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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

A Meal Enriched with Soy Isoflavones Increases Nitric Oxide-Mediated Vasodilation in Healthy Postmenopausal Women^1,2

³ Nutritional Sciences Division, School of Biomedical and Health Sciences, King's College London, London SE1 9NH, UK; ⁴ Cardiovascular Division, School of Medicine, King's College London, London SE1 7EH, UK; and ⁵ Unilever Corporate Research, Sharnbrook, Bedfordshire MK44 1LQ, UK

^* To whom correspondence should be addressed. E-mail: wendy.hall{at}kcl.ac.uk.

	ABSTRACT

TOP ABSTRACT Introduction Methods Results Discussion LITERATURE CITED

 
Evidence from infusion studies suggests that soy isoflavones influence nitric oxide-dependent vasorelaxation. It is uncertain whether orally consumed isoflavones have similar effects. Healthy postmenopausal women (n = 22) consumed 2 low-fat test meals in random order 1 wk apart, with 80 mg isoflavones (ISO) or without isoflavones (CON). Endothelium-dependent vasodilation, assessed by brachial artery flow-mediated dilatation (FMD), was measured in fasting subjects, and 4 and 6 h following the test meal, in addition to blood pressure and pulse wave analysis to derive the peripheral augmentation index (pAIx). Blood samples were taken after fasting, and 5 and 7 h following the test meal for serum isoflavone, plasma 8-isoprostane F₂, nitric oxide metabolites (NOx), glucose, and triacylglycerol analysis. Serum genistein and daidzein concentrations (geometric mean, 95% CI) reached 1.49 (1.20–1.84) µmol/L and 0.95 (0.70–1.30) µmol/L, respectively, following ISO (7 h). FMD and plasma NOx concentrations were greater following ISO compared with CON, indicating better postprandial endothelial function. FMD values (%, mean ± SD) were: CON, 5.49 ± 2.32, 4.35 ± 2.32, 4.40 ± 2.26; ISO, 5.38 ± 1.91, 5.08 ± 1.74, 6.11 ± 2.60, at baseline, 4 h, and 6 h, respectively (P < 0.01). Plasma NOx concentrations (µmol/L, mean ± SD) were: CON, 20.0 ± 5.1, 16.8 ± 5.1, 23.1 ± 6.0; ISO, 18.6 ± 6.3, 19.5 ± 5.1, 21.3 ± 10.1, at baseline, 5 h, and 7 h, respectively (P < 0.005). Treatment did not affect pAIx, blood pressure, or plasma 8-isoprostane F₂ concentrations. In conclusion, consuming an isoflavone-enriched low-fat meal acutely increases endothelium-dependent vasodilation in postmenopausal women. Regular consumption of soy isoflavones may protect against endothelial dysfunction.

	Introduction

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Prolonged activation of vascular mechanisms for protecting against adverse physico-chemical stimuli (inflammatory response, procoagulation, and vasoconstriction) can lead to endothelial dysfunction, an early event in the progression of atherosclerosis. Isoflavones have been suggested to protect the endothelium. For example, habitual dietary isoflavone intakes have been correlated with markers of endothelial function (8). Several studies have found that 6-wk to 12-mo supplementation with isoflavones improves endothelium-dependent vasodilation measurements (9,10), but others have not supported this (11–14). There is, however, persuasive evidence from animal studies that isoflavones can improve endothelial function (15,16). In addition, evidence from acute infusion studies in humans provides evidence to indicate that isoflavones may be beneficial to the endothelium (17,18). However, studies investigating the acute effects of oral ingestion of isoflavones on endothelial function are lacking. This is an important issue, because in vitro studies suggest that the effects of isoflavones on endothelial cell function are likely to be transient in duration; therefore, conflicting evidence from human dietary intervention may actually be related to timing of the endothelial function measurements. The aim of this study was to investigate whether an acute oral dose of soy isoflavones, consumed as part of a low-fat meal, resulted in changes in NO-dependent vasodilation compared with a control low-fat meal.

