title: Endothelin-1 and heme oxygenase-1 as modulators of sinusoidal tone in the stress-exposed rat liver.
abstract: Heme oxygenase (HO)-1 is up-regulated after ischemia/reperfusion and contributes to maintenance of hepatic perfusion and integrity. Blockade of HO-1 leads to an increased portal pressor response in the stress-exposed liver. We tested whether the increase in portal pressure reflects unmasking of a concomitant up-regulation of the vasoconstrictor endothelin (ET)-1. Hemorrhagic shock induced messenger RNAs encoding HO-1 (16-fold) and ET-1 (9-fold) with a similar time course in the liver. At maximum induction of both mediators, rats received either vehicle or the endothelin ET(A/B) antagonist bosentan (10 mg/kg intravenously). Subsequently, the HO pathway was blocked in all animals by tin-protoporphyrin (SnPP)-IX (50 micromol/kg intravenously). Portal and sinusoidal hemodynamics were measured using microflow probes and intravital microscopy, respectively. Blockade of the HO pathway led to a significant increase in portal resistance (sham/SnPP-IX, 0.17 +/- 0.046 mm Hg. min. mL(-1); shock/vehicle/SnPP-IX, 0.57 +/- 0.148 mm Hg. min. mL(-1); P <.05) and a decrease in sinusoids conducting flow (shock/vehicle/SnPP-IX: baseline, 28.3 +/- 0.85 sinusoids/mm; 10 minutes after SnPP-IX, 23.1 +/- 1.09 sinusoids/mm; P <.05). Intravital microscopy showed narrowing of failing sinusoids colocalizing with stellate cells after blockade of the HO pathway. Blockade of ET(A/B) receptors attenuated the increase in portal resistance (shock/bosentan/SnPP-IX, 0.29 +/- 0.051 mm Hg. min. mL(-1)) and prevented sinusoidal perfusion failure (shock/bosentan/SnPP-IX: baseline, 28.2 +/- 0.97 sinusoids/mm; 10 minutes after SnPP-IX, 28.8 +/- 1.18 sinusoids/mm) as well as sinusoidal narrowing. In conclusion, a functional interaction of the up-regulated vasodilatory HO system and the vasoconstrictor ET-1 on the sinusoidal level exists under stress conditions. Both mediator systems affect sinusoidal diameter via direct action on hepatic stellate cells in vivo.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of the Saarland, Homburg, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Rensing
authors.forename: Inge
authors.initials: I
authors.lastname: Bauer
authors.forename: Jian X
authors.initials: JX
authors.lastname: Zhang
authors.forename: Markus
authors.initials: M
authors.lastname: Paxian
authors.forename: Benedikt  H J
authors.initials: B
authors.lastname: Pannen
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Mark G
authors.initials: MG
authors.lastname: Clemens
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D008099:Liver / Q000378:metabolism*; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008981:Molsidomine / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D011169:Portal Vein / Q000502:physiology; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D020030:Nitric Oxide Donors; D011524:Protoporphyrins; D017466:Receptors, Endothelin; D013449:Sulfonamides; D008981:Molsidomine; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D000077300:Bosentan