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 ETB receptor gene. Male and female ETB-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 ETB-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 ETA/ETB dual receptor antagonist, markedly decreased the neointima/media ratio of the male wild-type rats and the male and female ETB-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 ETB 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 ETA 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 ETB receptor deficiency or its pharmacological blockade. The lack of a vasoprotective effect of estrogen and the augmentation of ETA receptor-mediated action seem to be responsible for the abolition of sex differences in the ETB receptor-inhibited condition.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.165308.
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ABBREVIATIONS:
- NO
- nitric oxide
- ET-1
- endothelin-1
- VSMC
- vascular smooth muscle cells
- sl
- spotting-lethal
- OVX
- ovariectomy
- E2
- 17β-estradiol
- PCR
- polymerase chain reaction
- SBP
- systolic blood pressure
- SD
- Sprague-Dawley
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- ERT
- estrogen replacement therapy
- ABT-627
- 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid
- J-104132
- (+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid
- A-192621
- 2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl) aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid.
- Received December 25, 2009.
- Accepted November 11, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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