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 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 < .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. (H EPATOLOGY 2002;36:1453-1465.)