Enhanced expression of endothelin B receptor at protein and gene levels in human cirrhotic liver

Yokomori, Hiroaki; Oda, Masaya

doi:10.1016/s0016-5085(08)80039-x

Cited by 11 publications

(14 citation statements)

References 30 publications

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“…In cirrhosis, staining became more intense and diffuse, with larger stellate cells possessing more developed projections. These findings are in complete agreement with those of Yokomori et al [16,17] in the same model [16] as well as in human cirrhosis [17]. In both preparations, these investigators [16,17] demonstrated increased ET B receptor staining on hepatic stellate cells and sinusoidal endothelial cells, particularly on hepatic stellate cells.…”

Section: Reduced Et-1 Clearance In Cirrhosissupporting

confidence: 89%

“…These findings are in complete agreement with those of Yokomori et al [16,17] in the same model [16] as well as in human cirrhosis [17]. In both preparations, these investigators [16,17] demonstrated increased ET B receptor staining on hepatic stellate cells and sinusoidal endothelial cells, particularly on hepatic stellate cells. In the carbon tetrachloride model of rat cirrhosis, Ghandi et al [18] have shown an increase in total ET receptor density with no change in affinity, whereas, in the biliary liver fibrosis model, another study [19] has shown a 5-fold increase in ET B receptor density with a significant reduction in binding affinity.…”

Section: Reduced Et-1 Clearance In Cirrhosissupporting

confidence: 89%

“…Immunohistochemical analysis of normal rat and human livers reveals the presence ET B receptors on hepatic sinusoidal lining cells which, by immunogold electron microscopic analysis, were identified as hepatic stellate cells and sinusoidal endothelial cells [16,17]. Since we demonstrate that ET-1 removal is ET B -receptordependent, access into the Disse space, where hepatic stellate cells and sinusoidal endothelial cells reside, must be a prerequisite for circulating ET-1 clearance.…”

Section: Et-1 Kinetics In the Rat Livermentioning

confidence: 60%

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Reduction in hepatic endothelin-1 clearance in cirrhosis

et al. 2003

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Circulating endothelin-1 (ET-1) levels are increased in cirrhosis. The liver is an important site for circulating ET-1 clearance through the ET(B) receptor. We evaluated ET-1 kinetics in cirrhosis to determine if a reduced liver clearance contributes to this process. Cirrhosis was induced by carbon tetrachloride in rats. Hepatic ET-1 clearance was measured in isolated perfused livers using the single bolus multiple indicator-dilution technique. Plasma ET-1 levels doubled in cirrhosis from 0.49+/-0.04 fmol/ml (mean+/-S.E.M.) to 1.0+/-0.18 fmol/ml ( P <0.01). Liver ET-1 extraction was reduced from 81+/-1% (mean+/-S.E.M.) in controls to 50+/-6% in cirrhosis ( P <0.01). Kinetic modelling revealed a major irreversible binding site for ET-1 that is blocked by the selective ET(B) receptor antagonist BQ788 and a minor non-specific reversible binding site that cannot be blocked with BQ788 or the selective ET(A) antagonist BQ123. Reduced hepatic clearance correlated with the biochemical markers of cirrhosis, portal vein perfusion pressure ( r =-0.457; P <0.001) and the increase in ET-1 levels ( r =-0.462; P =0.002). Immunohistofluorescence with specific anti-(ET(B) receptor) antibodies revealed a preponderant distribution of ET(B) receptors on hepatic stellate cells, which was increased in cirrhosis. We conclude that cirrhosis reduces ET-1 clearance probably by capillarization of hepatic sinusoids and reduced access to ET(B) receptors. This relates to the severity of cirrhosis and may contribute to the increase in circulating ET-1 levels.

