Evidence for multiple endothelin receptors in the guinea-pig pulmonary artery and trachea.

1. The responses of the three peptides, endothelin 1 (ET-1), endothelin 2 (ET-2) and endothelin 3 (ET-3) were analysed on isolated circular segments of pulmonary arteries and trachea from the guinea-pig. 2. In the pulmonary artery, the vasomotor responses to the endothelins, expressed as the maximum contraction (Emax%), had the order ET-1 greater than ET-2 greater than ET-3 while the order of potency (pD2) was ET-1 = ET-2 greater than ET-3. ET-1 and ET-2 caused cross-desensitization, but did not affect the responses to ET-3. ET-3 did not cause cross-desensitization to ET-1 or ET-2 although it induced homologous desensitization. Finally, the effects of ET-1 and ET-2 were additive to those of ET-3. The additive effect of ET-3 to those of ET-1 or ET-2 was more difficult to demonstrate, given the profound contraction produced by ET-1 and to a lesser extent by ET-2. 3. In the trachea, the rank order of potency, additivity and desensitization were different from the pulmonary artery. Basically, all three peptides were equipotent but less potent than ET-1 in the artery. There was no evidence for additivity and only a slight tendency to tachyphylaxis was seen. 4. The guinea-pig pulmonary artery appears to be endowed with one receptor type which is sensitive to ET-1/ET-2 and with another receptor type which responds preferentially to ET-3. In the trachea, neither of these receptors appears to be present since all three peptides apparently act on a homogeneous population of receptors with characteristics different from those of the two arterial receptors. This suggests a third non-isopeptide selective type of endothelin receptor.