Several factors contribute to systemic microcirculatory dysfunction during sepsis, including activation of procoagulant pathways, recruitment of leucocytes, and excess production of vasoactive agents (2). In healthy individuals, the activation of α1 adrenergic receptors by circulating catecholamines causes VSMC contraction and reduces blood flow through the vascular bed, which allows for the spatial distribution of cardiac output. During sepsis, the excessive release of vasodilators suppresses the response of the endothelium to catecholamines (3). The diffuse peripheral vasodilation contributes to systemic hypotension and organ dysfunction (35).
Based on our results, PAG treatment may provide a protective effect during sepsis by attenuating systemic vascular hyporesponsiveness to catecholamines; however, its effect in the hepatic sinusoid remains unclear. Previously, we showed that sinusoidal tone is modulated by HSCs, which contract in response to ET-1 (19). Hepatic stellate cells are activated following inflammatory stress, which enhances their contractility to ET-1 (26). The priming effect of LPS on the HSCs results in sinusoidal hyperconstriction, which is a main cause of tissue hypoxia and cell death (5). In support of the importance of ET-1 in hepatic dysfunction, elevated ET-1 levels are highly correlated to disease severity in cirrhosis (37). Thus, the sinusoid is a critical regulatory site for hepatic perfusion during sepsis. Previous work from our laboratory and others demonstrated that impaired synthesis of NO contributes to sinusoidal dysfunction (38–40). The vasoregulatory effect of H2S in the hepatic sinusoids remains unclear. Therefore, we investigated the effect of H2S on the sinusoids during endotoxemia by assessing its effect on ET-1 infusion.
Infusion of increasing concentrations of ET-1 resulted in progressive increase in portal pressure. In agreement with our previous reports, the effect of ET-1 was significantly potentiated by endotoxin treatment. Based on its vasodilatory action, we hypothesized that H2S would attenuate the hypersensitization of the hepatic sinusoid to ET-1 during endotoxemia. Surprisingly, we observed no effect of H2S on ET-1–induced vasocontriction in either control or endotoxin-treated rats. Interestingly, PAG treatment increased the vascular response to ET-1 in control livers but had no effect in the endotoxin group. These results suggest that H2S differentially modulates the vascular response to ET-1 when compared with PE.
This differential effect may be due to the cells responsible for modulating lumenal diameter. Portal terminal venules, as well as arterioles, are modulated by VSMCs. The vasodilatory effect of H2S is primarily the result of VSMC hyperpolarization via activation of KATP channels (11, 41, 42). Hepatic sinusoidal resistance is regulated by HSCs, which may be differentially regulated by H2S. It has been suggested that the H2S donor (NaHS) can prevent HSC contraction (43). However, that study was performed in isolated HSCs over the course of 18 h with NaHS. The spontaneous activation of HSCs following isolation may not reflect actual in vivo conditions (44). Furthermore, NaHS rapidly releases H2S, which if not contained in a closed system rapidly escapes culture media and enters the atmosphere in a short period during incubation (45). Although the finding of that study is promising, more conclusive research is needed to assess the effect of H2S on HSCs.
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