AIMS: 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.
AIMS: 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: Didier Lebrec; Jaime Bosch; Rajiv Jalan; Francis J Dudley; Rada Jessic; Richard Moreau; Juan Carlos Garcia-Pagan; Rajeshwar P Mookerjee; Eleonora Chiossi; Paul L M Van Giersbergen; Andjela Kusic-Pajic; Jasper Dingemanse Journal: Eur J Clin Pharmacol Date: 2011-11-20 Impact factor: 2.953
Authors: Alyssa M Schlenz; Catherine B McClellan; Teresa R M Mark; Alvin D McKelvy; Eve Puffer; Carla W Roberts; Sarah M Sweitzer; Jeffrey C Schatz Journal: J Pain Date: 2012-05-24 Impact factor: 5.820
Authors: Roberta L Keller; Theresa A Tacy; Karen Hendricks-Munoz; Jie Xu; Anita J Moon-Grady; John Neuhaus; Phillip Moore; Kerilyn K Nobuhara; Sam Hawgood; Jeffrey R Fineman Journal: Am J Respir Crit Care Med Date: 2010-04-22 Impact factor: 21.405
Authors: Vladimir Kuklin; Mikhail Kirov; Mikhail Sovershaev; Thomas Andreasen; Ole C Ingebretsen; Kirsti Ytrehus; Lars Bjertnaes Journal: Crit Care Date: 2005-03-14 Impact factor: 9.097