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• W2774057884 endingPage "e00374" @default.
• W2774057884 startingPage "e00374" @default.
• W2774057884 abstract "Dual endothelin ETA and ETB receptor antagonists are approved therapy for pulmonary artery hypertension (PAH). We hypothesized that ETB receptor-mediated clearance of endothelin-1 at specific vascular sites may compromise this targeted therapy. Concentration-response curves (CRC) to endothelin-1 or the ETB 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-1 CRC competitively indicative of ETA receptor antagonism. In rat small pulmonary arteries, bosentan 10 μmol L−1 left-shifted the endothelin-1 CRC, demonstrating potentiation consistent with antagonism of an ETB receptor-mediated endothelin-1 clearance mechanism. Removal of endothelium or L-NAME did not alter the EC50 or Emax of endothelin-1 nor increase the antagonism by BQ788. In the presence of BQ788 and L-NAME, bosentan displayed ETA receptor antagonism. In rat trachea (ETB), bosentan was a competitive ETB antagonist against endothelin-1 or sarafotoxin S6c. Modeling showed the importance of dual receptor antagonism where the potency ratio of ETA to ETB 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-1 constriction by ET dual antagonists, such as bosentan or the ETB antagonist BQ788, is possibly due to the competition of potentiation of endothelin-1 by blockade of ETB-mediated endothelin-1 clearance located on smooth muscle and antagonism of ETA- and ETB-mediated contraction. This conclusion may have direct application for the efficacy of endothelin-1 antagonists for treating PAH." @default.
• W2774057884 created "2017-12-22" @default.
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• W2774057884 date "2017-12-01" @default.
• W2774057884 modified "2023-09-23" @default.
• W2774057884 title "Distortion of KB estimates of endothelin-1 ETA and ETB receptor antagonists in pulmonary arteries: Possible role of an endothelin-1 clearance mechanism" @default.
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• W2774057884 doi "https://doi.org/10.1002/prp2.374" @default.
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