	Methods

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The study was approved by King's College London Research Ethics Committee. All subjects signed an informed consent form.

Subjects

Twenty-seven healthy, nonsmoking postmenopausal women aged 54–70 y were recruited from the community and university. Inclusion criteria were as follows: BMI, 18–36 kg/m², blood pressure <160/90 mm Hg, plasma triacylglycerol (TAG) <5.0 mmol/L, and plasma total cholesterol <8.0 mmol/L. Exclusion criteria included: menstruation during the last 12 mo; follicle-stimulating hormone >25 IU/L; current use of estrogen/progesterone, steroid medication (apart from topical corticosteroids), prescribed antiinflammatory or blood-thinning medication; a history of diabetes, myocardial infarction, angina pectoris, stroke, a diagnosis of cancer in the last 5 y (excluding basal cell carcinoma), or thrombosis; a history of excess alcohol intake or substance abuse; alcohol intake exceeding a moderate intake (>224 g/wk); abnormal liver function enzymes, hematology, and fasting glucose; or smoking or recent ex-smoker. Regular consumers of soy foods or soy isoflavone supplements who were unable to avoid consumption of these items for 2 wk before the study and during the study period were also excluded from the study. Consumption of soy foods and supplements during the previous 12 mo were assessed in the screening questionnaire and also by a short FFQ designed specifically for the study. Five subjects dropped out during the study due to inability to attend the metabolic research unit (2 subjects), difficulty obtaining blood samples (1 subject), and family bereavement (2 subjects); 22 subjects completed the study (Table 1).

The design of the study was a double-blind, randomized, placebo-controlled crossover. Subjects attended the Department of Clinical Pharmacology, St. Thomas' Hospital, London, on 2 separate occasions and at least 1 wk apart. Subjects were requested to avoid consuming soy foods for 2 wk before their first study visit and throughout the duration of the study period. On the day before each clinical visit, subjects were provided with a standard commercially available low-fat meal containing 8 g fat to be consumed before 2000 h. Subjects were also asked to follow a low-nitrate+nitrite diet the day before each visit to ensure low baseline levels of nitric oxide metabolites (NOx) in their blood for analysis. At the screening session, a list of foods high in nitrate+nitrite (19) was provided in the information booklet and subjects were requested to avoid consuming these food items on the day before the study visits. Subjects were also requested to only drink Buxton mineral water throughout the clinical visit and the day before, as it contained relatively low nitrate levels. Subjects refrained from alcohol, caffeine, and strenuous exercise the day before each visit and did not consume any of their own food or beverages except Buxton mineral water from 2000 until the end of the study day. Subjects arrived at the metabolic research unit between 0800 and 0900. Following a 10-min supine rest, vascular and blood pressure measurements and a fasting blood sample was taken from the antecubital vein in the forearm under venous stasis.

Subjects received a test meal to consume within 5 min, followed by 200 mL Buxton mineral water. Vascular and blood pressure measurements were taken at 4 and 6 h. Subjects rested supine for 10 min before each of these measurements; measurements were repeated in triplicate for pulse wave analysis and blood pressure. Blood samples were taken at 5 and 7 h. After the 5-h blood sample, subjects consumed a low-fat lunch consisting of soup and a bread roll.

Study foods

The isoflavone test meal (ISO) consisted of 60 g half-sugar orange spread mixed with 200 mg of soybean isoflavone dry extract 40% (Solgen 40, Solbar Plant Extracts), which provided 80 mg isoflavones; the control test meal (CON) consisted of 60 g half-sugar orange spread. Both orange spreads were served on 2 slices of toasted white bread (Table 2). The ISO and CON test meals were identical in appearance. The study investigators were also blinded to the identity of the test meals, as the isoflavone-enriched and control spreads had been prepared in advance and given a code by a 3rd party. The code was not broken until the end of the study. Following the 5-h blood sample, subjects were given a lunch consisting of a tin of low-fat chicken and tomato soup and a whole-meal bread roll (no spread) containing 1182 kJ, 4.2 g fat, 46.0 g carbohydrate, and 14.8 g protein, consumed with 200 mL Buxton mineral water. Subjects were allowed to sip Buxton mineral water as desired throughout the day, but they were dissuaded from drinking large volumes at once.

