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The Phytoestrogen Genistein Produces Acute Nitric Oxide-Dependent Dilation of Human Forearm Vasculature With Similar Potency to 17 -Estradiol
Abstract
Background:
Genistein, a phytoestrogen, may have estrogenic cardioprotective actions. We investigated whether genistein influences endothelium-dependent vasodilation in forearm vasculature of healthy human subjects and compared the effects of genistein with those of 17beta-estradiol.
Methods and results:
The brachial arterial was cannulated with a 27-gauge needle for drug infusion. Forearm blood flow responses were measured with strain-gauge plethysmography. Genistein (10 to 300 nmol/min, each dose for 6 minutes) produced a dose-dependent increase in forearm blood flow from 3.4+/-0.3 to 9.6+/-1.3 mL x min(-1) x 100 mL forearm(-1) (mean+/-SEM) in men (n=9, P:<0.0001 by ANOVA). The mean forearm venous concentration of genistein during infusion of the highest dose was 1.8+/-0.3 micromol/L in 6 additional men. Genistein produced a similar increase in blood flow in premenopausal women. Daidzein, another phytoestrogen, was ineffective, but equimolar concentrations of 17beta-estradiol caused similar vasodilation to genistein. Responses to genistein and 17beta-estradiol were inhibited to the same degree by the NO synthase inhibitor N:(G)-monomethyl-L-arginine. A threshold dose of genistein potentiated the endothelium-dependent vasodilator acetylcholine but not the endothelium-independent vasodilator nitroprusside.
Conclusions:
Genistein causes L-arginine/NO-dependent vasodilation in forearm vasculature of human subjects with similar potency to 17beta-estradiol and potentiates endothelium-dependent vasodilation to acetylcholine.
... In human investigations, NO also seems to be implicated as the vascular biomarker of interest after soy isoflavone exposure. Walker et al. (9) examined the effects of brachial artery dose-progressive genistein infusion in males age 20 to 51 yr on forearm blood flow as measured by strain-gauge plethysmography. Genistein infusion resulted in a dose-dependent increase in forearm blood flow in men nearly identical to equimolar concentrations of 17β-estradiol. ...
... During the 30-min steady state warm-up conducted at 55% W peak (172 ± 24 W), subjects (n = 25) exhibited a significantly reduced average HR after fermented soy supplementation (−4 ± 7 bpm, P = 0.010, [1][2][3][4][5][6][7]) when compared with placebo while stroke volume and cardiac output were relatively unchanged. Further analysis revealed a similar reduction in HR for the high fitness group (−5 ± 5 bpm, P = 0.011, [1][2][3][4][5][6][7][8][9]; 191 ± 20 W) while hemodynamics within the moderate fitness group (158 ± 15 W) were statistically unchanged. ...
... Average HR during the soy supplementation time trial was also significantly lower compared with the placebo trial by approximately 5 bpm (−5 ± 7, P = 0.001 [−8 to −2)]). Both power output (7 ± 3 W, P = 0.012[2][3][4][5][6][7][8][9][10][11][12]) and speed (0.42 ± 0.16 km·h −1 , P = 0.010 [0.11-0.74]) were significantly greater at 20 km, although not at 5, 10, or 15 km, for the fermented soy extract supplement time trial when compared with the placebo time trial(Figs. 1 and 2).In the high fitness group, soy supplementation was able to demonstrate a significant and proportionally larger improvement in completion time compared with the entire sample size (−0.24 ± 0.35, P = 0.047 [−0.47 to −0.004]), 0.24 min or 14 s faster; 0.72% improvement;Table 3). ...
Introduction:
Isoflavones, a chemical class of phytoestrogens found in soybeans and soy products, may have biological functions similar to estradiol. After binding with ERβ or perhaps independently of estrogen receptors, isoflavones may augment vascular endothelial relaxation, contributing to improved limb blood flow.
Purpose:
To determine if acute fermented soy extract supplementation influences 20-km time trial cycling performance and cardiac hemodynamics compared to a placebo.
Methods:
Subjects included twenty-five cyclists and triathletes (31 ± 8 y, VO2peak: 55.1 ± 8.4 mL·kg·min). Each subject completed a VO2peak assessment, familiarization, and two 20-km time trials in randomized order following ingestion of a fermented soy extract supplement or placebo. The fermented soy extract consisted of 30 g powdered supplement in 16 fl. ounces of water. The placebo contained the same quantities of organic cocoa powder and water. Each trial consisted of 60 min of rest, 30 min at 55% Wpeak, and a self-paced 20-km time trial.
Results:
Soy supplementation elicited a faster time to 20km completion (-0.22 ± 0.10 min; -37 s), lower average heart rate (-5 ± 1 bpm), and significantly greater power (7 ± 3 W) and speed (0.42 ± 0.16 km•h) during the last 5 km of the time trial compared to placebo. Analysis of the results by relative fitness level (< 57 vs. ≥ 57 mL⋅kg⋅min) indicated that those with a higher level of fitness reaped the largest performance improvement alongside a reduced heart rate (-5 ± 7 bpm).
Conclusion:
Ingestion of a fermented soy extract supplement improved sprint-distance performance through improvements in both power and speed. For those with great aerobic fitness, soy supplementation may help to decrease cardiac demand alongside performance improvement.
... It has been suggested that this inconsistency in estrogen's role is due to estrogen dose [26], hormonal status, estrogenic species, the region/neurotransmitter system involved, the seizure type/model used, and sex [27]. Estrogen modulation of seizures can confirm our findings since the similarity between estrogen and genistein goes beyond structure to reach influence in brain and peripheral organs [28,29]. Alfinito et al. demonstrated that fulvestrant or ICI 182,780, a pure aand bestrogen receptor antagonist [30], crosses the blood-brain barrier and affects brain and hypothalamic tissues [25]. ...
... demonstrated that acute vasodilation produced by genistein was the same in men and women, and also that genistein's potency was similar to that of 17b-estradiol [29]. Because of the similarity between genistein and estrogen [28,29,37], ovariectomized mice were used to avoid any bias from the endogenous estrogen interaction. ...
... demonstrated that acute vasodilation produced by genistein was the same in men and women, and also that genistein's potency was similar to that of 17b-estradiol [29]. Because of the similarity between genistein and estrogen [28,29,37], ovariectomized mice were used to avoid any bias from the endogenous estrogen interaction. Surprisingly, the results obtained from the ovariectomized mice were statistically similar to those elicited from males, sham and even intact females. ...
Genistein, a major source of phytoestrogen exposure for humans and animals, has been shown to mediate neuroprotection in Alzheimer’s disease and status epilepticus. In the present study, we investigated the effect of genistein on pentylenetetrazole-induced seizures in ovariectomized mice and the possible involvement of estrogenic and serotonergic pathways in the probable effects of genistein. Intraperitoneal (i.p.) administration of genistein (10 mg/kg) significantly increased the seizure threshold 30 min prior to induction of seizures 14 days after ovariectomy surgery. Administration of fulvestrant (1 mg/kg, i.p.), an estrogen receptor antagonist, completely reversed the anticonvulsant effect of genistein (10 mg/kg) in ovariectomized mice. Administration of the antagonist of serotonin receptor (5-HT3), tropisetron (10 mg/kg, i.p.), eliminated the anticonvulsant effect of genistein, whereas co-administration of m-chlorophenylbiguanide (5-HT3 receptor agonist; 1 mg/kg) and a non-effective dose of genistein (5 mg/kg) increased the seizure threshold. To conclude, it seems that estrogenic/serotonergic systems might be involved in the anticonvulsant properties of genistein.
... Although many studies have shown inhibitory effects of polyphenols including RWPC on LDL oxidation, there have been an equal number of studies that showed a null effect on this variable. Although there are contrasting view points on the effects of polyphenols on LDL oxidation variables, there is increasing evidence that these compounds possess additional protective function including altering hepatic cholesterol absorption, triglyceride assembly and secretion, the processing of lipoprotein in plasma in order to improve plasma lipid profile [23]. ...
... Physiological concentrations of isoflavones evoke acute endothelium-dependent increases in forearm blood flow [23][24][25][26][27] most likely mediated via NO [28]. A recent study in healthy postmenopausal women has shown that feeding an isoflavone enriched/low fat meal increases endotheliumdependent relaxation in vivo [29]. ...
Article looking at the future of clinical pharmacology in the NHS and the need for radical change to preserve the speciality in the NHS
... When administered intravenously to the brachial artery of healthy human subjects, genistein increases forearm blood flow with a similar potency to that of 17β-estradiol. It also potentiated the vasodilation response to Ach but not to SNP, and its effect was attenuated by N ω -monomethyl-L-arginine acetate (L-NMMA, i.e., NOS inhibitor), suggesting again that genistein increased the endothelial secretion of NO [234]. In post-menopausal women, the chronic ingestion of genistein (54 mg/day for 1 year) significantly improves flow-mediated dilation of the brachial artery with a similar potency to an estrogen/progestin scheme, in addition to lowering the plasma endothelin-1 levels [235,236]. ...
... In a study performed in pre-hypertensive and untreated hypertensive, post-menopausal and equolproducing female subjects, daidzein (63 mg) taken orally for 6 months neither changed their blood pressure nor improved their flow-mediated dilation [98]. When daidzein is administered intravenously to the brachial artery of healthy young subjects, it fails to change forearm blood flow [234]. ...
