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INVOLVEMENT OF THE ENDOTHELIN ETB RECEPTOR IN GENDER DIFFERENCES IN DEOXYCORTICOSTERONE ACETATE-SALT-INDUCED HYPERTENSION

Authors


Y Matsumura, Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. Email: matumrh@gly.oups.ac.jp

SUMMARY

  • 1In 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.
  • 2In 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 (inline image) production.
  • 3In 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 inline image production in male and OVX rats was much higher than that in intact females.
  • 4Daily 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.
  • 5Thus, 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.

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