ATZ-1993

Endothelin (ET)-1, which had been discovered as the most potent vasoconstrictive peptide, plays active roles in the various biological responses. However, it is controversial how is ET-1 involved in the vascular remodeling process. Therefore, present experiments were performed to investigate the role of ET-1 for the initiation/progression of intimal hyperplasia. Intimal hyperplasia was caused with the time to peak of 4 to 6 weeks after endothelial removal of the rabbit carotid artery and accompanied by increased ET-1 content as well as ET receptor density within the hyperplastic vessel wall. ET-1 receptors could be classified into three subtypes of ETA, ETB and tentative nonETA/nonETB. TUNEL- and Ki-67-positive cells were detectable with the time to peak of 1 to 2 weeks, whereas all positive cells disappeared within 6 weeks. ATZ1993 as a mixed type antagonist for ET-A, ET-B and nonETA/nonETB receptor subtypes inhibited the intimal hyperplasia, of which inhibition was accompanied by increased TUNEL- and p53-positive cells and decreased Bcl-2-positive cells. ET-1 accelerated the [3H]-thymidine incorporation by cultured vascular smooth muscle cells and, on the other hand, reduced TUNEL-positive cells, which was caused by the serum deprivation. The reduction of TUNEL-positive cells with ET-1 was blocked by ATZ1993 or BQ123 as an antagonist for ETA receptor, but unaffected by BQ788 as an antagonist for ETB receptor. These results strongly suggest that ET-1 plays crucial roles as a mitogen and an inhibitory factor of apoptosis in the vascular remodeling process after endothelial removal.