Endothelin-1 and heme oxygenase-1 as modulators of sinusoidal tone in the stress-exposed rat liver | Zendy

Hauke Rensing | Zendy; Inge Bauer | Zendy; Jian X. Zhang | Zendy; Markus Paxian | Zendy; Benedikt H. J. Pannen | Zendy; Yukihiro Yokoyama | Zendy; Mark G. Clemens | Zendy; Michael Bauer | Zendy

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Endothelin-1 and heme oxygenase-1 as modulators of sinusoidal tone in the stress-exposed rat liver

Author(s) -

Hauke Rensing,

Inge Bauer,

Jian X. Zhang,

Markus Paxian,

Benedikt H. J. Pannen,

Yukihiro Yokoyama,

Mark G. Clemens,

Michael Bauer

Publication year - 2002

Publication title -

hepatology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.488

H-Index - 361

eISSN - 1527-3350

pISSN - 0270-9139

DOI - 10.1053/jhep.2002.36934

Subject(s) - heme oxygenase , bosentan , endothelin 1 , intravital microscopy , endothelin receptor , blockade , portal hypertension , endothelin receptor antagonist , portal venous pressure , endocrinology , medicine , chemistry , antagonist , pharmacology , heme , receptor , microcirculation , biochemistry , cirrhosis , enzyme

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.

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