Isoflavones are phytoestrogen compounds with important biological activities, including improvement of cardiovascular health. This activity is most evident in populations with a high isoflavone dietary intake, essentially from soybean-based products. The major isoflavones known to display the most important cardiovascular effects are genistein, daidzein, glycitein, formononetin, and biochanin A, although the closely related metabolite equol is also relevant. Most clinical studies have been focused on the impact of dietary intake or supplementation with mixtures of compounds, with only a few addressing the effect of isolated compounds. This paper reviews the main actions of isolated isoflavones on the vasculature, with particular focus given to their effect on the determinants of blood pressure regulation. Isoflavones exert vasorelaxation due to a multitude of pathways in different vascular beds. They can act in the endothelium to potentiate the release of NO and endothelium-derived hyperpolarization factors. In the vascular smooth muscle, isoflavones modulate calcium and potassium channels, leading to hyperpolarization and relaxation. Some of these effects are influenced by the binding of isoflavones to estrogen receptors and to the inhibition of specific kinase enzymes. The vasorelaxation effects of isoflavones are mostly obtained with plasma concentrations in the micromolar range, which are only attained through supplementation. This paper highlights isolated isoflavones as potentially suitable alternatives to soy-based foodstuffs and supplements and which could enlarge the current therapeutic arsenal. Nonetheless, more studies are needed to better establish their safety profile and elect the most useful applications
... Soy isoflavones have the potential to promote vasodilation by influencing the endothelium and participating in the maintenance of vascular homeostasis. Genistein and daidzein, in particular, have been shown to enhance the secretion of nitric oxide in endothelial cells, leading to vasodilation, reduced vascular resistance, and ultimately, a decrease in blood pressure [19,68,69]. Additionally, soy isoflavones have been found to combat hypertension by influencing components within the renin-angiotensin-aldosterone system. ...
Background
Previous experimental studies have suggested that the consumption of soy isoflavones may have a potential impact on lowering blood pressure. Nevertheless, epidemiological studies have presented conflicting outcomes concerning the correlation between soy isoflavone consumption and blood pressure levels. Consequently, a comprehensive meta-analysis of all eligible randomized controlled trials (RCTs) was conducted to explore the influence of soy isoflavones on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in adults.
Methods
A thorough search of PubMed, Embase, and the Cochrane Library for relevant literature up to April 30, 2023 was conducted. RCTs involving adults that compared soy isoflavone supplementation with a placebo (the same matrix devoid of soy isoflavone) were included. The combined effect size was presented as the weighted mean difference (WMD) along with 95% confidence interval (CI), employing a fixed-effects model.
Results
Our meta-analysis included a total of 24 studies involving 1945 participants. The results revealed a significant reduction in both SBP and DBP with soy isoflavone supplementation. Subgroup analyses suggested more pronounced reductions in SBP and DBP for interventions lasting ≥6 months, in individuals receiving mixed-type soy isoflavone, and among patients with metabolic syndrome or prehypertension. However, we did not detect significant nonlinear associations between supplementation dosage and intervention duration concerning both SBP and DBP. The overall quality of evidence was deemed moderate.
Conclusions
The current meta-analysis revealed that supplementation with soy isoflavones alone effectively reduces blood pressure. Additional high-quality studies are required to investigate the efficacy of blood pressure reduction through supplementation with an optimal quantity and proportion of soy isoflavone.
... Isoflavonoids from soybean have been shown to have protective effect on human health, including in immunomodulation, cognition, risk reduction of certain cancers (eg. breast and prostate cancers), cardiovascular and skin diseases, osteoporosis, ease hot flashes and obesity, as well as relief of menopausal symptoms [7][8][9][10][11][12][13][14]. ...
Glycine max L. accumulates a large amount of isoflavonoid compounds, which is beneficial for plant defense, plant-microbe symbiotic interactions, and human health. Several CYP450 subfamily genes are involved in the flavonoid biosynthetic pathway in plants. In the present study, we found 24 CYP82 subfamily genes were differentially expressed in various tissues of soybean, in Phytophthora sojae-infected soybean varieties and in soybean hairy roots treated with cell wall glucan elicitor. Six of them (GmCYP82A2, GmCYP82A3, GmCYP82A4, GmCYP82A23, GmCYP82C20 and GmCYP82D26) were co-expressed with other known isoflavonoid pathway genes in soybean. Their enzymatic activity in yeast feeding assays showed that only GmCYP82D26 was able to convert naringenin to daidzein with both aryl migration and dehydration function. When GmCYP82D26 was over-expressed in soybean hairy roots, the contents of the two major isoflavonoid aglycones in soybean (daidzein and genistein) were reduced, but total flavonoids were not affected. When GmCYP82D26 was suppressed by RNAi in the hairy roots, daidzein content was decreased but genistein content was increased, with unchanged total flavonoid content. GmCYP82D26 was found to be localized in the endoplasmic reticulum at subcellular level when transiently expressed in tobacco leaf epidermis. GmCYP82D26 gene was preferentially expressed in roots, with low expression level in other tissues in soybean. Homology modeling and molecular docking showed that GmCYP82D26 could form hydrogen bond with both HEM and naringenin at C5–OH and C4 carbonyl. All these results indicated that GmCYP82D26 possesses new and dual enzymatic activity, which bridges the two branches (daidzein and genistein branch) of isoflavonoid pathway in soybean.
... Genistein is able to reverse the vascular changes related to the decrease in basal levels of NO observed during menopause and this reversal is directly related to the increase in endothelium-dependent NO production similar to that induced by estrogen, as well as related to the decrease in the production of endothelin-1 (potent endotheliumderived contraction factor) which implies the improvement of vasomotor symptoms observed during menopause [38][39][40][41][42]. The results obtained in these studies point to the consideration that genistein has the potential to effectively improve the vasomotor and emotional symptoms related to the postmenopausal period. ...
Active compounds from plants have been and continue to be of interest in the field of developing new therapeutic agents and many studies have demonstrated the biological effects of a variety of these compounds. Among these natural compounds are polyphenols, such as isoflavones derived from soy, also called phytoestrogens, which have been widely studied for their anticancer, antitumor, hypoglycemic, antioxidant properties, among others. Phytoestrogens are natural substances obtained from plants and have a chemical structure similar to 17β-estradiol and thus mimic the binding and estrogenic effects in different target tissues. Genistein is a phytoestrogen that represents approximately 60% of the total isoflavones found in soybeans and clinical and epidemiological studies demonstrate the beneficial effects of genistein against cardiovascular disease, diabetes, osteoporosis and against the symptoms of anxiety and depression related to menopause. Although the biological effects of genistein are beneficial and promising, certain implications, such as a mechanism of action not yet fully elucidated, effective therapeutic doses not established for humans, lack of specific scientific work with humans, among other conditions, have limited the clinical applications of genistein in a certain way. This study aimed to describe the potential benefits of genistein against symptoms observed in post-menopause and its biological effects on pathophysiology related to that period. The ability of genistein to exert different beneficial effects against changes induced by the absence of female gonadal hormones and without determining the adverse effects related to hormone replacement therapy with female gonadal hormones makes this phytoestrogen a likely candidate or therapeutic alternative in the treatment of signs and symptoms.
... This effect of isoflavone was found in the study carried out by Walker et al., in which the main components of isoflavone (genistein and daidzein) were administered to analyze the vasodilator effect when compared to estrogen. It was found that the acute administration of genistein in the brachial artery produces vasodilation in the forearm vasculature similar to that caused by estrogen, and that doses used compared to that consumed by Asian populations [57]. ...
Physical exercise and isoflavone supplementation are potential strategies to prevent and treat cardiovascular diseases in postmenopausal women. The aim of this study was to investigate whether there are additive effects of isoflavone supplementation when associated with combined aerobic and resistance exercise on resting and ambulatory blood pressure monitoring (ABPM) and in blood pressure variability (BPV). Thirty-one non-obese postmenopausal women were randomly allocated into two groups: placebo and exercise (Placebo n = 19); and isoflavone supplementation (100 mg/day) and exercise (isoflavone n = 19). ABPM and BPV were evaluated before and after 10 weeks of moderate combined (aerobic and resistance) exercise training. Generalized Estimating Equation (GEE) with Bonferroni correction and intention-to-treat analysis was used to compare the effects of interventions on resting BP, ABPM and BPV. Combined exercise training decreased resting systolic (SBP) and diastolic blood pressure (DBP) and reduced 24 h and awake ambulatory SBP, DBP and mean blood pressure over time, with no additional effects of isoflavone supplementation. No changes were observed in sleep period, or in BPV indexes (Standard Deviation of 24 h (SD), daytime and nighttime interval (SDdn) and average real variability (ARV) in both groups. We conclude that isoflavone supplementation does not potentiate the effects of combined training on resting and ambulatorial systolic and diastolic blood pressure in non-obese postmenopausal women.
... A meta-analysis of 17 RCTs suggested that isoflavone-containing soy products can modestly, but significantly improve endothelial function, as measured by flow mediated dilation (FMD) [165]. Finally, several studies have suggested that genistein significantly improves FMD, reduces endothelin-1 levels, and induces nitric oxide-dependent vasodilation to a similar extent of estrogen [166][167][168]. ...
Plant-based diets are associated with reduced risk of lifestyle-induced chronic diseases. The thousands of phytochemicals they contain are implicated in cellular-based mechanisms to promote antioxidant defense and reduce inflammation. While recommendations encourage the intake of fruits and vegetables, most people fall short of their target daily intake. Despite the need to increase plant-food consumption, there have been some concerns raised about whether they are beneficial because of the various 'anti-nutrient' compounds they contain. Some of these anti-nutrients that have been called into question included lectins, oxalates, goitrogens, phytoestrogens, phytates, and tannins. As a result, there may be select individuals with specific health conditions who elect to decrease their plant food intake despite potential benefits. The purpose of this narrative review is to examine the science of these 'anti-nutrients' and weigh the evidence of whether these compounds pose an actual health threat.
... Some flavonoids have been shown to relax endotheliumdenuded arteries. Genistein, one of the major isoflavones in soy protein, binds to estrogen receptor b 124 and can elicit endothelium dependant vasorelaxation in vitro 125 and in vivo 126 . ...
One aim of the present work was to isolate and determine the chemical structures of
flavonoids in different Libyan plants, for documentation and chemotaxonomic considerations with respect to these flavonoids. The findings of new flavonoids will expand the diversity of structures, which may through further examinations display other chemical and biological properties than previously known. At the same time, extensive spectroscopic methods, especially 2D NMR techniques will be applied to fully characterized the isolated compounds.
