We have recently reported that the ovarian steroid estradiol (E2) reduces angiotensin type 1 receptor (AT1R) binding in the pituitary and adrenal and attenuates angiotensin II (Ang il)-induced adrenocorticotropic hormone (ACTH) and aldosterone secretion in NaCI-deprived, ovariectomized (OVX) rats. Clinical and experimental data suggest aldosterone is mediator of the progression of cardiovascular and renal disease, and these diseases are known to progress less rapidly in women than in men. Therefore, ovarian steroid attenuation of aldosterone secretion may be one mechanism by which females are protected from cardiovascular and renal disease. Although our findings clearly indicate that E2 regulates adrenal responsiveness to Ang II, the effect of ovarian senescence per se on adrenal responsiveness to Ang II is not known. The central hypothesis to be tested in this proposal is that the decrease in circulating steroids that occurs with ovarian senescence leads to an increase in adrenal responsiveness to Ang II that can be normalized with appropriate hormone replacement therapy (HRT). We hypothesize that the decline in circulating ovarian steroid levels that occurs with ovarian senescence leads to an increased risk of developing cardiovascular and renal disease by increasing adrenal aldosterone responses to Ang II, and we hypothesize appropriate HRT can reverse this risk.
In Aim 1 of the proposed research, we will characterize the effect of ovarian senescence on pituitary and adrenal AT1R binding and Ang II-induced ACTH and aldosterone responses by examining these variable in young (6 month), cycling and old (24 month), noncycling Fischer 344BN rats. The Fischer 344BN rat is a rodent model of aging that has been recommended by the National Institute on Aging.
In Aim 2, we will determine the HRT regimen required to normalize pituitary and adrenal AT1R binding and ACTH and aldosterone responses to Ang II in old, noncycling rats to the levels observed in young, cycling rats. We will study pituitary and adrenal AT1R binding and ACTH and aldosterone responses to Ang II in young rats, in old untreated rats, and in old rats treated with E2, progesterone (P4), E2 and P4 combined, or with one of the estrogen receptor alpha or beta selective modulators. These studies will determine whether ovarian senescence leads to a defect in adrenal responsiveness to Ang II and will help determine which type of HRT is a viable option for normalizing adrenal function. It is anticipated that the results of these studies will provide preliminary data for submission of a future individual research project grant (R01) application on this topic.
| Zheng, Wei; Shi, Min; You, Sung-Eun et al. (2006) Estrogens contribute to a sex difference in plasma potassium concentration: a mechanism for regulation of adrenal angiotensin receptors. Gend Med 3:43-53 |
