Menopause or surgical castration results in significant changes in the hormonal milieu of the female cardiovascular system. Estrogen levels drop dramatically and are no longer cyclic leading to many vasomotor, physiological and psychological changes. The present application investigates systemic cardiovascular changes as well as changes which occur in the coronary circulation in response to surgical castration in nonpregnant sheep. Studies are planned to determine the effects of hormonal replacement therapy on systemic hemodynamics and coronary artery blood flow. We propose that normally occurring estrogens play an important role in decreasing systemic and coronary vascular resistance and that these changes are modulated by alterations in synthesis of endothelial cell vasodilators (prostacyclin and EDRF, i.e. NO) and/or vasoconstrictors (thromboxane A2 and endothelin-1). Furthermore, we hypothesize that removal of estrogens (as occurs in menopause) leads to increased coronary vascular resistance and reduced coronary blood flow. Preliminary data are provided which show that estrogens, although having only limited effects on blood pressure, significantly increase heart rate, cardiac output and produce large decreases in systemic vascular resistance. Additionally, estrogenic compounds increase coronary artery blood flow by as much as 30%. This vasodilation appears to be mainly due to EDRF release. Doses of estrogens, currently used to treat postmenopausal women, lead to significant increases in cardiac output and coronary blood flow in nonpregnant ewes. We hypothesize that decreased coronary vascular resistance and maintenance of normal endothelial responses leads to a reduced risk of coronary artery disease in women on hormone replacement therapy (HRT). Specifically, we will determine the effect of estrogen deprivation and HRT on systemic arterial blood pressure, heart rate, cardiac output, coronary blood flow and systemic and coronary vascular resistance in nonpregnant ewes. We will determine the effect of estrogen deprivation and HRT on circulating concentrations of prostacyclin (measured as 6 keto PGF1 alpha), TXB2, endothelial derived relaxing factor (EDRF, measured as plasma and urinary nitrates) or endothelin (measured by EIA). We will determine if estrogen deprivation or HRT leads to significant alterations in gene expression of synthetic enzymes for prostaglandins (prostaglandin H synthase isoforms), EDRF (nitric oxide synthase) or endothelin (preproendothelin mRNA) in selected blood vessels. Finally, we will determine the effects of altered hormonal environments on prostaglandin, EDRF or endothelin synthesis by utilizing specific pharmacological inhibitors to evaluate the role of each system in modulating cardiovascular changes observed with altered hormonal environments. These studies should greatly improve our understanding of the cardiovascular responses to hormone replacement therapy and lead to new directions for therapeutic intervention in cardiovascular disease.
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