Ovariectomy Augments Hypertension in Aging Female Dahl Salt-Sensitive Rats

Abstract

Abstract-The ovariectomized (OVX) Dahl salt-sensitive (DS) rat fed a low-salt diet is a model of postmenopausal hypertension. In addition to estrogen loss, aging can also contribute to postmenopausal hypertension. We hypothesized that: (1) female DS rats on a low-salt diet become hypertensive with age; (2) ovariectomy accelerates age-dependent hypertension in the DS rat caused by estrogen depletion; and (3) this hypertension correlates with increased type 1 angiotensin receptor (AT 1 R) number (Bmax). Blood pressure was monitored by telemetry from 3 to 12 months and AT 1 R Bmax was determined by Scatchard analysis in glomeruli and adrenal cortex. Three groups of DS rats were studied: intact, OVX, and 17␤-estradiol-replaced OVX (OVXϩE). In intact rats, aging to 12 months resulted in hypertension (159Ϯ6 mm Hg) and an 82% decrease in estrogen. Blood pressure in OVX was significantly higher than OVXϩE through 12 months of age (173Ϯ4 versus 150Ϯ8 mm Hg). At 4 months, OVX increased AT 1 R Bmax compared with intact and OVXϩE in both glomeruli and adrenal cortex. Aging also increased AT 1 R Bmax in these tissues in intact rats. In summary, female DS rats fed a low-salt diet have hypertension develop with age, that is accelerated by OVX and attenuated by estrogen replacement. Concurrently, AT 1 Rs are upregulated by age and OVX, which is prevented by estrogen replacement. This study suggests that an increased activity of the renin angiotensin system contributes to the development of hypertension, and estrogen protects against this process. Key Words: aging Ⅲ Dahl rats Ⅲ hypertension, sodium-dependent Ⅲ estrogen Ⅲ renin-angiotensin system T he prevalence of hypertension in premenopausal women is lower compared with men of the same age. 1 After menopause, the incidence of hypertension in women doubles and becomes similar to men, suggesting that the loss of female gonadal steroids caused by menopause are a risk factor for postmenopausal hypertension. 2 In addition, there is evidence that salt-sensitivity also contributes to postmenopausal hypertension. 3 The mechanisms of postmenopausal hypertension are not well-understood and few animal models exist to study this phenomenon. We have shown that adult (4 months) female normotensive Dahl salt-sensitive (DS) rats maintained on a low-salt (LS) diet become hypertensive after ovariectomy (OVX). 4 Thus, the ovariectomized DS rat serves as an experimental model of postmenopausal hypertension. Furthermore, this is the first animal model in which OVX results in spontaneous hypertension. These studies suggest that salt-sensitive premenopausal women may be protected against the development of hypertension because of the presence of female gonadal steroids and that after menopause, the protective effects of these hormones are lost, thus contributing to the development of hypertension. Although these observations implicate a role for estrogen (E), the effects of aging on the regulation of blood pressure could also contribute to the development of salt-sensitive hypertension in postmenopa...

Targeting of the Renin-Angiotensin System as an Adjunct to Estrogen Replacement Therapy

“…Requiring intensive efforts, blood pressures were measured by telemetry from 3 to 12 months of age as an extension of earlier work in which blood pressures were measured from 2 to 4 months of age in intact and OVX Dahl salt-sensitive rats on low-salt diet. 11 In the present study, a significant increase in blood pressure was observed in intact, OVX, and OVX plus estrogen-treated rats over the 9-month period ( Figure 1 in the Hinojosa-Laborde et al article 10 ). The elevation in blood pressure was quite substantial in the intact Dahl salt-sensitive rats on low-salt diet.…”

“…The data by Hinojosa-LaBorde et al 10 show a positive correlation between increases in blood pressure and AT 1 receptor binding in both the adrenal cortex and glomeruli of estrogen-depleted animals and an attenuation of both of these effects by estrogen replacement therapy. Evidence for upregulation of the AT 1 receptor and presumably an overactivation of the renin-angiotensin system in these 2 important target organs for angiotensin II effects on sodium homeostasis point to a loss of estrogen modulation of the renin-angiotensin system, which may play a role in postmenopausal hypertension.…”

“…The administration of a phytoestrogen-free diet is novel and points to the authors' attempt to minimize the influence of dietary derivedestrogens on blood pressure regulation. However, pair feeding of ovariectomized (OVX) and intact rats was not performed in this study as noted by the significantly higher body weights of OVX compared with intact and OVX plus estrogen treatment at both 4 and 12 months of age ( Table 1 in the Hinojosa-Laborde et al article 10 ). Therefore, the influence of elevated food/salt intake and body weights on the augmentation of blood pressure in this group of OVX rats cannot be ruled out.…”

Sex differences in the fetal programming of hypertension

“…Consequently, the value of estrogen replacement as prophylactic to hypertension is plausible. In animal studies, ovariectomy leads to hypertension in the aging female Dahl salt sensitive and female mRen (2).Lewis rats, models whereby the female rat is normotensive to their male counterparts (67,68). Thus, a protective role for estrogens against increases in blood pressure is suggested.…”

Estrogen is a modulator of vascular inflammation

“…Estrogen has an inhibitory effect on the RAS. Estrogen deficiency increases the levels of Renin and ACE and also upregulates AT1 receptor expression (28). These effects are reversed through estrogen treatment involving genomic signaling pathways (29,30).…”