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Induction of endothelium‐dependent relaxation in the rat aorta by IRL 1620, a novel and selective agonist at the endothelin ET B receptor
Author(s) -
Karaki Hideaki,
Sudjarwo Sri Agus,
Hori Masatoshi,
Takai Michihiro,
Urade Yoshihiro,
Okada Toshikazu
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13595.x
Subject(s) - agonist , endothelin receptor , endothelium , aorta , chemistry , endothelin 1 , endocrinology , receptor , medicine , endothelins , biology , pharmacology
1 The effects of a novel and selective agonist at the endothelin ET B receptor, IRL 1620 (Suc‐[Glu 9 , Ala 11,15 ] endothelin‐1 (8–21)), were examined in the isolated aorta of the rat. 2 IRL 1620 (1–300 n m ) changed neither the resting tone nor the cytosolic Ca 2+ level ([Ca 2+ ] i ) of the aorta without endothelium. In the presence of endothelium, however, IRL 1620 increased endothelial [Ca 2+ ] i with little effect on the muscle tone. In the absence of external Ca 2+ , IRL 1620 still induced a transient increase in endothelial [Ca 2+ ] i . 3 Noradrenaline (100 n m ) increased both muscle [Ca 2+ ] i and tension. IRL 1620 (1–300 n m ) relaxed the muscle with an increase in endothelial [Ca 2+ ] i only in the presence of endothelium. An inhibitor of nitric oxide synthase, 100 μ m N G ‐monomethyl‐ l ‐arginine, inhibited the relaxant effect of IRL 1620 but not the increase in endothelial [Ca 2+ ] 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 μ m ), although a selective antagonist of the ET A receptor, BQ‐123 (3 μ m ), was ineffective. Verapamil (10 μ m ) did not alter the effects of IRL 1620. 5 A muscarinic receptor agonist, carbachol (1 μ m ), also induced endothelium‐dependent relaxation with an increase in endothelial [Ca 2+ ] i . However, the effects of carbachol were not inhibited by the ET B antagonist, IRL 1038 (3 μ m ). 6 These results suggest that IRL 1620 is a selective agonist at the ET B receptor which increases endothelial [Ca 2+ ] i by releasing Ca 2+ from storage sites and by opening non‐L type Ca 2+ channels, activates nitric oxide synthase, releases nitric oxide, and relaxes vascular smooth muscle.