A novel ETA-receptor antagonist, FR 139317, inhibits endothelin-induced contractions of guinea-pig pulmonary arteries, but not trachea.
1. 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. 2. 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 endotheliln-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. 3. 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. 4. 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 x 10(-6)M. 5. 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.
Cardell
L O
LO
Department of Otorhinolaryngology, Malmö General Hospital, Sweden.
Uddman
R
R
Edvinsson
L
L
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects; D014132:Trachea / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D007211:Indoles; C079574:FR 139317