (-63 +/- 4% and -55 +/- 4%, respectively) than in normal rats (-45 +/- 6%). Similarly, the increase in portal territory vascular resistance was significantly more marked in portal vein stenosed and cirrhotic rats (+ 337 +/- 62% and + 214 +/- 24%, respectively) than in normal rats (+ 153 +/- 23%). Portal pressure did not change. Following the acute administration of L-NNA, no significant difference in splanchnic and systemic haemodynamics were noted between portal vein stenosed and normal rats, except for portal pressure. In cirrhotic rats, splanchnic and systemic values remained different from normal rats. This study confirms that NO plays a role in the haemodynamic changes in portal hypertension, and shows that NO inhibitors have a dose-dependent effect in conscious portal hypertensive rats.
authors.affiliation: Laboratoire d'Hémodynamique Splanchnique, Unité de Recherches de Physiopathologie Hépatique (INSERM U-24), Hôpital Beaujon, Clichy, France.
authors.forename: C
authors.initials: C
authors.lastname: Pilette
authors.forename: P
authors.initials: P
authors.lastname: Kirstetter
authors.forename: P
authors.initials: P
authors.lastname: Sogni
authors.forename: S
authors.initials: S
authors.lastname: Cailmail
authors.forename: R
authors.initials: R
authors.lastname: Moreau
authors.forename: D
authors.initials: D
authors.lastname: Lebrec
mesh_terms: D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D003243:Consciousness; D003250:Constriction; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D006975:Hypertension, Portal / Q000209:etiology / Q000503:physiopathology*; D008105:Liver Cirrhosis, Biliary / Q000150:complications; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase