{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T09:36:07Z","timestamp":1790415367774,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,12,5]],"date-time":"2017-12-05T00:00:00Z","timestamp":1512432000000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dual endothelin<jats:styled-content style=\"fixed-case\">ET<jats:sub>A<\/jats:sub><\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content>receptor antagonists are approved therapy for pulmonary artery hypertension (<jats:styled-content style=\"fixed-case\">PAH<\/jats:styled-content>). We hypothesized that<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content>receptor\u2010mediated clearance of endothelin\u20101 at specific vascular sites may compromise this targeted therapy. Concentration\u2010response curves (<jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content>) to endothelin\u20101 or the<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content>agonist sarafotoxin S6c were constructed, with endothelin receptor antagonists, in various rat and mouse isolated arteries using wire myography or in rat isolated trachea. In rat small mesenteric arteries, bosentan displaced endothelin\u20101<jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content>competitively indicative of<jats:styled-content style=\"fixed-case\">ET<jats:sub>A<\/jats:sub><\/jats:styled-content>receptor antagonism. In rat small pulmonary arteries, bosentan 10\u00a0\u03bcmol\u00a0L<jats:sup>\u22121<\/jats:sup>left\u2010shifted the endothelin\u20101<jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content>, demonstrating potentiation consistent with antagonism of an<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content>receptor\u2010mediated endothelin\u20101 clearance mechanism. Removal of endothelium or L\u2010<jats:styled-content style=\"fixed-case\">NAME<\/jats:styled-content>did not alter the<jats:styled-content style=\"fixed-case\">EC<\/jats:styled-content><jats:sub>50<\/jats:sub>or Emax of endothelin\u20101 nor increase the antagonism by<jats:styled-content style=\"fixed-case\">BQ<\/jats:styled-content>788. In the presence of<jats:styled-content style=\"fixed-case\">BQ<\/jats:styled-content>788 and L\u2010<jats:styled-content style=\"fixed-case\">NAME<\/jats:styled-content>, bosentan displayed<jats:styled-content style=\"fixed-case\">ET<jats:sub>A<\/jats:sub><\/jats:styled-content>receptor antagonism. In rat trachea (<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content>), bosentan was a competitive<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content>antagonist against endothelin\u20101 or sarafotoxin S6c. Modeling showed the importance of dual receptor antagonism where the potency ratio of<jats:styled-content style=\"fixed-case\">ET<jats:sub>A<\/jats:sub><\/jats:styled-content>to<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content>antagonism is close to unity. In conclusion, the rat pulmonary artery is an example of a special vascular bed where the resistance to antagonism of endothelin\u20101 constriction by<jats:styled-content style=\"fixed-case\">ET<\/jats:styled-content>dual antagonists, such as bosentan or the<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content>antagonist<jats:styled-content style=\"fixed-case\">BQ<\/jats:styled-content>788, is possibly due to the competition of potentiation of endothelin\u20101 by blockade of<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content>\u2010mediated endothelin\u20101 clearance located on smooth muscle and antagonism of<jats:styled-content style=\"fixed-case\">ET<jats:sub>A<\/jats:sub><\/jats:styled-content>\u2010 and<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content>\u2010mediated contraction. This conclusion may have direct application for the efficacy of endothelin\u20101 antagonists for treating<jats:styled-content style=\"fixed-case\">PAH<\/jats:styled-content>.<\/jats:p>","DOI":"10.1002\/prp2.374","type":"journal-article","created":{"date-parts":[[2017,12,9]],"date-time":"2017-12-09T01:16:39Z","timestamp":1512782199000},"source":"Crossref","is-referenced-by-count":8,"title":["Distortion of K<sub>B<\/sub>estimates of endothelin\u20101 ET<sub>A<\/sub>and ET<sub>B<\/sub>receptor antagonists in pulmonary arteries: Possible role of an endothelin\u20101 clearance mechanism"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0605-9682","authenticated-orcid":false,"given":"James A.","family":"Angus","sequence":"first","affiliation":[{"name":"Cardiovascular Therapeutics Unit Department of Pharmacology and Therapeutics University of Melbourne Melbourne Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J. 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