Soy Isoflavones on NO Production in Postmenopausal Women

描述(申请人提供)：心血管疾病是美国女性死亡的主要原因。绝经后的妇女最容易患上这种致命的疾病。绝经后妇女心血管死亡率的急剧上升在很大程度上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的产生逆转了恶化过程，但增加了患乳腺癌的风险。大豆中含有丰富的异黄酮类化合物，其化学结构与雌二醇相似，但具有抗癌作用。我们的初步数据显示，在接受大豆异黄酮治疗的绝经后妇女中，舒张压降低了12%，尿硝酸盐排泄增加了33%。据我们所知，目前还没有任何研究证实大豆异黄酮会刺激NO的产生。因此，我们建议采用双盲、随机、安慰剂对照设计，对56名正常血压偏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产生的刺激作用以及降低血压和血管阻力的作用。我们建议在异黄酮类或安慰剂治疗6周前和6周后，使用预先准备好的、持续6小时的L精氨酸输注来测量NO的产生。用气相色谱-质谱法测定血液和尿样中精氨酸和精氨酸-NO合成酶途径产物的同位素丰度。为了监测异黄酮组的血流动力学效应，我们将在异黄酮组或安慰剂组治疗前和治疗6周后测量24小时动态血压、动脉顺应性以及基础和缺血后前臂血流量。血浆异黄酮浓度是受试者依从性的一个指标，将通过高效液相色谱-质谱仪进行测量。样本量将使我们能够检测到一氧化氮产生的0.3%池/小时，尿硝酸盐排泄0.2mmold，动脉顺应性1毫米汞/毫升/分钟，前臂血流3mL.分钟-1.100毫升，舒张压8毫米汞柱。

DESCRIPTION (provided by applicant): 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 nitrate excretion was increased by 33% in postmenopausal women receiving soy isoflavone therapy. We are not aware of any studies confirming the stimulatory effect of soy isoflavones on NO production. Therefore, we propose to study 56 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 blood pressure and vascular resistance. We propose to use a primed, 6-h constant infusion 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-'5N2]arginine and the products of the arginine-NO synthase pathway in the blood and urine samples. To monitor the hemodynamic effects of isoflavone therapy, 24-h ambulatory blood pressure, arterial compliance, and basal and post-ischemic forearm blood flow will be measured, before and after 6 weeks of isoflavone or placebo therapy. 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 0.3 % pool/h in NO production, 0.2 mmol/d in urinary nitrate excretion, 1 mmHg/mL/min in arterial compliance, 3 mL.min-1.100 mL forearm-1 in forearm bloodflow, and8 mmHg in diastolic blood pressure.