Kinetics of endothelin-1 binding in the dog liver micro circulation in vivo

Endothelin-1 (ET-1) is a 21-amino acid peptide produced by vascular endothe lial cells that acts as a potent constrictor of hepatic sinusoids. Hepatic binding of tracer I-125-labeled ET-1 was investigated in anesthetized dogs with the multiple-indicator dilution technique with simultaneous measuremen ts of unlabeled immunoreactive ET-1 plasma levels. Despite 80% binding to a lbumin, tracer I-125-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 I-125-ET-1 were 0.084 +/- 0.033 ml . s(-1). g liver(-1) and 0.17 +/- 0.09 m l . s(-1). g liver(-1), respectively, and the dissociation rate constant fo r reversible binding was 0.24 +/- 0.12 s(-1). The specific ETA receptor ant agonist EMS-182874 did not modify binding to either site. The nonspecific E TA/ETB antagonist LU-224332 dose-dependently reduced irreversible binding o nly. ET-1 levels in the hepatic vein were significantly lower than in the p ortal vein but were not different from those in the hepatic artery. The rat io between hepatic vein and portal vein levels (0.64 +/- 0.31) was consider ably higher than survival fractions, suggesting a substantial simultaneous release of newly synthesized or stored ET-1 by the liver. These results dem onstrate both substantial clearance and production of ET-1 by the intact li ver. Hepatic ET-1 clearance is mediated by the ETB receptor, with the prese nce of reversible, nonspecific ET-1 binding at the liver surface.