title: Nitric oxide-deficiency regulates hepatic heme oxygenase-1.
abstract: Nitric oxide plays a crucial role in the maintenance of liver function and integrity. During stress, the inducible heme oxygenase-1 protein and its reaction products, including carbon monoxide, also exert potent hepatoprotective effects. We investigated a potential relationship between endogenous nitric oxide synthesis and the hepatic regulation of heme oxygenase-1. Inhibition of nitric oxide synthesis in vivo by injection of l-NAME led to a dose-dependent induction of heme oxygenase-1 mRNA, protein and activity in the rat liver, whereas did not affect the expression of other heat shock proteins. The effect of l-NAME was demonstrated by hemodynamic changes within the liver circulation as measured by ultrasonic flow probes. Inhibition of nitric oxide synthase led to a decline in hepatic arterial and portal venous blood flow, and subsequently caused liver cell damage. In contrast, the combined administration of l-NAME and the nitric oxide-independent intestinal vasodilator dihydralazine completely restored portal venous flow, abolished the liver cell damage, and prevented the upregulation of heme oxygenase-1, despite inhibition of nitric oxide production. In conclusion, nitric oxide deficiency upregulates hepatic heme oxygenase-1, which is reversible by maintaining hepatic blood flow. This interdependence has important implications for the development of therapeutic strategies aimed at modulating the activity of these hepatoprotective mediator systems.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany. alexander.hoetzel@uniklinik-freiburg.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoetzel
authors.forename: Armin
authors.initials: A
authors.lastname: Welle
authors.forename: René
authors.initials: R
authors.lastname: Schmidt
authors.forename: Torsten
authors.initials: T
authors.lastname: Loop
authors.forename: Matjaz
authors.initials: M
authors.lastname: Humar
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Klaus K
authors.initials: KK
authors.lastname: Geiger
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.forename: Benedikt H J
authors.initials: BH
authors.lastname: Pannen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004912:Erythrocytes / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood / Q000172:deficiency / Q000378:metabolism*; D009573:Nitrites / Q000097:blood / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006360:Heat-Shock Proteins; D009573:Nitrites; D012333:RNA, Messenger; D019335:Nitroarginine; D009569:Nitric Oxide; D051547:Heme Oxygenase-1; D019331:NG-Nitroarginine Methyl Ester