Endothelin-1 is involved in hepatic sinusoidal vasoconstriction after ischemia and reperfusion

Abstract

Endothelin-1 (ET-1), a vasoactive peptide, causes a significant rise in portal vein pressure, which is most likely a result of severe vasoconstriction in the liver. In this study, the effect of ET-1 on sinusoidal vasoconstriction in the liver after ischemia and reperfusion was directly investigated using intravital microscopy. In anesthetized female Sprague Dawley rats (200-250 g) ischemia of the median and left liver lobes was induced for 90 min by temporary ligation of the left pedicle. After declamping and a 90-min reperfusion period, the livers were exposed for intravital microscopy. Using a Nikon MM-11 fluorescence microscope (545 nm, 330x), a CCD camera (Cohu FK 6990), and a SVHS video recording unit, the hepatic microcirculation was directly investigated. Besides sham groups, two ischemia groups were studied, receiving ET-1 antiserum (anti-ET-1; 0.5 ml; Peptide Inst., Osaka, Japan) or NaCl 0.9% (0.5 ml) 5 min prior to reperfusion of the liver (n = 6/group). Following a transient drop in the mean arterial blood pressure in the anti-ET-1-treated groups, comparable systemic hemodynamic conditions among the four groups were noted during intravital microscopic assessment at the end of the 90-min reperfusion period. Reduction in the sinusoidal diameters during postischemic reperfusion (7.7 +/- 0.5 microm) was prevented by anti-ET-1 treatment (9.6 +/- 0.25 microm; P < 0.01; mean + SEM) back to control values (9.6 +/- 0.32 microm), while most of other microcirculatory parameters did not show significant differences. The results supported further the role of ET-1 in dysregulation of the sinusoidal vascular tone in the liver, e.g., after ischemia and reperfusion.

Perinecrotic Hypoxia Contributes to Ischemia/Reperfusion-Accelerated Outgrowth of Colorectal Micrometastases

“…In the past, several compounds that aim at restoring the endothelin-1/nitric oxide imbalance have been successfully applied to reduce microcirculatory disturbances and liver tissue damage. 18,19,54,70,71 Atrasentan is effective in reducing postischemic microcirculatory disturbances in models of renal, 72 cardiac, 73 and cerebral 74 I/R and we here show that, in combination with the nitric oxide donor L-arginine, it provides maximal improvement of the microcirculation after hepatic I/R. Second, agents that target the HIF-1␣ pathway, including 17-DMAG, are gaining increased attention as novel anticancer drugs.…”

“…After I/R, endothelin-1 is increased in the reperfusion period and exerts its vasoconstrictive action via the endothelin-A receptor, contributing to the microcirculatory disturbances after I/R. [52][53][54] Endothelin-1 may also directly stimulate tumor cell proliferation, 55,56 and its expression correlates with the stabilization of HIF-1␣. 57 Finally, the inflammatory response associated with I/R, including the influx of neutrophils and activation of Kupffer cells, may also contribute to the stimulation of tumor growth.…”

Posthepatic Manipulative Blood Extraction with Blood Transfusion Alleviates Liver Transplant Ischemia/Reperfusion Injury and Its Induced Lung Injury

“…And the MDA concentrations in SH-VC were significantly higher than that in IH-VC at 20 min，30 min，1h (P<0.05). The phenomenon that MDA concentration increased slowly in the early stage after transplantation is due to its incomplete reflow and injured microcirculation including endothelial cell swelling (Vollmar et al, 1994), vasoconstriction (Marzi et al, 1994), leucocyte entrapment (Fondevila et al, 2003;Yadav et al, 1998) and possibly intravascular haemoconcentration (Menger et al, 1988). This process prolongs the period of hypoxia, with areas of the liver remaining ischemic after early period of transplantation.…”

“…Increased accumulation of pulmonary TNF-a and neutrophil results in increased lung capillary permeability in that it can damage both vascular endothelium cells and lung epithelial cells. And the toxic lipid peroxidation reaction products mediated by ROS will furthermore cause cell injury and death (Marzi et al, 1994).…”

Untitled

“…1 The I-R injury affects postoperative liver function, postoperative recovery, and eventual clinical outcome. This phenomenon is a result of the interaction of various mechanisms such as endothelial and Kupffer cell swelling, 2 vasoconstriction due to endothelin-1 increase and nitric oxide decrease, 3 up-regulation of adhesion molecule expression because of humoral induction of inflammatory mediators and neutrophil infiltration, 4,5 and platelet aggregation within the sinusoids. 6 Release of oxygen-free radicals is associated with the activation of complement and Kupffer cells during the early phase of I-R injury (up to 2 h postreperfusion) which leads to cellular injury due to oxidative stress.…”