This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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 production.
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