Another purpose of the present study is to evaluated the biological activities of the extracts and the characterization of the active principles from these Libyan medicinal plant species. Finally, the present investigation also tries to study the fragmentation pattern of flavonoids isolated from medicinal plants by applying the tandem ESI-MS technique. Chapter 1 gives an introduction to the thesis, chapter 2 presents the methods used in this work, and chapter 3 gives the results and discussion.
... Arginine and Creatine, which are related to the pathway of Arginine and proline metabolism, were converted and synthesized through the Citrate cycle. Arginine act as a precursor for the synthesis of nitric oxide (NO) that enhances placental blood ow during pregnancy [53], which corroborates the previous report that daidzein have been shown to increase NO release [54]. In addition, Arginine upregulates the gene expression of rapamycin signaling pathway targets, which coordinate anabolism and catabolism through multiple pathways to promote body growth [55]. ...
Background: Daidzein (DAI) is a kind of natural isoflavonic phytoestrogen with estrogenic activity. However, little is known about its influence on early fetal growth in mammalian animals. In this study, we investigated the effects dietary DAI supplementation on early fetal development in sows. To explore the potential mechanisms, the metabolic profiles of amniotic fluid collected at 35 days of gestation (dg) was determined by using metabolomics.
Results: Results show that DAI supplementation at a dose of 200 mg/kg significantly enhanced the number of viable embryos at the early gestation stage (P < 0.05). DAI significantly elevated the concentrations of estrogen (E) and insulin-like growth factor-I (IGF-I) in the amniotic fluid (P < 0.05). Moreover, DAI tended to increase the concentration of progesterone, but decrease the concentration of tumor necrosis factor α (TNF-α) in the amniotic fluid (0.05<P<0.10). Interestingly, the activity of glutathione peroxidase (GSH-Px) was higher in the DAI group than in the CON group (P < 0.05). An ¹H NMR-based metabolomics analysis identified a number of metabolites in the amniotic fluid, and some critical metabolites such as arginine, creatine, and citrate were found to be significantly elevated upon DAI supplementation (P < 0.05). Importantly, the metabolic pathways involved in arginine and proline metabolisms were found to be significantly affected by DAI.
Conclusions: These findings suggested that dietary DAI supplementation may improve embryos survival by improving hormones, antioxidant capacity, and metabolic profiles in the maternal amniotic fluid.
... Genistein, a source of phytoestrogen was used to prevent Cisplatininduced renal injury in male rats, and also helps in decreasing inflammation and oxidative stress which were caused by its effect [15] . Phytoestrogens are natural estrogenic agents that are found in plants [16] . These agents may be used in decreasing the development of renal diseases [17] . ...
Cisplatin is an effective anticancer drug but it has many side effects at a dose which shows therapeutic response. The main dose limiting side effect is nephrotoxicity. Cisplatin mediated nephrotoxicity is remarkably documented by reactive oxygen species generation and decreased levels of antioxidant mechanisms in the body. A single dose of cisplatin (5mg/kg, i.p) caused a marked renal damage, characterized by a significant increase in serum creatinine, blood urea nitrogen (BUN) and relative weight of kidney with higher kidney malondialdehyde (MDA), reactive oxygen species (ROS), levels and lowered tissue nitrite, SOD, CAT, GSH levels compared to normal control. Different antioxidants have been proven to have nephro protectant action but in some cases the protective effect of these antioxidants is found to be altered in the presence of some hormones in the males and females. Hence the reasons for the change in the nephrotoxicity to be gender related are further discussed in the article.
... This dissociation is calcium-dependent [5,43]. 17β-Estradiol [43] and isoflavones (both daidzein and genistein) [44,45] have been shown to modulate eNOS by inducing a rapid non-genomic and membrane receptor-mediated influx of calcium, leading to NO production and a decrease in blood pressure; this process is not affected by anti-estrogens [5,40,46]. In the endothelium-independent pathway, calcium influx and efflux through l-type calcium channels and other transporters regulate myocyte contraction and blood pressure in a manner opposite to that induced by NO [5,39,47,48]. ...
Background
Estrogens and calcium regulate vascular health but caused adverse cardiovascular events in randomized trials.
Objectives
Whether phytoestrogenic soy isoflavones modulate the physiological effects of calcium on blood pressure was explored.
Design
A double-blind, randomized study assigned 99 premenopausal women to 136.6 mg isoflavones (as aglycone equivalents) and 98 to placebo for 5 days per week for up to 2 years. Blood pressure, serum calcium and urinary excretion of daidzein (DE) and genistein (GE) were measured repeatedly before and during treatment.
Results
Isoflavones did not affect blood pressure per intake dose assignment (i.e. intention-to-treat, n = 197), but significantly affected blood pressure per measured urinary excretion of isoflavones (i.e. per protocol analysis, n = 166). Isoflavones inversely moderated calcium effects on systolic blood pressure (SBP) (interaction term β-estimates: − 3.1 for DE, − 12.86 for GE, all P < 0.05), and decreased diastolic blood pressure (DBP) (β-estimates: − 0.84 for DE, − 2.82 for GE, all P < 0.05) after controlling for calcium. The net intervention effects between the maximum and no isoflavone excretion were − 17.7 and + 13.8 mmHg changes of SBP, respectively, at serum calcium of 10.61 and 8.0 mg/dL, and about 2.6 mmHg decrease of DBP.
Conclusions
Moderation by isoflavones of the physiological effect of calcium tends to normalize SBP, and this effect is most significant when calcium concentrations are at the upper and lower limits of the physiological norm. Isoflavones decrease DBP independent of calcium levels. Further studies are needed to assess the impact of this novel micronutrient effect on blood pressure homeostasis and cardiovascular health.
Trial registration
www.clinicaltrials.gov identifier: NCT00204490.
... Some flavonoids have been shown to relax endotheliumdenuded arteries. Genistein, one of the major isoflavones in soy protein, binds to estrogen receptor b 124 and can elicit endothelium dependant vasorelaxation in vitro 125 and in vivo 126 . ...
... Intracellular IP3R-mediated Ca 2+ release is not effected by naringenin. Formononetin, an O-methylated isoflavone, is contained in the roots of Astragalusmembranaceus [146] [147,148] and liquorice root. [149] It causes dose dependent (0.1-100 μM) vasorelaxant activity in isolated rat aorta rings in endothelium intact and endothelium denuded aortic rings, Formononetin in 100 μM causes increase in NO production much higher than that by acetylcholine and also by up-regulating enos mRNA expression. ...
... This effect of isoflavone was found in the study carried out by Walker et al., in which the main components of isoflavone (genistein and daidzein) were administered to analyze the vasodilator effect when compared to estrogen. It was found that the acute administration of genistein in the brachial artery produces vasodilation in the forearm vasculature similar to that caused by estrogen, and that doses used compared to that consumed by Asian populations [57]. ...
... The positive effect of soy diet on endothelial function might be mediated by isoflavones. Genistein, the predominant isoflavone, caused nitric oxidedependent relaxation in the human forearm microcirculation [36] and administration of the soy phytoestrogen genistein, at the dose of 54 mg/day for 6 months or 1 year, improved FMD in healthy postmenopausal women [37,38]. In the present study, the goal to increase serum concentration of soy isoflavones by the dietary period using commercially available whole soy foods was achieved. ...
... Isoflavones are proposed to be protective against CHD (2) . The beneficial effect of isoflavones on CHD may be derived from their atheroprotective properties mediated via: (a) reductions in blood lipids (3) and blood pressure (4) , (b) improved endothelial function (5,6) , (c) antioxidant activity that may prevent oxidative damage to LDL-cholesterol (7,8) and other properties (9)(10)(11) . ...
Equol, a metabolite of the dietary isoflavone daidzein, is produced by the action of gut bacteria in some individuals who are termed as equol-producers. It is proposed to have stronger atheroprotective properties than dietary isoflavones. We examined a cross-sectional association of dietary isoflavones and equol-producer status with coronary artery calcification (CAC), a biomarker of coronary atherosclerosis, among men in Japan. A population-based sample of 272 Japanese men aged 40–49 years recruited from 2004 to 2007 was examined for serum isoflavones, serum equol, CAC and other factors. Equol-producers were classified as individuals having a serum level of equol >83 n m . The presence of CAC was defined as a coronary Ca score ≥10 Agatston units. The associations of dietary isoflavones and equol-producers with CAC were analysed using multiple logistic regression. The median of dietary isoflavones, equol and CAC were 512·7 (interquartile range (IQR) 194·1, 1170·0), 9·1 (IQR 0·10, 33·1) and 0·0 (IQR 0·0, 1·0) n m , respectively. Prevalence of CAC and equol-producers was 9·6 and 16·0 %, respectively. Dietary isoflavones were not significantly associated with CAC. After multivariable adjustment, the OR for the presence of CAC in equol-producers compared with equol non-producers was 0·10 (95 % CI 0·01, 0·90, P <0·04). Equol-producers had significantly lower CAC than equol non-producers, but there was no significant association between dietary isoflavones and CAC, suggesting that equol may be a key factor for atheroprotective properties of isoflavones in Japanese men. This finding must be confirmed in larger studies or clinical trials of equol that is now available as a dietary supplement.
... 22 The underlying pathways is not understood well enough to give an exact mechanism. However, it has been suggested that soy isoflavones 23,24 or particular polyunsaturated fatty acids 25 are related to a lower concentration of pro-inflammatory cytokines. In addition, it has been suggested that ingestion of probiotic bacteria may have an independent effect on reduction of pro-inflammatory cytokines, 26 but the importance of anti-inflammatory role of probiotics on systematic inflammation is still unknown. ...
Introduction:
Even with the ultimate medical management, more than one-third of diabetic patients develop diabetic nephropathy. To our knowledge, there is no study that has examined the effect of probiotic soy milk on kidney function in type 2 diabetic patients with nephropathy. This clinical trial aimed to assess the effects of consumption of probiotic soy milk, compared with conventional soy milk, on kidney-related indexes in patients with diabetic nephropathy.
