Kento Kitada, Nozomi Yui, Chika Matsumoto
Dec 1, 2009
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2
Influential Citations
23
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Journal
Journal of Pharmacology and Experimental Therapeutics
Abstract
Endothelin-1 (ET)/ETA 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 ETB receptors on neointimal hyperplasia remains to be elucidated. In the present study, we investigated the pathological role of ETB 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 ETB 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 ETA 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 ETA/ETB dual receptor antagonist. Moreover, the spotting-lethal rats, which carry a naturally occurring deletion in the endothelin ETB 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 ETB-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 ETB receptor system leads to an aggravation of neointimal hyperplasia after balloon injury, and the augmentation of ETA-mediated actions are responsible for the neointimal hyperplasia aggravated by the pharmacological blockade of ETB receptor or by its genetic deficiency. The antagonism of the ETA receptor system is essential for preventing restenosis after angioplasty.