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 EC 50 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.
Highlights
In rats,[1] rabbits,[2] and nonhuman primates,[3] dual ETA and ETB receptor antagonists or ETB-selective endothelin-1 antagonists increased the immunoreactive endothelin-1 plasma level acutely by 3- to 10fold
While this intriguing mechanism of endothelin-1 clearance by ETB receptors was first determined in vivo, we asked, could this mechanism affect the pharmacodynamics of endothelin-1 interactions with ETA and ETB receptors mediating smooth muscle contraction in isolated tissue assays when determining the pKB of endothelin-1 receptor antagonists? The impact of sites of loss of agonist or antagonist concentrations on pKB estimations has been observed in the acid-secreting mouse stomach and further developed by Kenakin.[7]
In human small pulmonary arteries (150-200 lm i.d.) sarafotoxin S6c was more than 100-fold more potent than endothelin-1 and the authors concluded that both ETA and ETB receptor antagonists are required to antagonize endothelin-1.28 We found that the apparently weak antagonism of endothelin-1 by bosentan in rat pulmonary arteries is shared with ambrisentan and macitentan (Figure 5)
Summary
In rats,[1] rabbits,[2] and nonhuman primates,[3] dual ETA and ETB receptor antagonists or ETB-selective endothelin-1 antagonists increased the immunoreactive endothelin-1 plasma level acutely by 3- to 10fold. After chronic oral dosing in rats with A-182086, a dual ETA and ETB antagonist, the endothelin-1 plasma levels rose by more than 24-fold after 9 days.[4] Micro positron emission tomography using 18F-labeled endothelin-1 in anesthetized rats confirmed that endothelin-1 rapidly binds to rat lung and is cleared from the circulation (t0.5 0.43 minutes).[5] Pretreatment with the ETB-selective antagonist BQ788 decreased the endothelin-1 clearance by 85%. We have previously reported that endothelin-1 concentration-contraction curves in rat small interlobar pulmonary arteries were surprisingly LEFT-shifted; ie, endothelin-1 contractions were “potentiated” in the presence of the dual ETA and ETB antagonist bosentan 10 lmol LÀ1,8 an observation that is consistent with blockade of a site of loss of endothelin-1
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