Involvement of the endothelin ET(B) receptor in gender differences in deoxycorticosterone acetate-salt-induced hypertension.
1. In the present study, we investigated the role of endothelin ET(B) receptors in gender differences in the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ET(B) receptor gene. 2. In wild-type rats, the elevation of systolic blood pressure (SBP) by DOCA-salt treatment for 4 weeks was extremely lower in females than in males, but this gender difference was partially attenuated in ovariectomized (OVX) animals. These alterations of SBP corresponded with vascular superoxide () production. 3. In homozygous (sl/sl) group, the SBP of male, intact female and OVX rats was markedly elevated by DOCA-salt treatment to the same extent, indicating that the gender difference in DOCA-salt-induced hypertension was abolished by the genetic ET(B) receptor deficiency. There were similar increases in the vascular endothelin (ET)-1 content in the three DOCA-salt-treated animal groups, but vascular production in male and OVX rats was much higher than that in intact females. 4. Daily oral administration of ABT-627, an ET(A) receptor antagonist, to sl/sl rats for 2 weeks suppressed the DOCA-salt-induced hypertension more efficiently in intact female rats than in male animals. 5. Thus, vascular oxidative stress is related, at least in part, to differences in the development of DOCA-salt-induced hypertension between male and female rats, but this gender difference is abolished by the genetic ET(B) receptor deficiency, suggesting that ET(B) receptor-mediated vasoprotective actions contribute to the gender differences seen. In addition, in both sexes, vascular ET-1 overproduction and the ET(A) receptor-mediated action seem to be responsible for the enhanced susceptibility to DOCA-salt hypertension in genetic ET(B) receptor deficiency.
Kawanishi
Hideaki
H
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Hasegawa
Youichi
Y
Nakano
Daisuke
D
Ohkita
Mamoru
M
Takaoka
Masanori
M
Ohno
Yukihiro
Y
Matsumura
Yasuo
Y
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone / Q000008:administration & dosage / Q000633:toxicity*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D044023:Receptor, Endothelin B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012737:Sex Factors; D013481:Superoxides / Q000378:metabolism; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044023:Receptor, Endothelin B; D013481:Superoxides; D003900:Desoxycorticosterone; D004299:Dopamine beta-Hydroxylase; D000077868:Atrasentan