A novel ETA‐receptor antagonist, FR 139317, inhibits endothelin‐induced contractions of guinea‐pig pulmonary arteries, but not trachea

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Abstract
The effects of a proposed endothelin‐receptor antagonist, FR 139317, on the contraction induced by endothelin‐1, endothelin‐2 and endothelin‐3, were analysed on isolated circular segments of pulmonary arteries and rings of trachea from the guinea‐pig. The pharmacological profiles of endothelin‐1 and endothelin‐2 were almost identical in the guinea‐pig pulmonary artery, whereas endothelin‐3 demonstrated a weaker and less potent contractile effect. The contractions induced by endothelin‐1 and endothelin‐2 were competitively antagonized by FR 139317. Schild plot analysis revealed a straight line with a slope that did not differ from unity. The pA2 value was 6.65. In contrast, the endothelin‐3 induced contractile response was unaffected by FR 139317. In tracheal segments endothelin‐1, endothelin‐2 and endothelin‐3 evoked contractions of similar magnitude and sensitivity. FR 139317 had no effect on the endothelin‐induced contractions in tracheal segments. In ring segments of pulmonary artery and trachea, potassium, noradrenaline and histamine caused concentration‐dependent contractile effects. These contractions were not modified by FR 139317 in the concentration range 10−7 to 3 × 10−6 m. FR 139317 seems to be a selective ETA‐receptor antagonist which competitively antagonizes the endothelin‐1‐ and endothelin‐2‐induced contractions of guinea‐pig isolated pulmonary arteries. Thus, the guinea‐pig pulmonary artery appears to be endowed with one receptor type (ETA) which is antagonized by FR 139317 and with another endothelin‐receptor subtype which responds to endothelin‐3, but is not antagonized by FR 139317. In the trachea, all three peptides act on a homogeneous population of receptors which is unaffected by FR 139317. This suggests an ETA‐receptor in the guinea‐pig pulmonary artery and another receptor, probably of ETB‐type, in the guinea‐pig trachea.