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dc.contributor.authorAngus, JA-
dc.contributor.authorSoeding, PF-
dc.contributor.authorHughes, RJA-
dc.contributor.authorWright, CE-
dc.identifier.citationAngus JA, Soeding PF, Hughes RJA, Wright CE. Functional estimation of endothelin-1 receptor antagonism by bosentan, macitentan and ambrisentan in human pulmonary and radial arteries in vitro. Eur J Pharmacol. 2017; 804:111-116.en_US
dc.description.abstractEndothelin receptor antagonists are approved for pulmonary arterial hypertension. Development of selective ETA-receptor antagonists over mixed or dual receptor antagonists has depended on a range of receptor binding assays, second messenger assays and functional blood vessel assays. This study compared the 3 clinically-approved endothelin receptor antagonists in assays of human isolated pulmonary and radial arteries in vitro. METHODS: Human isolated pulmonary (i.d. 5.5mm) and human radial (i.d. 3.23mm) artery ring segments were mounted in organ baths for isometric force measurement. Single concentration-contraction curves to endothelin-1 were constructed in the absence or presence of bosentan (1-10µM), macitentan (0.03-0.3µM) or ambrisentan (0.1-1µM). RESULTS: All 3 endothelin antagonists caused competitive rightward shifts in the endothelin-1 concentration-response curves in both arteries. The Clark plot and analysis gave the following pKB values: bosentan, pulmonary artery 6.28±0.13 and radial artery 6.04±0.10; macitentan, pulmonary artery 8.02±0.13 and radial artery 7.49±0.08; and ambrisentan, pulmonary artery 7.38±0.13 and radial artery 6.96±0.10. CONCLUSIONS: Noting the maximum plasma levels attained from recommended oral doses of each antagonist in volunteers, the pKB findings here show that there would be significant antagonism of endothelin-1 contraction in the pulmonary and radial arteries at therapeutic plasma levels. This functional assay confirms in human tissue that much higher plasma concentrations of endothelin-1 receptor antagonists are required to be effective than those predicted from binding or other biochemical assays.en_US
dc.subjectHuman pulmonary arteryen_US
dc.subjectHuman radial arteryen_US
dc.titleFunctional estimation of endothelin-1 receptor antagonism by bosentan, macitentan and ambrisentan in human pulmonary and radial arteries in vitroen_US
dc.typeJournal Articleen_US
dc.identifier.journaltitleEuropean journal of pharmacologyen_US
dc.description.affiliatesAustralian and New Zealand College of Anaesthetistsen_US
item.openairetypeJournal Article-
item.fulltextNo Fulltext-
Appears in Collections:Scholarly and Clinical
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