Involvement of the endothelin ETB receptor in gender differences in deoxycorticosterone acetate-salt-induced hypertension

1. In the present study, we investigated the role of endothelin ETB 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 ETB 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 (O-2(-)) 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 ETB receptor deficiency. There were similar increases in the vascular endothelin (ET)-1 content in the three DOCA-salt-treated animal groups, but vascular (O-2(-)) production in male and OVX rats was much higher than that in intact females. 4. Daily oral administration of ABT-627, an ETA 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 ETB receptor deficiency, suggesting that ETB receptor-mediated vasoprotective actions contribute to the gender differences seen. In addition, in both sexes, vascular ET-1 overproduction and the ETA receptor-mediated action seem to be responsible for the enhanced susceptibility to DOCA-salt hypertension in genetic ETB receptor deficiency.