HYDROGEN SULFIDE DIFFERENTIALLY AFFECTS THE HEPATIC VASCULATURE IN RESPONSE TO PHENYLEPHRINE AND ENDOTHELIN 1 DURING ENDOTOXEMIA

Despite being protective in many disease states, hydrogen sulfide (H2S) contributes to organ injury in sepsis. Like the other gasotransmitters, nitric oxide and carbon monoxide, H2S is a modulator of the microcirculation. Because microcirculatory dysfunction is a main cause of organ injury during sepsis, the present study was designed to test the effect of H2S on microvascular dysfunction in isolated perfused livers. In most microcirculatory beds, endotoxin activates the endothelium, resulting in hyporesponsiveness to catecholamines and a derangement in blood flow distribution. We demonstrate that H2S treatment attenuates the increase in portal pressure during infusion of the alpha(1) adrenergic agonist, phenylephrine (PE) (P < 0.01). Hydrogen sulfide almost completely negated the increase in portal pressure in livers isolated from endotoxemic rats. Treatment with an inhibitor of endogenous H2S, DL-propargylglycine (PAG), reversed lipopolysaccharide-induced hyporesponsiveness to PE. Because hepatic microcirculatory dysfunction is associated with excessive sinusoidal vasoconstriction and not dilation, we investigated whether H2S affects endothelin 1 (ET-1)-induced vasoconstriction in isolated livers. Contrary to PE treatment, H2S did not affect the increase in portal pressure during infusion of ET-1, nor did it attenuate the hypersensitization of the liver to ET-1 during endotoxemia. Hepatic resistance in control rats was increased by PAG treatment during ET-1 infusion, but this increase was not exacerbated during endotoxemia. We monitored hepatic O-2 consumption to assess the effect of vascular changes on oxygen consumption following ET-1 treatment. Low-dose ET-1 infusion caused an increase in hepatic O-2 consumption, whereas low-dose ET-1 infusion decreased O-2 consumption in endotoxemic livers. Interestingly, whereas we observed no effect of PAG on the vascular response to ET-1 infusion during endotoxemia, PAG treatment did maintain O-2, suggesting a more complex effect of H2S inhibition. In summary, the discrepancies between the hepatic response to PE and ET-1 suggest that H2S differentially contributes to microcirculatory dysfunction in the systemic and hepatic microcirculations. We propose that this is due to H2S exerting a differential vasoactive function on presinusoidal and sinusoidal sites within the liver. Moreover, our findings suggest that H2S may contribute to the progression of sepsis by contributing to microvascular failure.