EFFECTS OF SOY ISOFLAVONES ON NITRIC OXIDE PRODUCTION IN POSTMENOPAUSAL WOMEN

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。心血管疾病是美国妇女死亡的主要原因。绝经后的妇女最容易患这种致命的疾病。绝经后妇女心血管死亡率的急剧增加主要是由于绝经期间一氧化氮（NO）产生减少导致动脉顺应性恶化。雌激素替代疗法通过刺激NO的产生逆转了恶化的过程，但增加了患乳腺癌的风险。大豆中含有大量异黄酮，其化学结构与雌二醇相似，但具有抗癌特性。我们的初步数据显示，接受大豆异黄酮治疗的绝经后妇女舒张压降低了12%，尿亚硝酸盐/硝酸盐排泄增加了20%。我们不知道有任何研究证实大豆异黄酮对一氧化氮产生的刺激作用。因此，我们建议采用双盲、随机、安慰剂对照设计，对40名正常血压高的健康绝经后妇女进行研究，以证实大豆异黄酮治疗对NO生成和舒张压降低的刺激作用。在NO生产过程中，l -精氨酸转化为NO和瓜氨酸，其中每一种都含有精氨酸的两个醌态氮原子中的一个。因此，我们建议在异黄酮或安慰剂治疗6周之前和之后，用L-[guanidino=15N2]精氨酸持续输注6小时来测量NO的产生。采用气相色谱-质谱法测定血液样品中L-[胍- 15n2]精氨酸和精氨酸- no合成酶途径产物（L-[脲- 15n]瓜氨酸，15NO2, 15NO3）的同位素丰度。血浆异黄酮浓度是受试者依从性的指标，将通过高效液相色谱-质谱法测定。样本量将使我们能够检测到一氧化氮产生20%的差异和舒张压12%的差异。由于一氧化氮在调节血管平滑肌张力、血小板粘附/聚集、白细胞粘附/迁移、神经元萎缩和骨吸收等方面具有重要的生理功能，因此确定大豆异黄酮对一氧化氮产生的有益作用至关重要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cardiovascular disease is the leading cause of death among women in the United States. Postmenopausal women are most susceptible to this deadly disease. The dramatic increase in cardiovascular mortality rate among postmenopausal women is largely due to deterioration in arterial compliance associated with the reduction in nitric oxide (NO) production during menopause. Estrogen replacement therapy reverses the deterioration process by stimulating NO production but introduces increased risk of breast cancer. Isoflavones, which have chemical structures similar to estradiol but possess anti-cancer properties, are found in abundance in soybeans. Our preliminary data showed that diastolic blood pressure was reduced by 12% and urinary nitrite/nitrate excretion was increased by 20% in postmenopausal women receiving soy isoflavone therapy. We are not aware of any studies confirming the stimulatroy effect of soy isoflavones on NO production. Therefore, we propose to study 40 healthy postmenopausal women with high-normal blood pressure, using a double-blind, randomized, placebo-controlled design, to confirm the stimulatory effect of soy isoflavone therapy on NO production and reduction in diastolic blood pressure. During NO production, L-arginine is converted to NO and citrulline with each containing on of the two quanidino nitrogen atoms of arginine. Therefore, we propose to use a primed, 6-h constant infustion of L-[guanidino=15N2]arginine to measure the NO production, both before and after 6 weeks of isoflavone or placebo therapy. Gas chromatography-mass spectrometry will be used to measure the isotopic abundance of L-[guanidino-15N2]arginine and the products of the arginine-NO synthase pathway (L-[ureido-15N]citrulline, 15NO2, 15NO3) in the blood samples. Plasma isoflavone concentrations, an index of subject compliance, will be measured by HPLC-mass spectrometry. The sample size will allow us to detect differences of 20% in NO production and 12% in diastolic blood pressure. With the many important physiological functions of NO in the regulation of vascular smooth muscle tone, platelet adhesion/aggregation, leukocyte adhesion/emigration, neuronal atrophy, and bone resorption, it is crucial to confirm the beneficial effect of soy isoflavones on NO productio