title: Receptor- and non-receptor-mediated clearance of big-endothelin and endothelin-1: differential effects of acute and chronic ETA receptor blockade.
abstract: OBJECTIVE
  The aims of this study were to define and characterize the different mechanisms and sites of clearance of plasma endothelin-1 (ET-1) and big endothelin-1 (BigET-1) and evaluate possible effects of ETA versus combined ETA and ETB receptor blockade or endothelin converting enzyme (ECE) inhibition.
  
  
  METHODS
  Time courses and sites of clearance were evaluated in Wistar-Kyoto rats after bolus injection of radiolabelled peptides into the carotid artery before or after treatment with LU1 35252 (ETA) and bosentan (ETA and ETB) as receptor antagonists or the ECE inhibitor phosphoramidon.
  
  
  RESULTS
  The study shows that differential clearance of 125I-ET-1 and 125I-BigET-1 is mediated by distinct tissue-specific, receptor- and non-receptor-mediated mechanisms. Low levels of plasma ET-1 are rapidly cleared, mainly in the pulmonary circulation, through a low-capacity saturable ETB receptor-linked mechanism. In contrast, BigET-1 clearance is markedly slower, confined largely to liver and kidneys, is essentially non-receptor-mediated and is independent of converting enzyme activity. Acute inhibition of both ETA and ETB receptors with bosentan dramatically prolonged 125I-ET-1 plasma half-life and shifted tissue uptake from lung to liver and kidneys. Pulmonary clearance of 125I-ET-1 was decreased by chronic but not acute treatment with the specific ETA receptor antagonist LU135252. In contrast, 125I-Big-ET-1 clearance and tissue uptake were essentially unchanged by all treatments.
  
  
  CONCLUSIONS
  Plasma levels and clearance studies on ET-1 and BigET-1 may provide differential information regarding pathological changes in their separate uptake mechanisms. Such data could have diagnostic or prognostic value in pulmonary, hepatic and renal pathophysiology or future therapeutic monitoring of treatment efficacy following administration of selective receptor antagonists.
authors.affiliation: Department of Clinical Research, University of Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Burkhardt
authors.forename: M
authors.initials: M
authors.lastname: Barton
authors.forename: S G
authors.initials: SG
authors.lastname: Shaw
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D016232:Endothelins / Q000378:metabolism*; D006020:Glycopeptides / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D010666:Phenylpropionates / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D010666:Phenylpropionates; D011480:Protease Inhibitors; D011498:Protein Precursors; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D013449:Sulfonamides; C107831:darusentan; D000077300:Bosentan; C008890:phosphoramidon