Effects of Endothelin Receptor Selective Antagonists, BQ-123 and BQ-788, on IRL 1620 and Endothelin-1 Responses of Airway and Vascular Preparations from Rats

Abstract

Summary: IRL 1620 (Suc-[Glu⁹, Ala^11,15]ET-1(8-21), a selective ET_B receptor agonist) contracted rat trachea and bronchus. The maximum response to IRL 1620 was less than that to endothelin-1 (ET-1) and, compared with ET-1 responses, IRL 1620 responses reached equilibrium more quickly. IRL 1620 responses were antagonized by the selective ET_B antagonist, BQ-788 (3 μM), but not by the selective ET_A antagonist, BQ-123 (3 μM). ET-1 concentration-response curves were shifted only in the presence of both BQ-123 and BQ-788 (3 μM). In the presence of BQ-123, the time course of ET-1 responses changed from being slow and sustained (ET_A, see below) to being more like that to IRL 1620 (ET_B). IRL 1620 did not contract pulmonary artery preparations from rats but ET-1 produced slow and sustained contractile responses which were antagonized by BQ-123 but not by BQ-788. Thus, ET-1 contracts rat pulmonary artery and aorta predominantly via ET_A receptors (responses blocked by BQ-123) and functional ET_B receptors are unlikely to be present (no responses to IRL 1620). In contrast, ET-1 contracts rat trachea and bronchus via ET_A and ET_B receptors (tissues contracted to IRL 1620, ET-1 responses were blocked by a combination of BQ-123 and BQ-788 and ET-1 responses resembled ET_B in character when ET_A receptors were blocked).