title: Hydrogen sulfide modulates sinusoidal constriction and contributes to hepatic microcirculatory dysfunction during endotoxemia.
abstract: Hydrogen sulfide (H₂S) affects vascular resistance; however, its effect on the hepatic microcirculation has not been investigated. Hepatic sinusoidal perfusion is dysregulated during sepsis, contributing to liver injury. Therefore, the present study determined the effect of H₂S on the hepatic microcirculation and the contribution of endogenous H₂S to hepatic microcirculatory dysfunction in an endotoxin model of sepsis. Portal infusion of H₂S increased portal pressure in vivo (6.8 ± 0.2 mmHg before H₂S vs. 8.6 ± 0.8 mmHg peak during H₂S infusion, P < 0.05). Using intravital microscopy, we observed decreased sinusoidal diameter (6.2 ± 0.27 μm before H₂S vs. 5.7 ± 0.3 μm after H₂S, P < 0.05) and increased sinusoidal heterogeneity during H₂S infusion (P < 0.05) and net constriction. Since hepatic H₂S levels are elevated during sepsis, we used the cystathionine γ lyase inhibitor DL-propargylglycine (PAG) to determine the contribution of H₂S to the hypersensitization of the sinusoid to the vasoconstrictor effect of endothelin-1 (ET-1). PAG treatment significantly attenuated the sinusoidal sensitization to ET-1 in endotoxin-treated animals. ET-1 infusion increased portal pressure to 175% of baseline in endotoxemic animals, which was reduced to 143% following PAG treatment (P < 0.05). PAG abrogated the increase in sinusoidal constriction after ET-1 infusion in LPS-treated rats (30.9% reduction in LPS rats vs. 11.6% in PAG/LPS rats, P < 0.05). Moreover, PAG treatment significantly attenuated the increase in NADH fluorescence following ET-1 exposure during endotoxemia (61 grayscale units LPS vs. 21 units in PAG/LPS, P < 0.05), suggesting an improvement in hepatic oxygen availability. This study is the first to demonstrate a vasoconstrictor action of H₂S on the hepatic sinusoid and provides a possible mechanism for the protective effect of PAG treatment during sepsis.
authors.affiliation: Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Norris
authors.forename: Nicole
authors.initials: N
authors.lastname: Feilen
authors.forename: Nhat H
authors.initials: NH
authors.lastname: Nguyen
authors.forename: Cathy R
authors.initials: CR
authors.lastname: Culberson
authors.forename: Min C
authors.initials: MC
authors.lastname: Shin
authors.forename: Madeleine
authors.initials: M
authors.lastname: Fish
authors.forename: Mark G
authors.initials: MG
authors.lastname: Clemens
mesh_terms: D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D016232:Endothelins / Q000494:pharmacology; D019446:Endotoxemia / Q000139:chemically induced / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000098:blood supply* / Q000503:physiopathology; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D055806:Microvessels / Q000503:physiopathology*; D017082:Portal Pressure / Q000187:drug effects; D011169:Portal Vein / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013447:Sulfites / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000480:Alkynes; D016232:Endothelins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D013447:Sulfites; D014662:Vasoconstrictor Agents; C009055:propargylglycine; C042345:hydrogen sulfite; D005998:Glycine
keywords: endothelin; endotoxemia; hydrogen sulfide; liver; microcirculation