Height and weight were recorded without shoes in light clothing. Waist circumference was measured at the level of the umbilicus and hip circumference was measured at the level of the femoral trochanter.

Assessment of endothelial function: flow-mediated dilatation

Endothelial function was assessed by measuring flow-mediated dilatation (FMD) of the brachial artery according to current guidelines (20). All measurements were made by the same observer who was blind to the allocation of treatment. A high resolution ultrasound (Siemens Accuson CV70) system with 7–10 mH linear array transducer, positioned by a stereotactic manipulator, was used to scan the brachial artery in a longitudinal section 2–15 cm above the elbow. After optimal positioning of the transducer, a baseline scan is recorded. Increased flow was induced by inflation of a pneumatic tourniquet placed around the forearm (distal to the arterial segment being scanned) to a pressure of 250 mm Hg for 5 min, followed by release. Another scan commenced 10 s before release of the cuff and continued for 3 min after cuff deflation. FMD is expressed as the percentage increase in brachial artery diameter from baseline to maximal dilation, which occurs 30–90 s after release of the cuff. After 10 min to allow vessel recovery, another resting scan was taken. Images were coded and recorded on videotape, then digitized for subsequent blinded analysis using automated edge detection software (Brachial Analyser, Medical Imaging Applications).

Assessment of arterial function: pulse wave analysis

Measurements were performed with subjects in a supine position in a quiet, temperature-controlled (22–24°C) environment after at least 15 min of rest. Blood pressure was recorded using an automated sphygmomanometer (Omron 70CP). The measurements were made by a single observer who was unaware of the treatment allocation. A micromanometer-tipped probe coupled to a SphygmoCor device (SphygmoCor VW apparatus with Sphygmocor analysis software; SphygmoCor version 7.01 AtCor Medical) was used to noninvasively record the pulse pressure wave at the radial artery by applanation tonometry. After 20 sequential waveforms had been acquired, the integral software was used to generate a mean peripheral waveform. Three successive recordings were obtained and measurements were repeated when the waveform(s) did not pass the automatic quality controls specified by the Sphygmocor software. The peripheral pressure waveform was used to determine the peripheral augmentation index (pAIx), which is primarily determined by the intensity and timing of reflected pressure waves, thereby providing a measure of both arterial stiffness and vasodilation of small muscular arteries/arterioles (21). The central augmentation index (which is derived from pAIx using a transfer function) is markedly responsive to administration of vasodilatory and vasoconstricting drugs (21) and therefore any acute changes in NO production following the test meals were expected to be evident from pAIx measurements.

Blood sample processing and analysis

A 10-mL EDTA tube, 4-mL fluoride oxalate tube, 3- x 4.5-mL sodium citrate tubes, and a 6-mL tube with no added preservative (for serum) were used for the collection of blood samples at 0 (baseline), 5, and 7 h.

    Nitric oxide metabolites. NO reacts with oxygen and is metabolized to nitrate and nitrite (NOx). A 3-mL sample of blood was collected into EDTA tubes for the analysis of plasma NOx. Samples were centrifuged at 1600 x g; 10 min at 4°C. Plasma samples were stored at –80°C before analysis. Defrosted samples underwent centrifugal filtration to remove proteins >10 kDa (Amicon Ultra Centrifugal Filter devices, Millipore) and total NOx concentration was analyzed using a Nitric Oxide Quantitation kit (Active Motif).

    Isoprostanes. Blood (3 x 4.5 mL) for analysis of isoprostanes was collected into ice-chilled sodium citrate tubes and was analyzed by GC-MS as previously described (22).

    Plasma TAG and glucose. Blood was collected into EDTA tubes (3 mL) for the analysis of plasma TAG and into fluoride oxalate tubes (4 mL) for analysis of plasma glucose. We determined plasma TAG and glucose concentrations using enzymatic assays on an ILab 650 biochemical analyzer (Instrumentation Laboratories).

