Induction of endothelium‐dependent relaxation in the rat aorta by IRL 1620, a novel and selective agonist at the endothelin ETB receptor

Abstract

The effects of a novel and selective agonist at the endothelin ETB receptor, IRL 1620 (Suc‐[Glu9, Ala11,15] endothelin‐1 (8–21)), were examined in the isolated aorta of the rat. 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. 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 μm NG‐monomethyl‐l‐arginine, inhibited the relaxant effect of IRL 1620 but not the increase in endothelial [Ca2+]i. In resting and noradrenaline‐stimulated aorta, the effects of IRL 1620 were inhibited by a selective antagonist of the ETB receptor, IRL 1038 (0.3–3 μm), although a selective antagonist of the ETA receptor, BQ‐123 (3 μm), was ineffective. Verapamil (10 μm) did not alter the effects of IRL 1620. A muscarinic receptor agonist, carbachol (1 μm), also induced endothelium‐dependent relaxation with an increase in endothelial [Ca2+]i. However, the effects of carbachol were not inhibited by the ETB antagonist, IRL 1038 (3 μm). These results suggest that IRL 1620 is a selective agonist at the ETB 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. 1993 British Pharmacological Society