AimsThe 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 ETAversus combined ETAand ETBreceptor blockade or endothelin converting enzyme (ECE) inhibition.MethodsTime 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 LU135252 (ETA) and bosentan (ETAand ETB) as receptor antagonists or the ECE inhibitor phosphoramidon.ResultsThe study shows that differential clearance of125I-ET-1 and125I-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 ETBreceptor-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 ETAand ETBreceptors with bosentan dramatically prolonged125I-ET-1 plasma half-life and shifted tissue uptake from lung to liver and kidneys. Pulmonary clearance of125I-ET-1 was decreased by chronic but not acute treatment with the specific ETAreceptor antagonist LU135252. In contrast,125I-Big-ET-1 clearance and tissue uptake were essentially unchanged by all treatments.ConclusionsPlasma 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.