Materials and methods:
In a randomized double-blinded placebo-controlled trial, 44 patients were randomly assigned to receive 200 mL/d of either soy milk containing Lactobacillus plantarum A7 or conventional soy milk for 8 weeks. Primary endpoints included urinary albumin excretion, estimated glomerular filtration rate, interlukin-18, serum sialic acid, and serum creatinine. Fasting blood samples and morning fasting spot urine samples were collected at the beginning and after 8 weeks for evaluation of biochemical parameters.
Results:
Forty patients completed the study. Administration of probiotic soymilk resulted in a significant reduction in albuminuria (P = .03), serum creatinine (P < .001), serum interleukin-18 (P = .002), and serum sialic acid (P = .001) compared with conventional soy milk. Probiotic soymilk supplementation also led to a significant improvement in estimated glomerular filtration rate (15.9 ± 10.8 mL/min versus 3.2 ± 8.4 mL/min, P < .001) compared with the control group.
Conclusions:
Probiotic soy milk was safe and well-tolerated by patients with diabetic nephropathy for 8 weeks. Probiotic soy milk also improved indexes of kidney function in type 2 diabetic patients with nephropathy.
... (van der Schouw et al. 2002; Walker et al. 2001). Oxidised LDL is an important early initiator of formation of precursors of atherosclerotic plaques in the walls of blood vessels (Griffin, 1999). ...
... Estrogen has been reported to reduce the risk of cardiovascular system via multiple effects [18,48,49] and reduce hypertrophy in ER-dependent mechanism [33]. Moreover, evidences have enlightened that estrogens and phytoestrogens shared the structural similarities and their proactive effects in the reduction of cardiovascular risk, such as genistein, calycosin, provinols, and delphinidin [31,35,50,51]. Furthermore, the cardioprotective ability of phytoestrogen anthocyanin may be attributed to its capacity to enhance NOS activity, NO release [52,53], antioxidative activity [54] and NF-κB reduction [55]. ...
Doxorubicin (Dox) is extensively used for chemotherapy in different types of cancer, but its use is limited to because of its cardiotoxicity. Our previous studies found that doxorubicin-induced insulin-like growth factor II receptor (IGF-IIR) accumulation causes cardiomyocytes apoptosis via down-regulation of HSF1 pathway. In these studies, we demonstrated a new mechanism through which anthocyanin protects cardiomyoblast cells against doxorubicin-induced injury. We found that anthocyanin decreased IGF-IIR expression via estrogen receptors and stabilized heat shock factor 1 (HSF1) to inhibit caspase 3 activation and apoptosis of cardiomyocytes. Therefore, the phytoestrogen from plants has been considered as another potential treatment for heart failure. It has been reported that the natural compound anthocyanin (ACN) has the ability to reduce the risk of cardiovascular disease (CVD). Here, we demonstrated that anthocyanin acts as a cardioprotective drug against doxorubicin-induced heart failure by attenuating cardiac apoptosis via estrogen receptors to stabilize HSF1 expression and down-regulated IGF-IIR-induced cardiomyocyte apoptosis.
... Intake of isoflavonoids has been suggested to ease such post-menopausal ailments in women as osteoporosis [23] and hot flashes [24]. Furthermore, dietary intake of isoflavonoids has been linked with reduction in the risk of cardiovascular disease and high blood cholesterol levels [25,26]. ...
Isoflavonoids are plant natural products, almost exclusive to legumes, synthesized by the phenylpropanoid pathway. They are actors in symbiosis with nitrogen-fixing bacteria and involved in plant pathogen and stress response. Isoflavonoids are noted for their wide range of human health benefits. Isoflavonoids, as phytoestrogens, can bind to estrogen receptors and modulate their activity in animals including humans. Soybean seeds contain three isoflavone aglycones that are glycosylated and/or malonylated and stored in vacuoles. The biosynthetic pathway starts with the recruitment of phenylalanine and enters its first committed branch step with the conversion of flavanone to isoflavone. Soybean seeds accumulate large amounts of isoflavonoids as a result of de novo synthesis and transport. The isoflavonoid content and composition in the seed are complex polygenic traits that are highly variable. Environmental factors, including drought, light conditions, fertilization, temperature and CO2 levels, and genetic factors, such as specific pathway gene members, transcription factors coordinating expression and conjugating enzymes, have all been shown to have an effect on isoflavonoid content. Understanding the genetic and molecular basis for isoflavonoid biosynthesis and its regulatory mechanisms will allow manipulation of content in soybean seeds and metabolic engineering of isoflavonoids in nonleguminous plants.
... 95,96 Rapid signaling by estrogen action was shown to lead to increased nitric oxide within minutes after addition of estrogen. 97 Nitric oxide generation is involved in many beneficial effects on the cardiovascular system. Nitric oxide induces EC growth and migration, vasodilatation, and platelet inhibition, resulting in prevention of thrombus formation and leukocyte-EC adhesion. ...
Estrogen has important effects on cardiovascular function including regulation of vascular function, blood pressure, endothelial relaxation, the development of hypertrophy and cardioprotection. However, the mechanisms by which estrogen mediates these effects are still poorly understood. As detailed in this review, estrogen can regulate transcription by binding to two nuclear receptors, ERα and ERβ, which differentially regulate gene transcription. ERα and ERβ regulation of gene transcription is further modulated by tissue specific co-activators and co-repressors. Estrogen can bind to ERα and ERβ localized at the plasma membrane as well as GPER to initiate membrane delimited signaling, which enhances kinase signaling pathways that can have acute and long term effects. The kinase signaling pathways can also mediate transcriptional changes, and can synergize with the estrogen receptor to regulate cell function. This review will summarize the beneficial effects of estrogen in protecting the cardiovascular system through ER-dependent mechanisms with an emphasis on the role of the recently described ER-membrane signaling mechanisms.
... La principale classe è quella degli isoflavoni, sostanze non steroidee contenute soprattutto nella soia, la cui struttura molecolare presenta varie analogie con l'estradiolo consentendone il legame ai recettori estrogenici. Gli isoflavoni sono attivi nei confronti della sintomatologia vasomotoria ma esplicano i loro effetti benefici anche sull'apparato cardiovascolare in quanto riducono i livelli di colesterolo totale, colesterolo LDL e trigliceridi, inibiscono l'ossidazione delle lipoproteine e inducono la vasodilatazione ossido-nitrico-dipendente migliorando la funzione endoteliale (12). ...
Introduction. Hormone Replacement Therapy (HRT) with estroprogestinic preparations (EP) shows a controversial benefit/risk ratio because of an increased risk of major cardiovascular events and a cancer risk that is still an object of debate. The purpose of this study is to search for alternative treatments to EP therapy through the use of natural substances such as Phytoestrogens and Berberine, or the use of Tibolone, a molecule with tissue-specific action, which may provide a better cardiovascular safety profile and greater compliance. Materials and methods. 24 postmenopausal women aged 45-58 (mean age 52.2±3.2 years) were divided into two groups. Group A: 10 women treated with a preparation of Phytoestrogens and Berberine (Berberis aristata Berberine hydrochloride 588mg equivalent to 500mg, Glycine max 150mg equivalent to 60mg of soy isoflavones: Estromineral Lipid ®); Group B: 14 women treated with Tibolone (2.5 mg / day: Livial ®). At recruitment and after 6 months of therapy BMI was assessed and serum levels of glucose, total cholesterol, HDL, LDL and triglycerides were measured out. Results. After 6 months of therapy the women in Group A showed a statistically significant reduction (P<0.05) in BMI, total cholesterol and LDL-cholesterol; the women of Group B showed a statistically significant reduction (P<0.05) of total cholesterol, LDL-cholesterol, triglycerides and glucose. Conclusions. Both treatments favorably modify the metabolic profile of patients showing comparable reductions of total cholesterol and LDL cholesterol.
... nitric oxide-dependent dilatation of human forearm vasculature with similar potency to 17ß-estradiol (19). Squadrito et al. demonstrated that the mean baseline ratio of nitric oxide to endothelin was significantly increased after six months of genistein treatment (20). ...
Aim: The aim of the study was to evaluate the effect of isoflavones on cardiovascular risk markers including plasma nitrite/nitrate, homocysteine, and lipid levels in Turkish women in the early postmenopausal period. Materials and Methods: Ninety participants between 42 and 59 years of age were randomly assigned to receive twice a day either isoflavone tablet (n:45) or placebo tablets (n = 45). Plasma nitrite/nitrate, homocysteine, and lipid levels were measured at baseline and after the 6 months of treatment. Results: After 6 months, isoflavone resulted in a statistically significant decrease in total cholesterol, low-density lipoproteins, triglyceride levels, serum homocysteine and an increase in high-density lipoproteins and serum nitrites/nitrates. Lipoprotein-a level did not change in both groups. Conclusions: Six months of treatment with isoflavones had a favorable effect on serum nitrites/nitrates, homocysteine and lipid levels in Turkish women in the early postmenopausal period. Although there is not enough evidence yet from large randomized clinical trials to make a recommendation about the use of phytoestrogens for prevention of cardiovascular disease in postmenopausal years, our results show that phytoestrogens improve the biomarkers of some cardiovascular risk markers in Turkish women in the early postmenopausal period.
... Particularly, soybeans and soy products are abundant sources of isoflavoens with approximately 0.2-1.6 mg of isoflavones/g dry weight (Kurzer et al., 1997). Many animal and human studies as well as epidemiological studies have suggested that increased consumption of soy-based food is associated with decreases in cardiovascular disease, and the protective effects on cancers and osteoporosis (Jenkins et al., 2000;Walker et al., 2001;Hutchins et al., 2005;Kawakami et al., 2005;Ma et al., 2008). Based on the bioactivities of the enzyme and the beneficial effects of soy meals, in this study, we evaluated the effects of β-glucosidase on feed usage, growth performance, activities of digestive enzyme and a set of physiological parameters in broilers. ...
