Presently, there is a scarcity of data regarding the effects of estrogen on the natural history of hypertension. Only in the early decades of life is there prevalence of hypertension more frequent in men than women. The increased incidence of hypertension in women after age 50 suggests that endocrine changes associated with a decline in ovarian function play a role in the pathogenesis and clinical manifestation of hypertension. The natural history of estrogen reduction with age could carry with it an increased risk of cardiovascular disease, perhaps mediated by hypertension. Consequently the value of estrogen replacement as prophylactic to hypertension disease and as an important supplement to antihypertensive therapy seems plausible. These issue have not been adequately addressed, and furthermore, it has not been clearly demonstrated whether estrogen is protective in regard to hypertension. Unquestionably, more that one system plays a role in the pathogenesis of hypertension, but major derangements include he renin-angiotensin system (RAS) and the control of vascular tone by tissue autocoids such as vasodilator-endothelial derived relaxing factors (EDRF), nitric oxide (NO) and prostaglandins (PG). The transgenic hypertensive rat (mRen-2) 27 affords us a unique opportunity to explore these interactions, since we have demonstrated an increase in EDRF/NO activity in this monogenetic model of high blood pressure. Furthermore, our preliminary data would suggest that estrogen modulates both the RAS and vasodepressor system, We propose to explore the interactions of estrogen with the circulating and local vascular RAS and vascular endothelium. Our hypothesis is: estrogen is protective against hypertension through an influence on the renin-angiotensin system, which shifts the vasoconstrictor-vasodilator balance. As a consequence of this interaction, estrogen augments the effectiveness of anti-hypertensive treatment. We propose to address these issues by: 1) testing the hypothesis that estrogen acts to modulate vascular tone by augmenting NO or PG release or by down regulating angiotensin vascular receptors. Changes in vascular tone will be evaluated in ovariectomized rats treated with estrogen alone or in combination with progesterone. In whole animals, we will evaluate the hemodynamic consequences of sex hormone replacement on vascular tone. Direct measures will be made of endothelium-dependent and independent relaxation in regional vascular beds, in aortic rings and vascular cells in culture; 2) characterizing the effects of estrogen on circulating and local tissues expression (isolated vascular blood vessels or across the hindlimb and mesenteric vascular beds) of angiotensin peptides in ovariectomized hypertensive and normotensive female rats. 3) testing the hypothesis that estrogen potentiates the antihypertensive effects of angiotensin converting enzyme inhibition.
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