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Section: Reduced Et-1 Clearance In Cirrhosissupporting

confidence: 89%

Section: Reduced Et-1 Clearance In Cirrhosissupporting

confidence: 89%

Section: Et-1 Kinetics In the Rat Livermentioning

confidence: 60%

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Reduction in hepatic endothelin-1 clearance in cirrhosis

et al. 2003

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“…Thus, although the ET B receptor is more generally distributed with concentration in the collecting system, the ET A receptor seems to be the predominant vasoconstrictive receptor in accordance with its localization mainly on the vascular smooth muscle [34]. In normal human liver tissue, ET B is predominantly expressed on hepatic sinosoidal endothelial cells and hepatic stellate cells, whereas ET A is only expressed in small amounts [35]. However, ET-1 has been shown to constrict the portal vein predominantly via ET A in isolated rabbit livers [36].…”

Section: Discussionmentioning

confidence: 86%

ETA receptors mediate vasoconstriction, whereas ETB receptors clear endothelin-1 in the splanchnic and renal circulation of healthy men

Böhm¹,

Pernow²,

Lindstrøm³

et al. 2003

Clinical Science

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The contribution of the endothelin (ET) receptors ET(A) and ET(B) to basal vascular tone and ET-1-induced vasoconstriction in the renal and splanchnic vasculature was investigated in six healthy humans. ET-1 was infused alone and in combination with the selective ET(A) receptor antagonist BQ123 or the selective ET(B) receptor antagonist BQ788 on three different occasions. BQ123 did not affect basal arterial blood pressure, splanchnic vascular resistance (SplVR) or renal vascular resistance (RVR), but inhibited the increase in vascular resistance induced by ET-1 [64+/-18 versus -1+/-7% in SplVR ( P <0.05); 36+/-6 versus 12+/-3% in RVR ( P <0.0001)]. BQ788 increased basal SplVR and RVR [38+/-16% ( P =0.01) and 21+/-5% ( P <0.0001) respectively], and potentiated the ET-1-induced vasoconstriction. Plasma ET-1 increased more after ET(B) blockade than under control conditions or after ET(A) blockade. These findings suggest that the ET(A) receptor mediates the splanchnic and renal vasoconstriction induced by ET-1 in healthy humans. The ET(B) receptor seems to function as a clearance receptor and may modulate vascular tone by altering the plasma concentration of ET-1.

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“…Endothelin induces constriction of HSC, via ET-A receptor activation, and relaxation of EC via triggering of ET-B receptors and subsequent release of NO. Upon activation, HSC express ET-A and ET-B receptors (86), and in particular ET-A plays an important role during liver fibrosis (87). In recent years many attempts have been explored to attenuate hepatic ET production or antagonize its effects (82,(88)(89)(90).…”

Section: Drugs To Be Targetedmentioning

confidence: 99%

Targeting hepatic stellate cells for cell-specific treatment of liver fibrosis

Beljaars¹

2002

Front Biosci

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Since hepatic stellate cells (HSC) play a crucial role in the development of liver fibrosis, this cell is the major target for anti-fibrotic drugs. Most of the experimental drugs that influenced the HSC activity showed however low efficacy in vivo. Either a low uptake of the compounds in the cells that cause disease might account for this lack of effect, or side-effects in other cells may limit the dosage of the drugs. These side-effects may even counteract the beneficial effects. Therefore a selective delivery of drugs to the HSC may comprise a promising new way to improve liver fibrosis. The targeting to HSC has become a feasible option, because albumin-based carriers have been developed that preferentially distribute to HSC in fibrotic rat livers. In addition to the targeting of drugs, also the selective delivery of genes to HSC in fibrotic livers is of interest for therapeutic purposes and a start is made in this respect. The present review discusses the drugs to be targeted to HSC and summarizes some of the problems encountered during this novel strategy in the treatment of liver fibrosis.

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Enhanced expression of endothelin B receptor at protein and gene levels in human cirrhotic liver

Cited by 11 publications

References 30 publications

Reduction in hepatic endothelin-1 clearance in cirrhosis

Reduction in hepatic endothelin-1 clearance in cirrhosis

ETA receptors mediate vasoconstriction, whereas ETB receptors clear endothelin-1 in the splanchnic and renal circulation of healthy men

Targeting hepatic stellate cells for cell-specific treatment of liver fibrosis

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