Distortion of K(B) estimates of endothelin‐1 ET(A) and ET(B) receptor antagonists in pulmonary arteries: Possible role of an endothelin‐1 clearance mechanism

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 EC (50) 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.