    Serum isoflavones. A 6-mL blood sample was taken into a serum tube and allowed to clot for 10 min before centrifuging at 1600 x g; 10 min, 4°C. Serum was stored at –80°C until analysis. Serum daidzein, genistein, and equol (equol results not reported here) were analyzed using time-resolved fluorescence immunoassays (DELFIA, Perkin-Elmer Life Sciences) (23). Daidzein was measured directly from serum, whereas genistein and equol required prior extraction of the serum sample. Mean extraction efficiency was calculated from the assayed extracted and unextracted daidzein values and used to adjust the extracted genistein values (mean recovery 20.1%). Therefore, all reported serum genistein concentrations have been adjusted for extraction efficiency and all daidzein concentrations are reported from unextracted serum.

Statistical analysis

Data were analyzed using GraphPad Prism version 5.01 software (GraphPad Software). Values in the text are means ± SD unless otherwise indicated. Postprandial differences in means or mean changes from baseline were analyzed using 2-way repeated-measures ANOVA, with treatment and time as within-subject factors. Data were log-transformed where necessary. Post hoc analysis using Bonferroni t tests was conducted when main effects were identified by the 2-way ANOVA. Values of P 0.05 were considered significant.

	Results

TOP ABSTRACT Introduction Methods Results Discussion LITERATURE CITED

 
Serum genistein concentrations (geometric mean, 95% CI) reached 1.49 (1.20–1.84) µmol/L following ISO and 0.06 (0.05–0.08) µmol/L following CON (P < 0.0001) at 7 h. At 7 h, serum daidzein concentrations (geometric mean, 95% CI) reached 0.95 (0.70–1.30) µmol/L following ISO and 0.07 (0.06–0.08) µmol/L following CON (P < 0.0001) (Fig. 1). FMD was greater following ISO than CON at 6 h after the meal (P < 0.05) (Table 3). Brachial artery diameter before hyperemia did not differ between treatments or time points (CON: baseline, 3.16 ± 0.48; 4 h, 3.19 ± 0.51; 6 h, 3.20 ± 0.48 mm; ISO: baseline, 3.23 ± 0.45; 4 h, 3.15 ± 0.44; 6 h, 3.13 ± 0.43 mm), although there was a significant treatment x time interaction (P < 0.01); post hoc analysis did not reveal any specific pairwise treatment differences for each time point. PAIx and systolic and diastolic blood pressure did not differ between test meals but decreased at 6 h after both meals (time effect for all, P < 0.0001) (Table 3). Plasma 8-isoprostane F₂ concentration did not change significantly over time or differ between meals (Table 3). Plasma NOx differed between treatments over time (P = 0.0028) (Table 3); post hoc analysis of the raw data did not reveal any significant pairwise comparisons, but post hoc analysis of the change from baseline (CON: 5 h, –3.20 ± 3.89; 7 h, 3.11 ± 5.29 µmol/L; ISO: 5 h, 0.95 ± 4.96; 7 h, 2.74 ± 4.35 µmol/L) showed that plasma NOx concentrations were lower at 5 h following CON compared with no change following ISO (P < 0.01). Plasma TAG and glucose changed over time following both meals (P < 0.01), but test meals did not differ in the changes (data not shown).

View larger version (18K): [in this window] [in a new window]   FIGURE 1  Serum genistein and daidzein concentrations in healthy postmenopausal women following consumption of ISO and CON test meals on 2 separate occasions. Values are medians ± interquartile range, n = 22. Treatment effect, P < 0.0001; treatment x time, P < 0.0001; time effect, P < 0.0001 for both serum genistein and daidzein, 2-way repeated measures ANOVA on log-transformed data. *Difference between treatments at that time point for both genistein and daidzein, P < 0.0001.

