Inhibition of endothelin ETB receptor system aggravates neointimal hyperplasia after balloon injury of rat carotid artery.

Endothelin-1 (ET)/ET(A) receptor system has been known to play an important role in the pathogenesis of neointimal hyperplasia after endothelial injury. However, the pathological role of endothelin ET(B) receptors on neointimal hyperplasia remains to be elucidated. In the present study, we investigated the pathological role of ET(B) receptors on neointimal hyperplasia in balloon-injured rat carotid arteries by pharmacological blockade with use of 2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (A-192621), a selective ET(B) receptor antagonist, 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627), a selective ET(A) receptor antagonist, and (+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (J-104132), an ET(A)/ET(B) dual receptor antagonist. Moreover, the spotting-lethal rats, which carry a naturally occurring deletion in the endothelin ET(B) receptor gene, were used to examine the effects of genetic deficiency for this receptor subtype. Two weeks after balloon injury, the ratio of the neointimal to the medial area (neointima/media ratio) was determined. Treatment with A-192621 (30 mg/kg/day) for 2 weeks after injury significantly increased the neointima/media ratio in the injured artery. In contrast, ABT-627 (10 mg/kg/day) and J-104132 (10 mg/kg/day) markedly decreased the neointima/media ratio to the same extent. Furthermore, the neointima/media ratio in the injured artery of the ET(B)-deficient rat was significantly increased compared with that of the wild-type rat, and this increase was abolished by treatment with J-104132. These findings suggest that the inhibition of the ET(B) receptor system leads to an aggravation of neointimal hyperplasia after balloon injury, and the augmentation of ET(A)-mediated actions are responsible for the neointimal hyperplasia aggravated by the pharmacological blockade of ET(B) receptor or by its genetic deficiency. The antagonism of the ET(A) receptor system is essential for preventing restenosis after angioplasty.