The effects of β-glucosidase on the overall growth performance and a set of physiological parameters of broilers were investigated. 240 male, one-day old Avine broiler chickswere randomly allocated to four treatment groups and fed with a corn-soybean meal supplemented with 0% (control), 0.2%, 0.4% and 0.6% β-glucosidase. The 0.2% β-glucosidase group, but not the 0.4% and 0.6% β-glucosidase groups, showed a significantly increased average daily weight gain (p<0.05) over that of the control. All three β-glucosidase feed groups showed significantly higher feed conversion ratios than the control group (p<0.05). Feed supplementation of 0.2% β-glucosidase significantly raised the contents of serum isoflavone aglycones as shown by decreases of genistin and daizin (p<0.01) and an increase of daidzein (p<0.01). The 0.2% β-glucosidase feeding significantly increased the intestinal amylase activity while it had little effect on lipase and trypsin activities (p>0.05). 0.2% β-glucosidase feeding also significant elevated the levels of high-density lipoprotein cholesterol and malate dehydrogenase while lowering the level of low-density lipoprotein cholesterol (LDL-C). Finally, β-glucosidase improved the anti-oxidative activities of the animals; the 0.2% β-glucosidase feed group had higher activities of superoxide dismutase (p<0.05), glutathione peroxidase and glutathione reductase in the liver (p<0.05), and malondialdehyde level in the serum (p<0.05).
Background and aims
Atherosclerosis is a chronic process playing a crucial role in the pathogenesis of cardiovascular disease. Sex-specific differences in the incidence of atherosclerosis indicate that estrogen has a protective effect on the cardiovascular disease. However, the role of sex on endothelium responses in animal models of high cholesterol (HC) diet-induced atherosclerosis has not been fully investigated. This study was aimed to investigate vascular responses in HC-fed rats.
Methods and results
Male and female Sprague rats (12-week-old) were treated with either a standard diet (n=12 of each sex) or an HC enriched diet (n=12 of each sex) containing 2% cholesterol for 24 weeks. HC treated animals (both sexes) showed increased levels of total cholesterol, LDL-cholesterol, triglyceride and blood pressure (BP) compared to control rats. While the BP of control rats (both sexes) was increased following aminoguanidine administration (AG, 100 mg/kg i.p.), it was not changed in HC animals (both sexes). The hypotensive effect of acetylcholine was significantly impaired in male HC-treated rats. In vitro experiments demonstrated that aortic rings from HC group (both sexes) had an increased contractile response to phenylephrine and a decreased vasodilatory response to acetylcholine. The vasorelaxant effect of acetylcholine in HC rats (only male) was improved by applying 10⁻⁵ molar genistein (tyrosine kinase inhibitor) or AG.
Conclusion
HC diet alters endothelium function through Nitric oxide (NO) and tyrosine kinase pathways in male rats.
Genistein is the simplest secondary metabolite in soybeans and belongs to a group of compounds called isoflavones. It is a phytoestrogen and it makes up more than 60% of soy isoflavones. Studies have shown the anti-inflammatory, anti-apoptotic, and anti-angiogenic effects of genistein in addition to its modulatory effects on steroidal hormone receptors. In this review, we discuss the pharmacologic and therapeutic effects of genistein on various diseases.
Practical applications
In this review, we have discussed the therapeutic effects of genistein as the main constituent of soybeans on health conditions. Its antioxidant, anti-inflammatory, anti-apoptotic and, anti-angiogenic effects need more attention. The pharmacological properties of genistein make this natural isoflavone a potential treatment for various diseases such as postmenopausal symptoms, cancer, bone, brain, and heart diseases. Special emphasis should be given to it, resulting in using it in clinical as a safe, potent, and bioactive molecule.
The Roselle (Hibiscus sabdariffa) is being extensively used in folk medicine owing to its rich phytochemical profile including polyphenols, especially anthocyanins, organic acids, and polysaccharides, thereby offering greater prospects in therapeutic and medicinal uses. The Roselle infusions or decoctions present significant therapeutic options against various degenerative ailments such as hyperlipidemia, hypertension, diabetics, cancer, hepatoprotection, nephroprotection, and many others. The previous work supports the scientific hypothesis that Roselle plant enriched with bioactive constituents plays an imperative role in the management of degenerative and chronic diseases that are associated with oxidative stress. However, well-designed animal and human studies are underway to precisely quantify the therapeutic potential of purified phytochemical preparations. This work aims to review and document the scientific evidence about the potential therapeutic uses of the Roselle plant.
The flavone apigenin is widely distributed in vegetables and fruits and has a variety of pharmacological effects. However, there is no definitive scientific evidence that apigenin could act as a phytoestrogen and exert exerting estrogenic or antiestrogenic efficacy in vivo. Therefore, this study was established an ovariectomy (OVX) and estrogenized mouse model to evaluate the effects of apigenin on reproductive target tissues. Our data demonstrated that apigenin could exert a double-directional adjusting estrogenic effect in vivo. Specifically, treatment with apigenin reversed the weight changes caused by abnormal estrogen levels and altered the status of vaginal epithelial cells via the estrogen receptors. In addition, we found that apigenin exhibited a significant estrogenic activity, as indicated by the reversal of uterine atrophy. Apigenin treatment could also regulate the target tissue coefficient changes and estrogen disorders caused by excessive estrogen. Importantly, the administration of apigenin could upregulated the estrogen receptor (ER) α and ER β expression as a partial agonist. Our results demonstrate that apigenin has a double directional adjusting function in different physiological environments.
Daidzein (DAI) is a kind of natural isoflavonic phytoestrogen with estrogenic activity. However, little is known about its influence on early fetal growth in mammalian animals. The current study aimed to explore the characteristics of amniotic fluid exposure to dietary DAI using ¹H NMR-based metabolomics and biochemical analysis. Here, we found that DAI supplementation at a dose of 200 mg kg⁻¹ significantly enhanced the number of viable embryos at the early gestation stage (P < 0.05). DAI significantly elevated the concentrations of estrogen (E) and insulin-like growth factor-I (IGF-I) in the amniotic fluid (P < 0.05). Moreover, DAI tended to increase the concentration of progesterone, but decrease the concentration of tumor necrosis factor α (TNF-α) in the amniotic fluid (0.05 < P < 0.10). Interestingly, the activity of glutathione peroxidase (GSH-Px) was higher in the DAI group than in the CON group (P < 0.05). An ¹H NMR-based metabolomics analysis identified and quantified more than 30 compounds in the amniotic fluid, and some critical metabolites such as arginine, creatine, and citrate were found to be significantly elevated upon DAI supplementation (P < 0.05). Importantly, the metabolic pathways involved in arginine and proline metabolisms were found to be significantly affected by DAI. Collectively, dietary DAI may improve embryo survival by improving hormones, antioxidant capacity, and metabolic profiles in the maternal amniotic fluid.
Abstract This study was conducted to determine the impact of effective dose ED50 estrogenic plant (phytoestrogen)) extracted from the beans, white beans dry on the effectiveness of osteoblasts Osteoblast cells (in vitro). Through study some parameters genetic and some standards Plant estrogens extracted from white kidney beans, and then extracted effective dose ED50-estrogenic plant, designed the experiment and that Ba for the distribution of random for 48 of the female rabbits into six groups (8 / group) were injected into the first group with saline and used a control (G1) with injected intramuscularly second group 0.07 mg / kg of plant estrogens (G2) and the third 0.1 mg / kg (G3) and fourth 0.2 mg / kg(G4 and the fifth 0.5 mg / kg (G5) and sixth 0.7 mg / kg (G6) daily for four weeks then was measured some occupational standards (such as total cholesterol Total Cholesterol (TC) , high-density lipid protein High lipoprotein density (HDL) and identified the effective dose was 0.2 mg/ kg .Been studying the biological activity of bone cells after estrogen treatment plant at the cells osteoblasts, has been influential estimate the concentration of estrogen on bone and vital cell concentrations using upward (400,200,100,50,25,12.5, micrograms / ml) for 24, 48 and 72 hours. found a concentration of 50 micrograms is the most effective and less toxic. But the study showed that the effect of dose of 25 micrograms was the most effective in activating genes that produce collagen. As for the study of the effect of plant estrogens on the effectiveness of genes collagen and fibronectin observed increase of the activity of bone cells, a collagen, a gene responsible for a building material intra-tissue bone, as well as some of the genes responsible for a building cell membrane proteins, which works on the adhesion of bone cells to Article interfaces Fibronectin and that these genes reduces the process of programmed cell death .
Genistein (4',5,7-trihydroxyisoflavone) is a phytoestrogen with potential health benefits in the prevention of cardiovascular disease. However, the evidence regarding its effects on hypertension has not been conclusive. Therefore, we examined the impact of oral genistein supplementation on systolic blood pressure (SBP) and diastolic blood pressure (DBP) via a systematic review and meta-analysis of randomized controlled trials (RCTs). PubMed, ISI Web of Science, Scopus and the Cochrane library databases (until August 2019) were searched to identify potential RCTs with information on genistein supplementation and hypertension. Weighted Mean Difference (WMD) was pooled using a random-effects model. Pooling four RCTs (four treatment arms) together did not show any significant reduction of SBP (WMD: -5.32 mmHg, 95% CI: -14.59 to 3.96) and DBP (WMD: -2.06 mmHg, 95% CI: -6.41 to 2.28) compared to that of the placebo group. However, subgroup analysis by intervention duration suggested that more than 6 months genistein supplementation in metabolic syndrome patients can significantly decrease SBP (WMD: -13.73 mmHg, 95% CI: -18.10 to -9.37) and DBP (WMD: -5.18 mmHg, 95% CI: -6.62 to -3.74). Generally, present study indicated that genistein supplementation had no effect on hypertension, but it seems that longer intervention duration of more than 6 months especially among metabolic syndrome patients may lead to the effectiveness of genistein.
