Ovarian Hormones Modulate Endothelin-1 Vascular Reactivity and mRNA Expression in DOCA-Salt Hypertensive Rats

Abstract

Abstract-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. Key Words: deoxycorticosterone Ⅲ vasoconstriction Ⅲ endothelin Ⅲ estrogen Ⅲ receptors, endothelin I n deoxycorticosterone (DOCA)-salt hypertension and other experimental models of hypertension, male rats develop an earlier and more severe form of hypertension than do female rats. 1-2 We have recently suggested that differential activation of endothelin-1 (ET-1) pathways, expressed by a functional upregulation of ET B receptors, may play a role in the higher blood pressure (BP) levels observed in male DOCA-salt hypertensive rats. [3][4] We observed that mesenteric arterioles from male but not female DOCA-salt rats display incre...

Effects of estrogen on the vascular system

“…Changes in ET Bmediated vascular responses were associated with increased ET-1 and ET B receptor gene expression in male, but not in female, animals (49). Furthermore, we observed that ovariectomy increases the vasoconstricting responses to the ET B agonist and that estrogen replacement therapy restores IRL-1620-induced responses, supporting our suggestion that the ovarian hormones modulate ET-1/ ET B receptor vascular responses/expression in DOCA-salt hypertension (50).…”

Sex Steroids, Cardiovascular Disease, and Hypertension

“…21 In premenopausal women, a differential ratio of ET A to ET B receptors has also been found, favoring a vasodilator effect of endothelin via ET B receptors. 22 In recent animal studies, estradiol 23 or its metabolites 24 have been shown to inhibit endothelin synthesis and improve endothelial dysfunction in ovariectomized female spontaneously hypertensive rats 25 and DOCA-salt hypertensive rats. 23 Therefore, estrogens should be cardiovascular protective because of their positive effect on endothelin inhibition.…”

Alteration at translational but not transcriptional level of transferrin receptor expression following manganese exposure at the blood–CSF barrier in vitro

“…Rat GAPDH was used as an internal control with a forward primer 5′ -CAC CAC CCT GTT GCT GTA-3′ and reverse primer 5′ -TAT GAT GAC ATC AAG AAG GTG G-3′ (David et al, 2001) to generate a 219-bp product.…”