Effects of a potent, non-selective endothelin receptor antagonist, [Thr18, gamma-MeLeu19]-endothelin-1, on the isolated blood vessels.

The endothelin (ET) receptor has been classified as the ETA1, ETA2, ETB1 and ETB2 subtypes. BQ-123 and RES-701-1 are the ETA1 and ETB1 antagonists, respectively, whereas BQ-788 is the ETB1/ETB2 antagonist. To find the ETA2 antagonist, the effects of [Thr18, gamma-MeLeu19]-ET-1 (TM-ET-1) were examined. In the rabbit saphenous vein, contraction induced by ET-1 is due to simultaneous activation of the ETA1, ETA2, ETB1 and ETB2 receptors whereas contraction induced by sarafotoxin S6c is mediated by the ETB1 and ETB2 receptors. Neither BQ-123 nor RES-701-1 inhibited these contractions. TM-ET-1 antagonized the effects of ET-1 and sarafotoxin S6c. In the vein in which the ETB1/ETB2 receptors were desensitized and the ETA1 receptor was inhibited by BQ-123, ET-1 still induced contraction. This contraction was inhibited by TM-ET-1. In the rat aorta with endothelium, ET-3 induced endothelium-dependent relaxation by activating the endothelial ETB1 receptor. TM-ET-1 inhibited the effect of ET-3 without changing the relaxation induced by carbachol. In the rat aorta without endothelium, ET-1 induced contraction by activating the smooth muscle ETA1 receptor. TM-ET-1 inhibited this contraction. These results suggest that TM-ET-1 is a novel antagonist against the ETA2 receptor that also inhibits other types of the ET receptors.