A C-terminal linear analog of endothelin (ET)-1, IRL 1666, antagonizes both subtypes of the ET receptor, ET_A and ET_B

• Published in: Japanese Journal of Pharmacology 1993, Vol.61 (suppl.1), p.257-257
• Main Authors: Maki Makatani, Ichiro Umemura, Naoki Teno, Naomi Uchida, Takashi Inui, Michihiro Takai, Takaki Yamamura
• Format: Article
• Language: Japanese
• ISSN: 0021-5198

ETs (ET-1, ET-2 and ET-3) are very potent vasoactive peptides consisting of 21 amino acid residues with two intramolecular disulfide bonds, which also have diverse functions in nonvascular tissues mediated by at least two receptor subtypes, ET_A and ET_B . In studies on the structure-activity relationships of ET-1, IRL 1666, N^α -succinyl 「Ala^11,15 , Gly^18 」-ET-1(10-21), was found to be a potent inhibitor of both ET_A (Ki：96 nM) and ET_B (Ki：250 pM) receptors in porcine lung membranes when measured by a previously reported method (B.B.R.C. 184, 953, 1992). Intracellular Ca^2+ levels were measured using Fura-2 in ET_A receptor dominant A10 smooth muscle cells and ET_B -receptor dominant human Girardi heart (GH) cells. IRL 1666 up to 10 μM did not cause 「Ca^2+ 」i increases in either cell type, indicating an absence of agonistic action. However, IRL 1666 concentration-dependently inhibited 「Ca^2+ 」i increases induced by 10 nM ET-1 with IC_50 Values of around 1 μM and 2 μM in A10 and GH cells, respectively. These results indicate that IRL 1666 is a bifunctional antagonist of ET_A and ET_B receptors.