Hydrogen sulfide modulates sinusoidal constriction and contributes to hepatic micorcirculatory dysfunction during endotoxemia

… MAP) and heart rate (HR). A MouseOx pulse oximeter (Starr Life Sciences, Pittsburgh,
PA) was used to monitor arterial oxygen saturation and HR to ensure the stability
of the rat during the experiment. Two pericentral and two … 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.

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