Ovarian hormones modulate endothelin-1 vascular reactivity and mRNA expression in DOCA-salt hypertensive rats.
We previously demonstrated a differential activation of the endothelin-1 (ET-1) pathway in male and female deoxycorticosterone (DOCA)-salt hypertensive rats, with the male rats exhibiting marked alterations in vascular and pressor responses to ET-1 and Suc-[Glu,(9)Ala(11,15)]-ET-1(8-21) (IRL-1620), an ET(B) agonist. Mechanisms underlying these gender differences are unclear, and we hypothesized that the ovarian hormones attenuate vascular ET(B) responses in female DOCA-salt rats. Female Wistar rats were randomized in 3 groups: sham-operated, ovariectomized (OVX), and OVX plus hormone replacement with estradiol (E) or estradiol/progesterone (EP). Two weeks later, rats were uninephrectomized and further randomized in DOCA-salt (subcutaneous injections of desoxycorticosterone and drinking water containing NaCl/KCl) and control normotensive (subcutaneous injections of vehicle and tap water). Blood pressure was evaluated both by direct and standard tail-cuff methods. Responses to IRL-1620 were evaluated in vivo/in situ in the mesenteric microcirculation. mRNA expression of ET-1 and ET(A/B) receptors was evaluated in mesenteric arteries by reverse transcription-polymerase chain reaction and expressed relative to GAPDH. OVX-DOCA rats developed a more severe form of hypertension than did DOCA rats. Treatment with E or EP restored blood pressure to levels observed in DOCA rats. In the mesentery, IRL-1620 induced vasodilatation in control rats, a mild vasoconstriction in DOCA rats, and marked vasoconstriction in OVX-DOCA rats. Both E and EP decreased IRL-1620-induced vasoconstriction in the DOCA group. In the normotensive group, OVX did not change blood pressure or IRL-1620-induced vasodilation. Removal of the ovaries increased ET-1 mRNA in arteries from DOCA and control rats, although treatment with E or EP reversed these changes. Vascular ET(B) receptor mRNA levels were greatly enhanced in OVX-DOCA but not OVX-control rats. Hormone replacement with E or EP restored ET(B) receptor expression in the DOCA group. A greater blood pressure-lowering effect of bosentan (ET(A)/ET(B) blocker) was observed in OVX-DOCA rats. The observation that OVX worsens hypertension as well as the altered ET(B) receptor-mediated responses and the effects of bosentan in female DOCA rats supports our suggestion that the ovarian hormones modulate ET-1/ET(B) receptor vascular responses/expression in DOCA-salt hypertension.
David
F L
FL
Departments of Pharmacology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, SP, Brazil.
Carvalho
M H
MH
Cobra
A L
AL
Nigro
D
D
Fortes
Z B
ZB
Rebouças
N A
NA
Tostes
R C
RC
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D003900:Desoxycorticosterone / Q000008:administration & dosage; D019332:Endothelin-1 / Q000235:genetics / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D004958:Estradiol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D010446:Peptide Fragments / Q000494:pharmacology; D017419:Potassium, Dietary / Q000008:administration & dosage; D011374:Progesterone / Q000097:blood / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013997:Time Factors; D014599:Uterus / Q000254:growth & development; D014661:Vasoconstriction / Q000187:drug effects
D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D017419:Potassium, Dietary; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D017673:Sodium Chloride, Dietary; C074308:sovateltide; D003900:Desoxycorticosterone; D011374:Progesterone; D004958:Estradiol