Despite significant decreases in cardiovascular disease mortality in the past three decades, it still remains the leading cause of death in women. Following menopause and the accompanying loss of estrogen, women experience a unique, accelerated rise in CVD risk factors. Dysfunction of the endothelium represents an important antecedent to CVD development, with rapid declines in endothelial vasodilator function reportedly taking place across the menopause transition. Importantly the decline in endothelial function is independent of chronological age and is associated with estrogen deficiency. Estrogen-mediated effects, including increasing nitric oxide bioavailability and attenuating oxidative stress and inflammation, contribute to preserving endothelial health. This review will discuss studies that have probed the role of estrogen on endothelial vasodilator function in women at discrete stages of the menopause transition and the effects of estradiol supplementation in postmenopausal women. Estrogen receptor signaling is also an important aspect of endothelial function in women and studies suggests that expression is reduced with both acute and prolonged estrogen deficiency. Changes in regulatory mechanisms of estrogen receptor alpha expression as well as sensitivity to estrogen may underly the differential effects of estrogen therapy in early (≤5 years past final menstrual period) and late postmenopausal women (>5 years past final menstrual period). Lastly, this review presents potential therapeutic targets, that includes increasing L-arginine bioavailability and estrogen receptor activation, to prevent endothelial dysfunction in postmenopausal women as a strategy for decreasing CVD mortality in this high risk population.
This study aimed to investigate the effects of L-arginine supplementation on blood pressure, protein excretion, lipid profile in salt-induced hypertensive pregnant rats. Female Sprague-Dawley rats were divided into 4 groups. Control Preg (normal rat chow). Control Preg + L-ARG (normal rat chow and daily oral L-Arginine from 16th – 20th week). Salt Preg (high salt diet, 8%). Salt Preg + L-ARG (high salt diet, 8% and daily oral L-Arginine from 16th – 20th week. Non-invasive BP was recorded using a tail-cuff machine at 1 st and 2nd trimesters. On day 19 of pregnancy, invasive BP was obtained by carotid artery cannulation connected to LabChart-7 pro software. This was followed by blood samples collection for lipid profile analysis. L-arginine significantly reduced (P < 0.05) systolic, diastolic, MAP at 1 st, 2nd trimesters, day 19 of pregnancy, LDL, plasma and urinary creatinine and protein levels in Control Preg + L-ARG and Salt Preg + L-ARG groups compared to other groups. Urinary Na + and K + were significantly higher (P < 0.05) in Salt Preg + L-ARG group compared to other groups. Total cholesterol level was significantly higher (P < 0.05) in salt groups compared to control groups. Triglyceride level and urine volume were significantly higher (P < 0.05) in Salt Preg group compared to other groups. It also significantly increased (P < 0.05) HDL in Control Preg + L-ARG and Salt Preg + L-ARG groups compared to other groups. L-arginine supplementation ameliorates some deleterious effects in salt- induced hypertensive pregnant rats possibly through its known NO vasodilatory effect and might also mediate a diuretic like action.
Interest in soy protein, both as a dietary supplement and as a component of diet, has increased rapidly based on the assumption that it may provide certain health benefits, particularly the reduction of coronary heart disease. The putative cardiovascular benefits of soy protein are related in part to the observation that Asian populations consuming diets rich in soy protein have lower rates of cardiovascular disease (CVD) than Western populations. Mortality rates due to CVD are eight times higher for men and women living in the U.S. than for Japanese men and women living in Asia. However, Japanese men and women who have migrated to the U.S. have risks of CVD similar to Western populations.
Isoflavones, plant polyphenols with estrogenic activity, are becoming widely distributed in foods and sold as supplements. Their similarity to estrogens suggests potential cardiovascular benefits. Two major areas, those of lipid lowering and of improved vascular function, will be reviewed. The novel properties of isoflavone metabolites formed in vivo that may confer specific cardiovascular protection are documented. Although lipid lowering is at best modest, effects on vasculature have been more consistent. Arterial compliance, a parameter of the elasticity or distensibility of large arteries is improved by as much as reported for estrogens. Vasodilatory effects of isoflavones or their metabolites on the microcirculation, suppression of adhesion molecules, antioxidant properties and inhibition of experimental atherosclerosis may provide opportunities for pharmacological intervention.
Genistein (4′, 5, 7-trihydroxyisoflavone), a naturally occurring flavonoid characteristic of Leguminoseae plants, is a phyto-oestrogen exerting oestrogenic activity as both an agonist and an antagonist substance. A large body of evidence suggests that genistein possesses many physiological and pharmacological properties that make this molecule a potential agent for the prevention and treatment of a number of chronic diseases. Growing evidence suggests that genistein could act as a vasodilating, anti-thrombotic, and anti-atherosclerotic agent, exerting these effects through different mechanisms of action. This paper aims to review data from the literature assessing the beneficial effects of genistein on hypertension, one of the most important cardiovascular disease risk factors along with hyperglycemia and hyperlidipemia. In addition, we discuss the chemistry, main sources and bioavailability of genistein. Scientific findings support genistein's potential as a promising anti-hypertensive agent in different experimental models. However, clinical trials are very limited and more research will be required before genistein intake can be recommended as part of therapies targeting raised blood pressure.
Background & aim:
Although dietary soy intake is linked with health benefits, a relation with stroke has not been established. The present study examined the association between the intake of tofu, the richest source of dietary soy, with stroke mortality in a general population cohort of Japanese men and women.
Methods:
Data comprise 9244 Japanese enrolled in the National Nutrition Survey of Japan in 1980. Participants were free of cardiovascular disease and followed for 24 years. Dietary intake was estimated from 3-day weighed food records. Multivariable Cox regression models were used to estimate hazard ratios across levels of tofu intake.
Results:
During follow-up, there were 417 deaths due to stroke (88 cerebral hemorrhage [CH], 245 cerebral infarction [CI], and 84 of other subtypes). Among all men, and in women aged 65 years or more, tofu intake was unrelated to each form of stroke. For young women (<65 years of age), a significantly lower risk of CH in the top versus bottom quartile of tofu intake was observed (Multivariable-adjusted HR = 0.26, 95% CI: 0.08-0.85).
Conclusions:
In this large prospective study with long follow-up of Japanese men and women, consumption of tofu was unrelated to the risk of stroke except for CH in women <65 years of age. Whether the association in younger women is real or due to chance alone warrants further study.
Based on the literature data concerning modeling of venous diseases in experiments on animals the authors discuss various models of venous endothelial dysfunction. The models of venous thrombosis and L-NAME-induced endothelial dysfunction are considered to be the simplest and most readily reproducible.
Objective:
To evaluate the effect of genistein supplementation on the oxidative/nitrative stress and antioxidant capacity of normotensive and preeclamptic placental trophoblast.
Methods:
The stress status of placental trophoblast was assessed by measuring their respective markers before and after incubation with genistein.
Results:
A significant increase in stress along with decrease in antioxidant status was observed in preeclamptic placental trophoblast, whereas genistein incubation significantly alters oxidant-antioxidant status.
Conclusion:
The study revealed that genistein may play a significant role in controlling oxidative/nitrative stress during preeclampsia. Hence, genistein can be used as an effective dietary supplement for the treatment and management of preeclampsia.
This review will describe the present state of knowledge of (a) the activity of soy proteins on cholesterolemia, (b) the therapeutic properties of soy proteins for atherosclerosis reduction, (c) the potential cardiovascular health benefits and harmful effects of soy isoflavones (phytoestrogens), and (d) the present knowledge of the beneficial effects of nonsoy legumes on cardiovascular health.
The soybean is a source of protein, fats, oligosaccharides, and dietary ber. It is considered to be a complete food because in addition to these macronutrients, it also contains minerals (Liu, 1999; Mateos-Aparicio et al., 2008), essential amino acids and bene cial secondary metabolites; phytochemicals such as iso avones and other phenolic compounds (Sakthivelu et al., 2008). Soy intake is the highest in Asia, where iso avone intake is estimated to be 20-50 mg/day (Adlercreutz et al., 1991; Cassidy, 2003). Amongst the Western population, soy consumption is much lower and infrequent; iso avone intake is negligible at less than 1 mg/day on an average (Cassidy, 2003; Setchell et al., 1999). Table 12.1 shows commonly consumed soy products.
Of the edible Soybean (SB) products in the U.S. market, the consumption of Soybean Oil (SBO) is the greatest because of its contribution to the diet. SBO is the major edible oil in the United States. The predominant dietary sources of SBO are salad and cooking oil (48%), and baking and frying fats (34%). SBO has a unique fatty acid profile; it is comprised predominantly of unsaturated fatty acids, including Monounsaturated Fatty Acids (MUFA) and Polyunsaturated Fatty Acids (PUFA), of which the predominant PUFA is linoleic acid (LA), and to a much lesser extent, α-Linolenic Acid (ALA). Soybeans are also a source of protein. Consumption of soybean products containing soy protein has risen in recent years, although this remains significantly less than the consumption of SBO. One component of soy protein that also gained interest is isoflavones (bioactive molecules contained in soy protein) because of their potential health effects. Based on dietary assessment data for energy and fat, SBO accounts for about 12% of calories in the average American diet. This chapter discusses the health effects of SBO and its constituent fatty acid profile, as well as soy protein and its bioactive components.
This chapter describes the physiological effect of soy isoflavones as an agonist for the beta-type estrogen receptor (ERbeta) and its various health benefits as well as its role as a weak estrogen. A high-nutritional intake of soy isoflavones contributes to a low nanomolar serum concentration of genistein, which is a relatively potent agonist of ERbeta. The binding affinity of serum concentration of genistein is lower than its affinity for the alpha isoform of the estrogen receptor (ERalpha) and also far too low to inhibit tyrosine kinases or topoisomerase II. A derivate of bacterial metabolism of daidzein is S-Equol, which is a selective agonist for ERbeta. The favorable influence of soy isoflavones on endothelial function in postmenopausal women is mentioned to be due to the expression of both ERalpha and ERbeta by vascular endothelium and both the receptors have the potential to activate nitric oxide synthase. Soy isoflavones reportedly do not have any direct hepatic affect or uterotrophic activity. The various health benefits of soy isoflavones include, favorable effect on bone metabolism, reducing the risk for prostate and colorectal cancer and has a protective role in breast cancer.
