PHARMACOLOGICAL PROFILES OF CONTRACTILE ENDOTHELIN RECEPTORS IN GUINEA-PIG HILAR BRONCHUS

Characterization of the receptors mediating contractions to endothelin-1 (ET-1), endothelin-3 (ET-3), sarafotoxin S6c (STXc), or IRL 1620 in isolated epithelium-denuded hilar bronchus of guinea pig using as antagonists BQ-123 (ET(A) receptor-selective) and Ro 46-2005 (ET(A/B) nonselective) was investigated. ET-1, ET3, STXc, and IRL 1620 produced only contraction, and their concentration-response curves were obtained at the same concentration range (10(-10)-10(-7)M). The potency order was the following: STXc = ET-3 = ET- 1 > IRL 1620. BQ-123 (10(-5)M) had no marked effect on the contraction induced by ET-3 or STXc, whereas it attenuated the response induced by high concentration of ET-1 (3 x 10(-8) - 10(-7)M). The contraction induced by IRL 1620 was antagonized by BQ-123 (3 x 10(-6) - 10(-5)M). Ro 46-2005 (10(-5)M) failed to inhibit the responses to ET-1 and ET-3. Ro 46-2005 (10(-5)M) slightly, but significantly, shifted the concentration-response curve for STXc to the right (pK(B) 4.94 +/- 0.10, n = 7), and the maximum response was potentiated to about 127%. The curve for IRL 1620 was shifted in parallel by Ro 46-2005 (3 x 10(-6) - 10(-5)M) to the right (mean pK(B) 6.35 +/- 0.09, n = 8). These results suggest that ET, receptors primarily mediate contraction to ET-1, ET-3, STXc, and IRL 1620, and the relative inhibitory activities of ET antagonists vary with the agonist used. However, ET-1 and ET-3 might also activate non-ET(B) receptor or unknown mechanisms.