Kinetics of endothelin-1 binding in the dog liver microcirculation in vivo

Abstract

Endothelin-1 (ET-1) is a 21-amino acid peptide produced by vascular endothelial cells that acts as a potent constrictor of hepatic sinusoids. Hepatic binding of tracer (125)I-labeled ET-1 was investigated in anesthetized dogs with the multiple-indicator dilution technique with simultaneous measurements of unlabeled immunoreactive ET-1 plasma levels. Despite 80% binding to albumin, tracer (125)I-ET-1 was avidly extracted by the liver, with only 15 +/- 6% of the peptide surviving passage through the organ. Exchange of ET-1 between plasma and binding sites, probably located on the surface of liver cells, was quantitatively described by a barrier-limited, space-distributed variable transit time model. Reversible and irreversible parallel binding sites were found. Reversible and irreversible plasma clearances of unbound (125)I-ET-1 were 0.084 +/- 0.033 ml. s(-1). g liver(-1) and 0.17 +/- 0.09 ml. s(-1). g liver(-1), respectively, and the dissociation rate constant for reversible binding was 0.24 +/- 0.12 s(-1). The specific ET(A) receptor antagonist BMS-182874 did not modify binding to either site. The nonspecific ET(A)/ET(B) antagonist LU-224332 dose-dependently reduced irreversible binding only. ET-1 levels in the hepatic vein were significantly lower than in the portal vein but were not different from those in the hepatic artery. The ratio between hepatic vein and portal vein levels (0.64 +/- 0.31) was considerably higher than survival fractions, suggesting a substantial simultaneous release of newly synthesized or stored ET-1 by the liver. These results demonstrate both substantial clearance and production of ET-1 by the intact liver. Hepatic ET-1 clearance is mediated by the ET(B) receptor, with the presence of reversible, nonspecific ET-1 binding at the liver surface

Endothelial cell-specific ETB receptor knockout: autoradiographic and histological characterisation and crucial role in the clearance of endothelin-1This article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

“…It is well established that the lungs, kidneys, and liver are important sites of ET-1 clearance (Fukuroda et al 1994;Dupuis et al 1999;Tran Duc et al 2003;Johnström et al 2005). One limitation of our study is that we did not measure the activity of these main organs at the end of the [ 125 I]ET-1 clearance studies.…”

Positron emission tomography using 18F‐labelled endothelin‐1 reveals prevention of binding to cardiac receptors owing to tissue‐specific clearance by ETB receptors in vivo

“…Interestingly, early dynamic data revealed an increase in time to reach equilibrium after pretreatment, suggesting blockade of ET B receptor‐mediated uptake. This is supported by the observation in isolated perfused liver that binding to ET B receptors is the major route of clearance for ET‐1 in single pass experiments (Dupuis et al ., 1999). We cannot at this point conclude whether the later dynamic data, suggesting increased levels of binding to liver tissue, reflect increased levels of binding to ET A receptors in lipocytes (Housset et al ., 1993) or an increase in metabolic activity in liver cells (Gandhi et al ., 1993).…”

The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair

“…Surprisingly, relatively few studies have investigated this method which, for instance, is ideally suited to probe the permeability properties of hepatic sinusoids and to assess receptor-binding kinetics within the hepatic microcirculation (87, 148,308,311,853). By means of multiple indicator dilution technique, Dupuis et al (164), investigating the hepatic binding of tracer 125 I-labeled ET-1, could demonstrate that there is both substantial clearance and production of ET-1 by the intact liver and that ET-1 clearance is mediated by the ET B receptor with the presence of reversible, nonspecific ET-1 binding at the liver surface. As an extension of the latter observation, it was demonstrated that ET-1 markedly decreases extravascular albumin space in both controls and cirrhosis (659) and that cirrhosis reduces ET-1 clearance probably by capillarization of hepatic sinusoids and reduced access to ET B receptors.…”