Nitric oxide-deficiency regulates hepatic heme oxygenase-1.
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.
Hoetzel
Alexander
A
Department of Anesthesiology and Critical Care Medicine, University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany. alexander.hoetzel@uniklinik-freiburg.de
Welle
Armin
A
Schmidt
René
R
Loop
Torsten
T
Humar
Matjaz
M
Ryter
Stefan W
SW
Geiger
Klaus K
KK
Choi
Augustine M K
AM
Pannen
Benedikt H J
BH
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
D006360:Heat-Shock Proteins; D009573:Nitrites; D012333:RNA, Messenger; D019335:Nitroarginine; D009569:Nitric Oxide; D051547:Heme Oxygenase-1; D019331:NG-Nitroarginine Methyl Ester