title: Endothelin ETB receptor is involved in sex differences in the development of balloon injury-induced neointimal formation.
abstract: The purpose of this study was to evaluate the involvement of endothelin (ET)(B) receptor-mediated action in the sex differences in balloon injury-induced neointimal formation using the spotting-lethal rat, which carries a naturally occurring deletion in its ET(B) receptor gene. Male and female ET(B)-deficient and wild-type rats underwent balloon injury of the carotid artery. In the wild-type rats, the neointima/media ratio was significantly lower in females than in males, but this sex difference was attenuated by ovariectomy and restored by treatment with 17β-estradiol (20 μg/kg/day). In the ET(B)-deficient rats, the neointima/media ratio of the male and female rats was markedly increased to the same level, and this increase was not affected by ovariectomy or 17β-estradiol treatment. Treatment with (+)-(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) (10 mg/kg/day), an ET(A)/ET(B) dual receptor antagonist, markedly decreased the neointima/media ratio of the male wild-type rats and the male and female ET(B)-deficient rats, but not the female wild-type rats. In addition, 2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (A-192621) (30 mg/kg/day), a selective ET(B) receptor antagonist, abolished the sex difference of balloon injury-induced neointimal formation. 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627) (10 mg/kg/day), a selective ET(A) receptor antagonist, and J-104132 (10 mg/kg/day) markedly decreased the neointima/media ratio to the same extent in males but not intact females. These results indicate that the sex difference in balloon injury-induced neointimal formation was abolished by genetic ET(B) receptor deficiency or its pharmacological blockade. The lack of a vasoprotective effect of estrogen and the augmentation of ET(A) receptor-mediated action seem to be responsible for the abolition of sex differences in the ET(B) receptor-inhibited condition.
authors.affiliation: Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka.
authors.forename: Kento
authors.initials: K
authors.lastname: Kitada
authors.forename: Nozomi
authors.initials: N
authors.lastname: Yui
authors.forename: Maki
authors.initials: M
authors.lastname: Koyama
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Kimura
authors.forename: Rie
authors.initials: R
authors.lastname: Suzuki
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tanaka
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Mori
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ohkita
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D002404:Catheterization / Q000009:adverse effects; D019332:Endothelin-1 / Q000097:blood; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D008297:Male; D058426:Neointima / Q000209:etiology*; D010052:Ovariectomy; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000235:genetics; D044023:Receptor, Endothelin B / Q000235:genetics / Q000502:physiology*; D012727:Sex Characteristics; D013599:Systole
chemical_list: D019332:Endothelin-1; D004967:Estrogens; D011725:Pyridines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C119319:J 104132