ESTROGEN MODULATION OF THE CARDIOVASCULAR SYSTEM

心血管系统的雌激素调节

• 批准号: 3369810
• 负责人: KENNETH E CLARK
• 金额: $ 22.56万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3369810
• 关键词: blood pressure; cardiac output; cardiovascular pharmacology; endothelin; enzyme inhibitors; estradiol; female; gene induction /repression; heart circulation; heart rate; hormone therapy; nitric oxide; nonhuman therapy evaluation; progesterone; prostacyclins; prostaglandin F; prostaglandin endoperoxide synthase; sheep; thromboxanes; vascular endothelium; vascular resistance; vasoconstrictors; vasodilators

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.

更年期或手术去势会导致显著的改变 女性心血管系统的荷尔蒙环境。雌激素水平 急剧下降，不再是周期性的，导致许多血管运动， 生理和心理上的变化。本申请 研究系统性心血管变化以及 发生在冠脉循环中，以回应手术去势 未怀孕的绵羊。计划进行研究，以确定 激素替代疗法对全身血流动力学和冠状动脉的影响 血液流动。我们认为正常产生的雌激素起一种 在降低体循环和冠脉阻力中的重要作用 而这些变化是由合成的改变所调制的 内皮细胞血管扩张剂(前列环素和EDRF，即NO)和/或 血管收缩药(血栓素A2和内皮素-1)。此外，我们 假设去掉雌激素(发生在更年期)会导致 冠状动脉血管阻力增加，冠脉血流量减少。 提供了初步数据，表明雌激素，尽管具有 对血压的影响有限，显著增加心脏 心率、心输出量和全身血管产生较大的下降 抵抗。此外，雌激素化合物还能增加冠状动脉 血液流量高达30%。这种血管扩张似乎主要是由于 至EDRF版本。雌激素的剂量，目前用于治疗 绝经后妇女，导致心输出量和 未怀孕母羊的冠状血流量。我们假设减少了 冠状动脉血管阻力与正常内皮细胞的维持 治疗措施可降低女性患冠状动脉疾病的风险 激素替代疗法(HRT)。具体来说，我们将确定 雌激素剥夺和激素替代疗法对体循环动脉血的影响 血压、心率、心输出量、冠脉血流量和全身 以及未怀孕母羊的冠状血管阻力。我们将决定 去雌激素和激素替代疗法对循环血药浓度的影响 前列环素(6-酮-前列腺素F1α)、TXB2、血管内皮细胞 衍生松弛因子(EDRF，以血浆和尿硝酸盐测量) 或内皮素(用EIA法测定)。我们将确定雌激素是否 剥夺或HRT会导致基因表达的显著变化 前列腺素合成酶(前列腺素H合成酶 异构体)、内源性一氧化氮合酶(EDRF)或内皮素(Pre-ET) M RNA)在选定的血管中。最后，我们将确定影响 激素环境改变对前列腺素、EDRF或内皮素的影响 利用特异性药物抑制物进行合成评价 观察到的每个系统在调节心血管变化中的作用 荷尔蒙环境发生了变化。这些研究应该会有很大改进 我们对激素替代引起的心血管反应的理解 治疗和引导治疗干预的新方向 心血管疾病。