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

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 ETA/B antagonist bosentan (10 mg/kg intravenously). Subsequently, the HO pathway was blocked in all animals by tin‐protoporphyrin (SnPP)‐IX (50 μmol/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 < 0.05) 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 < 0.05). Intravital microscopy showed narrowing of failing sinusoids colocalizing with stellate cells after blockade of the HO pathway. Blockade of ETA/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. (HEPATOLOGY2002;36:1453–1465).