P57 Hydrogen sulfide differentially regulates hepatic blood flow at sinusoidal and extrasinusoidal sites during endotoxemia

Abstract

Background The predominant effect of Hydrogen sulfide (HSS) on the vasculature is considered to be vasodilation. The vasodilatory action of H2S occurs through hyperpolarization of vascular smooth muscle cells via KATP channel opening. H2S has been shown to improve tissue perfusion in disease states, such as ischemia/reperfusion injury, where blood flow is inadequate. During sepsis, liver injury results in increased sensitivity to Endothelin 1 (ET-1) resulting in sinusoidal hyperconstriction and heterogeneous hepatic blood flow. Unlike the other gaseous vasodilators NO and CO which ameliorate liver injury by improving sinusoidal blood flow, H2S has been shown to be deleterious during sepsis. Although a vasodilatory effect of H2S has been reported on overall hepatic portal resistance, functional liver blood flow is determined by sinusoidal constriction mediate by contraction of hepatic stellate cells; the effects of H2S at this site has not been studied. Therefore, we investigated the vasoactive effect of H2S on hepatic blood flow during endotoxemia using modulators of portal venular (phenylephrine) and sinusoidal (ET-1) vessels. Methods Portal vascular response was determined using an isolated perfused rat liver. Total portal flow was maintained constant and portal resistance estimated by monitoring inflow pressure. For determination of the response to endotoxemia, rats were administered 1 mg/kg E. coli endotoxin 6 h prior to liver isolation. Sinusoidal response was determined using intravital microscopy. The liver microcirculation was viewed using NADH fluorescence for contrast and sinusoid diameter was determined off-line using morphmetric software (PTI). Results H2S inhibited the increased portal pressure response to PE infusion (20μM) from (4.7 ± 0.3 vs 3.2 ± 0.3, P Conclusion Our findings suggest H2S has both dilator and constrictor effects in the hepatic circulation with the constrictor effects leading to the heterogeneous perfusion and focal hypoxia previously observed in sepsis and endotoxemia. These sinusoid constrictor effects are likely to be a major contributor to the deleterious effects of H2S observed in sepsis.