Women typically have increased cardiovascular disease following menopause. One of the major risk factors for cardiovascular disease is hypertension, and after menopause, blood pressure increases progressively in women. However, the mechanism(s) responsible for the post-menopausal increase in blood pressure are yet to be elucidated. Activation of the renin-angiotensin system (RAS), increases in endothelin, and oxidative stress are hallmarks that characterize postmenopausal (PM) women. Androgens may also be increased. Progress in elucidating the mechanisms responsible for PM hypertension has been hampered by the lack of a suitable animal model. In recent studies we have characterized the aging female spontaneously hypertensive rat (SHR) as a model of PM hypertension, since they exhibit many of the humoral characteristics found in PM women. Female SHR stop cycling at 10-12 mos of age and serum estradiol levels are decreased. By 18 mos of age, blood pressure is increased by 20-25 mm Hg, compared to pre-menopausal SHR. Just as found in PM women, PM SHR exhibit increased plasma renin activity and renal vasoconstriction. In preliminary studies losartan reduced the blood pressure in PM rats, implicating a role for the RAS in PM hypertension in the rat. We also have preliminary data indicating that endothelin receptor (ETA) antagonism attenuates the higher blood pressure which supports a causative role for endothelin in the hypertension, as suggested in PM women. Oxidative stress is present in PM SHR as in PM women, and chronic antioxidant treatment results in a reduction in blood pressure. Serum testosterone has been found to be increased in some postmenopausal women in whom androgens were measured serially over 10 years. In PM SHR, serum testosterone is increased, and in preliminary studies flutamide, an androgen receptor antagonist, reduces blood pressure. Thus the aging female SHR closely resembles many of the cardiovascular characteristics in postmenopausal women and is an appropriate model in which to study PM hypertension. Based on our preliminary studies the overall working hypothesis is that the increase in blood pressure in PM rats is caused by a shift to the right in the pressure-natriuresis relationship mediated by activation of the renin-angiotensin system with subsequent increases in endothelin and oxidative stress. We also propose that an increase in androgens contributes to the hypertension by activating, the renal RAS and endothelin system and promoting oxidative stress. These hypotheses will be tested in conscious, chronically instrumented female SHR and Sprague Dawley rats, that are pre-menopausal (4 and 8 mos) or postmenopausal (18 mos) and in age-matched male SHR (18 mos), by employing an integration of biochemical, molecular and physiological techniques. Specifically, in Aim 1, the hypothesis that activation of the RAS plays a central role in mediating the increase in blood pressure in PM SHR will be tested. The hypotheses that endothelin contributes to the increased blood pressure in PM SHR and that angiotensin II mediates the increase in endothelin will be tested in Aim 2.
In Aim 3, the hypotheses that oxidative stress plays an important role in PM hypertension, and the RAS and endothelin mediate the oxidative stress will be tested. Finally, in Aim 4 the role that androgens play in PM hypertension will be determined. The hypotheses to be tested are that androgens play a role in PM hypertension by activating the RAS, stimulating endothelin synthesis and oxidative stress.
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