title: Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids.
abstract: The mechanisms that regulate vascular resistance in the liver are an area of active investigation. Previously, we have shown that nitric oxide (NO) modulates hepatic vascular tone in the normal rat liver. In this study, the production of NO is examined in further detail by isolating sinusoidal endothelial cells (SEC) from the rat liver. Endothelial NO synthase (eNOS) was present in SEC based on Western blotting and confocal immunofluorescence microscopy. Exposure of SEC to flow increased the release of NO. To investigate the relevance of these in vitro findings to the intact liver, we modified an in situ perfusion system to allow for direct measurement of NO release from the hepatic vasculature. NO was released from the hepatic vasculature in a time-dependent manner, and administration of N-monomethyl-L-arginine reduced NO release and increased portal pressure. Immunostaining of intact liver demonstrated eNOS localization to endothelial cells lining the hepatic sinusoids. These findings demonstrate that SEC in vitro and in vivo express eNOS and produce NO basally, and increase their production in response to flow. Additionally, an increase in portal pressure concomitant with the blockade of NO release directly demonstrates that endogenous endothelial-derived NO modulates portal pressure.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: V
authors.initials: V
authors.lastname: Shah
authors.forename: F G
authors.initials: FG
authors.lastname: Haddad
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Cardena
authors.forename: J A
authors.initials: JA
authors.lastname: Frangos
authors.forename: A
authors.initials: A
authors.lastname: Mennone
authors.forename: R J
authors.initials: RJ
authors.lastname: Groszmann
authors.forename: W C
authors.initials: WC
authors.lastname: Sessa
mesh_terms: D000818:Animals; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000098:blood supply / Q000166:cytology* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions; D014655:Vascular Resistance; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase