Distortion of KB estimates of endothelin‐1 ETA and ETB receptor antagonists in pulmonary arteries: Possible role of an endothelin‐1 clearance mechanism

摘要

Dual endothelin ET_A and ET_B receptor antagonists are approved therapy for pulmonary artery hypertension (PAH). We hypothesized that ET_B receptor‐mediated clearance of endothelin‐1 at specific vascular sites may compromise this targeted therapy. Concentration‐response curves (CRC) to endothelin‐1 or the ET_B 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 ET_A 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 ET_B 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 ET_A receptor antagonism. In rat trachea (ET_B), bosentan was a competitive ET_B antagonist against endothelin‐1 or sarafotoxin S6c. Modeling showed the importance of dual receptor antagonism where the potency ratio of ET_A to ET_B 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 ET_B antagonist BQ788, is possibly due to the competition of potentiation of endothelin‐1 by blockade of ET_B‐mediated endothelin‐1 clearance located on smooth muscle and antagonism of ET_A‐ and ET_B‐mediated contraction. This conclusion may have direct application for the efficacy of endothelin‐1 antagonists for treating PAH.