INDUCTION OF ENDOTHELIUM-DEPENDENT RELAXATION IN THE RAT AORTA BY IRL-1620, A NOVEL AND SELECTIVE AGONIST AT THE ENDOTHELIN ET(B)-RECEPTOR

1 The effects of a novel and selective agonist at the endothelin ET(B) receptor, IRL 1620 (Suc-[Glu9, Ala11,15] endothelin-1 (8-21)), were examined in the isolated aorta of the rat. 2 IRL 1620 (1-300 nM) changed neither the resting tone nor the cytosolic Ca2+ level ([Ca2+]i) of the aorta without endothelium. In the presence of endothelium, however, IRL 1620 increased endothelial [Ca2+]i with little effect on the muscle tone. In the absence of external Ca2+, IRL 1620 still induced a transient increase in endothelial [Ca2+]i. 3 Noradrenaline (100 nM) increased both muscle [Ca2+]i and tension. IRL 1620 (1-300 nM) relaxed the muscle with an increase in endothelial [Ca2+]i only in the presence of endothelium. An inhibitor of nitric oxide synthase, 100 muM N(G)-monomethyl-L-arginine, inhibited the relaxant effect of IRL 1620 but not the increase in endothelial [Ca2+]i. 4 In resting and noradrenaline-stimulated aorta, the effects of IRL 1620 were inhibited by a selective antagonist of the ET(B) receptor, IRL 1038 (0.3-3 muM), although a selective antagonist of the ET(A) receptor, BQ-123 (3 muM), was ineffective. Verapamil (10 muM) did not alter the effects of IRL 1620. 5 A muscarinic receptor agonist, carbachol (1 muM), also induced endothelium-dependent relaxation with an increase in endothelial [Ca2+]i. However, the effects of carbachol were not inhibited by the ET(B) antagonist, IRL 1038 (3 muM). 6 These results suggest that IRL 1620 is a selective agonist at the ET(B) receptor which increases endothelial (Ca2+]i by releasing Ca2+ from storage sites and by opening non-L type Ca2+ channels, activates nitric oxide synthase, releases nitric oxide, and relaxes vascular smooth muscle.