ESTROGEN MODULATION OF THE CARDIOVASCULAR SYSTEM
雌激素对心血管系统的调节
基本信息
- 批准号:2227230
- 负责人:
- 金额:$ 23.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 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 synthase nonhuman therapy evaluation progesterone prostacyclins prostaglandin F prostaglandin endoperoxide synthase sheep thromboxanes vascular endothelium vascular resistance vasoconstrictors vasodilators
项目摘要
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.
更年期或手术阉割会导致身体状况发生显着变化
女性心血管系统的荷尔蒙环境。 雌激素水平
急剧下降并且不再循环导致许多血管舒缩,
生理和心理的变化。 本申请
研究全身心血管变化以及
因手术去势而发生在冠状循环中
未怀孕的羊。 计划进行研究以确定其影响
对全身血流动力学和冠状动脉的激素替代治疗
血流(量。 我们认为正常存在的雌激素起着
在降低全身和冠状血管阻力方面发挥重要作用
并且这些变化是通过合成的改变来调节的
内皮细胞血管扩张剂(前列环素和 EDRF,即 NO)和/或
血管收缩剂(血栓素 A2 和内皮素-1)。 此外,我们
假设去除雌激素(如更年期发生的情况)会导致
冠状血管阻力增加,冠状动脉血流量减少。
提供的初步数据表明,雌激素虽然具有
对血压影响有限,显着增加心脏
心率、心输出量并导致全身血管大幅减少
反抗。 此外,雌激素化合物会增加冠状动脉
血流量减少多达 30%。 这种血管舒张似乎主要是由于
到 EDRF 版本。 目前用于治疗的雌激素剂量
绝经后妇女的心输出量显着增加
非怀孕母羊的冠状动脉血流量。 我们假设减少了
冠状血管阻力和正常内皮细胞的维持
反应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全身动脉血的影响
血压、心率、心输出量、冠状动脉血流量和全身血流量
和非怀孕母羊的冠状血管阻力。 我们将确定
雌激素剥夺和 HRT 对循环浓度的影响
前列环素(以 6 酮 PGF1 α 测定)、TXB2、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(通过 EIA 测量)。 我们将确定是否有雌激素
剥夺或 HRT 会导致基因表达的显着改变
前列腺素合成酶(前列腺素 H 合酶)
同种型)、EDRF(一氧化氮合酶)或内皮素(前内皮素原)
mRNA)在选定的血管中。 最后我们来确定一下效果
前列腺素、EDRF 或内皮素的荷尔蒙环境改变
利用特定的药理学抑制剂来评估合成
观察到的每个系统在调节心血管变化中的作用
荷尔蒙环境改变。 这些研究应该会大大提高
我们对激素替代的心血管反应的理解
治疗并为治疗干预带来新的方向
心血管疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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KENNETH E CLARK其他文献
KENNETH E CLARK的其他文献
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{{ truncateString('KENNETH E CLARK', 18)}}的其他基金
MOLECULAR MECHANISMS OF ESTROGENS VASCULAR ACTIONS
雌激素血管作用的分子机制
- 批准号:
6527425 - 财政年份:2000
- 资助金额:
$ 23.33万 - 项目类别:
MOLECULAR MECHANISMS OF ESTROGENS VASCULAR ACTIONS
雌激素血管作用的分子机制
- 批准号:
6126001 - 财政年份:2000
- 资助金额:
$ 23.33万 - 项目类别:
MOLECULAR MECHANISMS OF ESTROGENS VASCULAR ACTIONS
雌激素血管作用的分子机制
- 批准号:
6390329 - 财政年份:2000
- 资助金额:
$ 23.33万 - 项目类别:
MOLECULAR MECHANISMS OF ESTROGENS VASCULAR ACTIONS
雌激素血管作用的分子机制
- 批准号:
6603399 - 财政年份:2000
- 资助金额:
$ 23.33万 - 项目类别:
ESTROGEN MODULATION OF THE CARDIOVASCULAR SYSTEM
雌激素对心血管系统的调节
- 批准号:
2227229 - 财政年份:1993
- 资助金额:
$ 23.33万 - 项目类别:
EDRF REGULATION OF UTERINE AND UMBILICAL BLOOD FLOW
EDRF 对子宫和脐血流量的调节
- 批准号:
2225939 - 财政年份:1993
- 资助金额:
$ 23.33万 - 项目类别:
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