Tyrosine-specific protein kinase activity of the epidermal growth factor (EGF) receptor, pp60v-src and pp110gag-fes was inhibited in vitro by an isoflavone genistein. The inhibition was competitive with respect to ATP and noncompetitive to a phosphate acceptor, histone H2B. By contrast, genistein scarcely inhibited the enzyme activities of serine- and threonine-specific protein kinases such as cAMP-dependent protein kinase, phosphorylase kinase, and the Ca2+/phospholipid-dependent enzyme protein kinase C. When the effect of genistein on the phosphorylation of the EGF receptor was examined in cultured A431 cells, EGF-stimulated serine, threonine, and tyrosine phosphorylation was decreased. Phosphoamino acid analysis of total cell proteins revealed that genistein inhibited the EGF-stimulated increase in phosphotyrosine level in A431 cells.
Acute estrogen administration relaxes vascular smooth muscle by decreasing intracellular Ca2+ concentration ([Ca2+]i). In the present study, we examined the hypothesis that this reduction in [Ca2+]i is mediated in part by enhanced Ca2+ efflux. Coronary artery smooth muscle cells were isolated from gonad-intact, sexually mature female pigs. The [Ca2+]i response to endothelin-1 was measured using fluo 3 and confocal microscopy. 17beta-Estradiol (E2beta), but not 17alpha-estradiol or triamcinolone acetonide, caused a concentration-dependent (IC50 = 10 nM) decrease in the [Ca2+]i response to endothelin-1. This decrease was blocked by the specific estrogen receptor antagonist ICI-182780. Under conditions in which Ca2+ influx and sarcoplasmic reticulum Ca2+ reuptake were blocked, E2beta still decreased [Ca2+]i. The response was blocked by extracellular lanthanum. These data indicate that E2beta decreases [Ca2+]i in coronary artery smooth muscle by affecting Ca2+ efflux via a receptor-mediated mechanism.
The first quantitative method for the determination of both lignans and isoflavonoid phytoestrogens in plasma is presented. Using ion-exchange chromatography the diphenols are separated into two fractions 1) the biologically “active” fraction containing the free compounds + mono- and disulfates and 2) the biologically “inactive” fraction containing the mono- and diglucuronides and the sulfoglucuronides. After hydrolysis the fractions are further purified by solid phase extraction and ion exchange chromatography. Losses during the complete procedure are corrected for using radioactive estrogen conjugates during the first steps and later by adding deuterated internal standards of all compounds measured (matairesinol, enterodiol, enterolactone, daidzein, O-desmethylangolensin, equol, and genistein). The final determination is carried out by isotope dilution gas chromatographγ-mass spectrometry in the selected ion monitoring mode (GC/MS/SIM). The diphenols may be measured at concentrations as low as 0.2 to 1.0 nmol/1. Results of plasma analyses of all compounds in 27 pre- and postmenopausal omnivorous and vegetarian women are presented for the first time. The most important findings are that the free+sulfate fraction is low for genistein (3.8% of total), but as much as 21-25% of enterolactone and enterodiol occurs in mis fraction. A good correlation between plasma and urine values was found. Total concentrations of individual compounds vary greatly between the subjects (from pmol/1 to μmol/l), the vegetarians having higher values, particularly one vegan subject. The highest total enterolactone concentration value exceeded 1 ümol/1. It is concluded that a highly specific method for the assay of 3 lignans and 4 isoflavonoids in plasma has been developed. This method will be useful in future studies of lignan and isoflavonoid metabolism.
Maxi-K channels consist of a pore-forming α subunit and a regulatory β subunit, which confers the channel with a higher Ca²⁺ sensitivity. Estradiol bound to the β subunit and activated the Maxi-K channel (hSlo) only when both α and β subunits were present. This activation was independent of the generation of intracellular signals and could be triggered by estradiol conjugated to a membrane-impenetrable carrier protein. This study documents the direct interaction of a hormone with a voltage-gated channel subunit and provides the molecular mechanism for the modulation of vascular smooth muscle Maxi-K channels by estrogens.
NG monomethyl-L-arginine (L-NMMA), a specific inhibitor of the synthesis of endothelium-derived nitric oxide (NO), was infused into the brachial arteries of healthy volunteers to study the role of NO in the control of forearm blood flow. L-NMMA caused a 50% fall in basal blood flow and attenuated the dilator response to infused acetylcholine but not that to glyceryl trinitrate. These results indicate that the dilator action of endothelium-derived NO contributes to the control of basal and stimulated regional blood flow in man. Impairment of production of NO might account for the abnormalities in vascular reactivity that characterise a wide variety of disease states.
To determine if endogenous local levels of nitric oxide (NO) modulate atherogenesis, we studied the effect of inhibiting NO with NG-nitro-L-arginine methyl ester (L-NAME) on early neointima formation in cholesterol-fed rabbits. Male rabbits were fed for 5 weeks with a 0.5% cholesterol diet alone or treated in addition during the last 4 weeks with L-NAME (12 mg/kg per day SC) via osmotic minipump. Endothelial cell function was assessed in isolated aortic rings by vascular reactivity and levels of cyclic GMP. In L-NAME-treated rabbits there was inhibition of endothelium-dependent relaxations to acetylcholine and the calcium ionophore A23187 as well as impaired cyclic GMP accumulation in response to acetylcholine. Neointima formation in the ascending thoracic aorta was assessed by determining media and intima cross-sectional areas with computerized image analysis. Compared with rabbits that consumed the cholesterol diet alone, L-NAME-treated rabbits had significant increases in lesion area (0.29 +/- 0.04 versus 0.15 +/- 0.03 mm2) and in lesion/media ratio (0.06 +/- 0.01 versus 0.03 +/- 0.01). Plasma levels of cholesterol and fluorescent lipid peroxide products were unchanged, suggesting no difference in cholesterol metabolism or oxidation. Because arterial blood pressure was not altered by L-NAME treatment, the increased atherogenesis could not be attributed to an increase in blood pressure. These results indicated that local inhibition of NO accelerates early neointima formation possibly because of modulating monocyte recruitment or foam cell lipid accumulation.
Women are protected from coronary artery disease until the menopause. Ovarian hormones are vasoactive substances that influence both hemodynamic parameters and atheroma formation. Intravenous ethinyl estradiol has been shown to reverse acetylcholine-induced vasoconstriction in cynomolgus monkeys and humans, and 17 beta-estradiol improves exercise-induced myocardial ischemia in female patients. We investigated the effect of the naturally occurring estrogen 17 beta-estradiol on the coronary circulation in postmenopausal women and men with coronary artery disease.
We studied nine postmenopausal women 59 +/- 3 years old, mean +/- SEM, and seven men 52 +/- 4 years old with proven coronary artery disease. They underwent measurement of coronary artery diameter and coronary blood flow after intracoronary infusion of acetylcholine 1.6 and 16 micrograms/min before and 20 minutes after intracoronary administration of 2.5 micrograms of 17 beta-estradiol into atherosclerotic, nonstenotic coronary arteries. Changes in coronary artery diameter were measured by quantitative angiography, and changes in coronary blood flow were measured with an intracoronary Doppler catheter. In female patients, acetylcholine 1.6 and 16 micrograms/min caused constriction before the administration of 17 beta-estradiol (-6 +/- 2% and -8 +/- 5%, respectively, compared with baseline). This constrictor response was converted to dilatation after intracoronary administration of 17 beta-estradiol (+8 +/- 2% and +9 +/- 3%, respectively; P < .01 before versus after estrogen). Acetylcholine 1.6 and 16 micrograms/min increased coronary blood flow before and after the infusion of 17 beta-estradiol. However, the mean acetylcholine-induced increases in coronary flow were significantly greater (P < .009) after (126 +/- 37% and 248 +/- 89%, respectively) than before (94 +/- 31% and 143 +/- 49% mL/min, respectively) the administration of 17 beta-estradiol. 17 beta-Estradiol alone had no significant effect on coronary diameter or coronary blood flow (P > .05). Isosorbide dinitrate (1 mg) caused dilatation of the coronary arteries by 11 +/- 2% (P < .005). In men, acetylcholine 1.6 and 16 micrograms/min caused constriction both before and after the administration of 17 beta-estradiol and caused similar increases in coronary blood flow both before and after the intracoronary administration of 17 beta-estradiol. Infusion of intracoronary placebo in six female control patients 55 +/- 3 years old and six male control patients 56 +/- 3 years old did not change coronary diameter responses or coronary blood flow responses to acetylcholine.
17 beta-Estradiol modulates acetylcholine-induced coronary artery responses of female but not male atherosclerotic coronary arteries in vivo. These human data confirm reports from studies in cynomolgus monkeys that estrogen modulates the responses of atherosclerotic coronary arteries. An enhancement of endothelium-dependent relaxation by natural estrogen (as used in most hormone replacement therapy) may be important in postmenopausal women with established coronary heart disease and may contribute to the acute effect of 17 beta-estradiol on blood flow and its long-term protective effect on the development of coronary artery disease.
A low mortality from prostatic cancer is found in Japanese men consuming a low-fat diet with high content of soy products, a rich source of isoflavonoids. We therefore assayed four isoflavonoids in plasma of 14 Japanese and 14 Finnish men. The geometric mean plasma total individual isoflavonoid levels were 7 to 110 times higher in the Japanese than in the Finnish men. Genistein, a tyrosine kinase inhibitor, occurred in the highest concentration (geometric mean 276 nmol/L). We hypothesise that these high phyto-oestrogen levels may inhibit the growth of prostatic cancer in Japanese men, which may explain the low mortality from prostatic cancer in that country.
Although hormone replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanisms that mediate this apparent benefit are unclear. Because improvement in vasomotor function may represent one of the beneficial effects of estrogen administration, we investigated the acute effects of physiological levels of estrogen on the vascular responses of estrogen-deficient postmenopausal women.