View this table: [in this window] [in a new window]   TABLE 3 Effects of ISO and CON test meals on FMD, pAIx, systolic and diastolic blood pressure, plasma 8-isoprostane F2, and NOx in healthy postmenopausal women1

	Discussion

TOP ABSTRACT Introduction Methods Results Discussion LITERATURE CITED

The similarity in pAIx between treatments suggests that consumption of isoflavones specifically increases shear stress-induced NO production. This may be important under certain physiological conditions, such as augmentation of NO production during physical activity. Both pAIx and blood pressure significantly decreased 6 h following both test meals, which was also 2 h after the standard lunch and at the time when plasma glucose concentrations were elevated (>6 mmol/L). The vasodilatory effects of insulin may have mediated this decrease in pAIx and blood pressure. The fact that 8-isoprostane F₂ concentrations were unaffected by either test meal suggested that reduced oxidative stress may not have played an important role in the observed effects on endothelium-dependent vasodilation, although antioxidant activity cannot be completely excluded as a possible mechanism without further investigation.

There is conflicting evidence in the literature as to whether chronic consumption of isolated soy isoflavones can modulate endothelial function (4). Because the isoflavone-induced postprandial endothelium-dependent vasodilatory effects shown in this study were apparent within 6 h of ingestion, the mechanism is likely to be linked to activation of nongenomic endothelial NO synthase-related cell signaling pathways. The isoflavone extract contained both genistein/genistin and daidzein/daidzin and therefore it is not clear whether the acute effects on endothelium-dependent vasodilation are induced by 1 of these isoflavones or both. Acute endothelium-dependent vasodilation occurred during brachial artery infusion of genistein at plasma concentrations of 2 µmol/L in healthy men and premenopausal women, whereas daidzein had no effect (17). This suggests that daidzein may be ineffective in inducing NO-dependent vasodilation, although circulating genistein and daidzein would have been circulating in their conjugated forms in the present study and it cannot be assumed that isoflavone aglycones and conjugated forms would have equivalent effects on the vasculature. Interestingly, the circulating genistein:daidzein ratio found at peak concentrations was 1.50:1, almost the same ratio of genistein/genistin:daidzein/daidzein provided in the soy isoflavone extract (1.45:1). This suggests that genistein provided from this extract was equal in bioavailability to daidzein, in contrast to previous findings (25); however, the study was not designed to test isoflavone bioavailability, and more frequent time points are required to confirm time to peak concentrations for each form of isoflavone.

In conclusion, these findings demonstrate that consumption of isoflavones has an acute effect on endothelial function in postmenopausal women. This suggests that postmenopausal women consuming isoflavones at intervals throughout the day (thereby continuously maintaining elevated circulating levels of isoflavones) may benefit from an improvement in their endothelial function. Maintaining a regular dietary intake of isoflavones over a number of years could potentially retard atherosclerosis development in postmenopausal women through the antiinflammatory and vasodilatory actions of NO, but large, robustly designed, randomized, controlled dietary intervention trials are required to confirm this.

	ACKNOWLEDGMENTS

 
We thank Benyu Jiang and Marina Cecelja from the Clinical Pharmacology department of St. Thomas' Hospital for their help in the measurement and analysis of FMD.

	FOOTNOTES

 
¹ Author disclosures: W. L. Hall, N. L. Formanuik, D. Harpanich, M. Cheung, D. Talbot, T. A. B. Sanders, and P. J. Chowienczyk, no conflicts of interest.

² Isoflavone extract (Solgen 40) was provided by Solbar Plant Extracts Ltd, Ashdod, Israel.

⁶ Abbreviations used: CON, control test meal; FMD, flow-mediated dilatation; ISO, isoflavone test meal; NO, nitric oxide; NOx, nitric oxide metabolite; pAIx, peripheral augmentation index; TAG, triacylglycerol.

Manuscript received 27 February 2008. Initial review completed 28 March 2008. Revision accepted 9 April 2008.

	LITERATURE CITED

TOP ABSTRACT Introduction Methods Results Discussion LITERATURE CITED

 

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hall, W. L. Articles by Sanders, T. A. B. Search for Related Content PubMed PubMed Citation Articles by Hall, W. L. Articles by Sanders, T. A. B. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB NITRIC OXIDE