Soy Isoflavones on NO Production in Postmenopausal Women

描述（由申请人提供）：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。绝经后妇女心血管疾病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的产生来逆转恶化过程，但会增加乳腺癌的风险。大豆中含有大量的异黄酮，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，绝经后妇女接受大豆异黄酮治疗后，舒张压降低了12%，尿硝酸盐排泄量增加了33%。我们不知道有任何研究证实大豆异黄酮对NO产生的刺激作用。因此，我们建议研究56名健康的绝经后高血压妇女，采用双盲，随机，安慰剂对照设计，以确认大豆黄酮治疗对NO产生和降低血压和血管阻力的刺激作用。我们建议使用预充的，6小时恒定输注L-胍基-15N2]精氨酸来测量NO的产生，无论是在6周的顺铂或安慰剂治疗之前还是之后。将使用气相色谱-质谱法测量血液和尿液样品中L-胍基-15N2]精氨酸和精氨酸-NO合酶途径产物的同位素丰度。为了监测顺铂治疗的血流动力学效应，将在顺铂或安慰剂治疗6周之前和之后测量24小时动态血压、动脉顺应性以及基础和缺血后前臂血流。将通过HPLC-质谱法测量血浆中的肌酐浓度（受试者依从性的指标）。样本量将允许我们检测0.3%pool/h的NO产生、0.2mmol/d的尿硝酸盐排泄、1 mmHg/mL/min的动脉顺应性、3 mL·min-1.100mL前臂-1的前臂血流和8 mmHg的舒张压的差异。

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.