The study included 40 postmenopausal women 60 +/- 8 years old (mean +/- SD), 20 of whom had one or more conditions associated with vascular dysfunction (hypertension, hypercholesterolemia, diabetes, or coronary artery disease). The forearm vascular responses to the endothelium-dependent vasodilator acetylcholine were studied before and during infusion of 17 beta-estradiol into the ipsilateral brachial artery. In 31 subjects, the effect of estradiol on the responses to the endothelium-independent vasodilator sodium nitroprusside was also studied. Women with risk factors for vascular dysfunction had significantly reduced vasodilator responses to acetylcholine (P = .01) and to sodium nitroprusside (P < .001) compared with healthy subjects. Intra-arterial infusion of 17 beta-estradiol increased the forearm venous estradiol concentration from 16 +/- 10 to 318 +/- 188 pg/mL, levels typical of reproductive-age women at midcycle, but caused no vasodilation. However, estradiol potentiated the forearm vasodilation induced by acetylcholine by 18 +/- 30% (P < .001) in women with risk factors for vascular dysfunction and by 14 +/- 23% (P = .03) in healthy women. Estradiol also potentiated the forearm vasodilation induced by sodium nitroprusside in women with risk factors for vascular dysfunction by 14 +/- 21% (P < .001) but not in healthy women.
Physiological levels of 17 beta-estradiol selectively potentiate endothelium-dependent vasodilation in healthy postmenopausal women and potentiate both endothelium-dependent and endothelium-independent vasodilation in post-menopausal women with risk factors for atherosclerosis and evidence of impaired vascular function. These vascular effects may be partly responsible for the long-term benefit of estrogen therapy on cardiovascular events in postmenopausal women.
Oestradiol-17 beta causes relaxation of isolated coronary arteries and increases blood flow in several vascular beds in human beings and animals. Oestrogen replacement therapy is associated with a lower incidence of cardiovascular disease, but the acute effects of oestradiol-17 beta on myocardial ischaemia are unknown. We have studied the acute effect of sublingual oestradiol-17 beta on exercise-induced myocardial ischaemia in eleven women (mean age 58 [SD 8] years) with coronary artery disease. The women did two treadmill exercise tests on separate days; 40 min before the test they took sublingual oestradiol-17 beta (1 mg) or placebo, in random order. Plasma oestradiol-17 beta concentrations were confirmed to be higher after sublingual oestradiol-17 beta than after placebo (2531 [1192] vs 155 [168] pmol/L, p < 0.001). Oestradiol-17 beta increased both time to 1 mm ST depression (456 [214] vs 579 [191] s, p < 0.004; difference of medians 92 [95% CI 46-254]) and total exercise time (569 [249] vs 658 [193] s, p < 0.01; difference 54 [10-212]). Acute administration of oestradiol-17 beta therefore has a beneficial effect on myocardial ischaemia in women with coronary artery disease. This effect may be due to a direct coronary-relaxing effect, to peripheral vasodilation, or to a combination of these mechanisms. Oestradiol-17 beta may prove to be a useful adjunct to the treatment of angina in postmenopausal women with coronary heart disease.
We examined whether prostaglandin (PG) H2, as an endothelium-dependent contracting factor, or the disturbed production of endothelium-derived relaxing factor, impairs endothelium-dependent relaxation and whether long-term inhibition of nitric oxide (NO) synthesis aggravates atherosclerosis in hypercholesterolemic rabbits. Male New Zealand White rabbits were fed one of the following diets: (1) standard chow; (2) 2% cholesterol-supplemented chow; (3) standard chow with 80 micrograms/mL N omega-nitro-L-arginine methylester (L-NAME), an NO synthetase inhibitor, in their drinking water; or (4) 2% cholesterol-supplemented chow with 80 or 160 micrograms/mL L-NAME in their drinking water. The rabbits were fed these diets for 8 or 12 weeks. Then aortic rings were obtained, and changes in isometric tension were recorded. Intimal atherosclerotic areas of the thoracic aortas were subsequently measured by planimetry. The cholesterol-supplemented diet significantly impaired endothelium-dependent aortic relaxation to acetylcholine. Pretreatment with the thromboxane A2/PGH2 receptor antagonist ONO-3708 did not reverse this impaired response. Vessels from both normocholesterolemic and hypercholesterolemic rabbits given L-NAME showed more impaired endothelium-dependent relaxation than those from their dietary counterparts not given L-NAME. Morphometric analysis revealed marked enlargement of intimal atherosclerotic areas in aortas from L-NAME-treated hypercholesterolemic rabbits compared with those from untreated hypercholesterolemic rabbits. These findings suggest that PGH2 does not contribute to impaired endothelium-dependent relaxation and that long-term administration of L-NAME promotes atherosclerosis by inhibition of NO synthesis in the hypercholesterolemic rabbit thoracic aorta.
Estrogen replacement therapy has been associated with a reduction in cardiovascular events in postmenopausal women. One of the mechanisms responsible may be a beneficial effect of estrogen on coronary vascular function. We therefore studied the short-term effects of estrogen on coronary artery dimensions and microvascular resistance in postmenopausal women.
Twenty postmenopausal women 61 +/- 7 years old participated in this study. Seven had angiographic evidence of atherosclerosis of the left coronary artery. Coronary artery diameters were measured by quantitative coronary angiography. Blood flow velocity was measured with a Doppler wire placed in a proximal left coronary artery segment. Left coronary artery infusions of acetylcholine (range, 10(-8) to 10(-5) mol/L estimated delivered concentrations) and of adenosine (n = 18) and sodium nitroprusside (n = 10) were performed before and during concomitant continuous intracoronary infusion of 17 beta-estradiol to test endothelium-dependent and independent vasodilation, respectively. Intracoronary infusion of estradiol increased coronary sinus estradiol levels from postmenopausal (16 +/- 11 pg/mL) to premenopausal (282 +/- 121 pg/mL) levels. Estradiol did not affect basal coronary artery diameter, blood flow, or resistance. Epicardial coronary artery constriction induced by acetylcholine infusion in the control study (maximum, 10 +/- 15% from baseline) was prevented during repeat acetylcholine infusion with concomitant estradiol administration (P < .001). Estradiol potentiated the vasodilator coronary microvascular response to acetylcholine as manifest by significantly greater coronary flow (P < .001) and lower coronary resistance (P < .02). The reduction in coronary resistance from baseline in response to acetylcholine was significantly potentiated by estradiol (P = .01), with a mean decrease in coronary vascular resistance during acetylcholine infusion of 20 +/- 38% before and 35 +/- 33% during concomitant estradiol administration. The effect of estradiol on coronary dynamics was similar in women with and women without angiographically apparent left coronary artery atherosclerosis and was most prominent in women with the most impaired responses to acetylcholine at both the epicardial (r = -.72, P < .001) and microvascular (r = -.59, P = .006) coronary artery levels. In contrast, estradiol did not affect the coronary epicardial or microvascular vasodilator responses to adenosine or sodium nitroprusside.
Physiological levels of 17 beta-estradiol acutely and selectively potentiate endothelium-dependent vasodilation in both large coronary conductance arteries and coronary microvasuclar resistance arteries of postmenopausal women. This effect may contribute to the reduction in cardiovascular events observed with estrogen replacement therapy.
The first quantitative method for the determination of both lignans and isoflavonoid phytoestrogens in plasma is presented. Using ion-exchange chromatography the diphenols are separated into two fractions 1) the biologically "active" fraction containing the free compounds + mono- and disulfates and 2) the biologically "inactive" fraction containing the mono- and diglucuronides and the sulfoglucuronides. After hydrolysis the fractions are further purified by solid phase extraction and ion exchange chromatography. Losses during the complete procedure are corrected for using radioactive estrogen conjugates during the first steps and later by adding deuterated internal standards of all compounds measured (matairesinol, enterodiol, enterolactone, daidzein, O-desmethylangolensin, equol, and genistein). The final determination is carried out by isotope dilution gas chromatography-mass spectrometry in the selected ion monitoring mode (GC/MS/SIM). The diphenols may be measured at concentrations as low as 0.2 to 1.0 nmol/l. Results of plasma analyses of all compounds in 27 pre- and postmenopausal omnivorous and vegetarian women are presented for the first time. The most important findings are that the free+sulfate fraction is low for genistein (3.8% of total), but as much as 21-25% of enterolactone and enterodiol occurs in this fraction. A good correlation between plasma and urine values was found. Total concentrations of individual compounds vary greatly between the subjects (from pmol/l to mumol/l), the vegetarians having higher values, particularly one vegan subject. The highest total enterolactone concentration value exceeded 1 mumol/l. It is concluded that a highly specific method for the assay of 3 lignans and 4 isoflavonoids in plasma has been developed. This method will be useful in future studies of lignan and isoflavonoid metabolism.
To examine the effects of soy phytoestrogens on coronary vascular reactivity in atherosclerotic male and female rhesus monkeys.
A prospective, randomized, blinded, controlled study.
Comparative Medicine Clinical Research Center of an academic medical center.
Twenty-two young adult rhesus monkeys with pre-existing diet-induced atherosclerosis.
Monkeys were fed soy-based diets for 6 months identical in composition, except that the isoflavones were extracted from one flow-isoflavone) and intact in the other (high-isoflavone). Quantitative coronary angiography was performed at the end of the study period. Females in the low-isoflavone group under went a second angiography after an acute IV dose of genistein.
Percent change in diameter of the proximal left circumflex coronary artery in response to intracoronary acetylcholine and nitroglycerin, compared with control diameter.
Arteries from males constricted in response to acetylcholine. Arteries from females in the low-isoflavone group constricted (-6.2% +/- 2.8%, mean +/- SEM), whereas arteries from females in the high-isoflavone group dilated (6.4% +/- 1.2%, mean +/- SEM). Intravenous administration of genistein caused dilation in the previously constricting low-isoflavone females (3.3% +/- 2.8%).
Like mammalian estrogens, dietary soy isoflavones enhance the dilator response to acetylcholine of atherosclerotic arteries in female monkeys.
The rat estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study we investigated the messenger RNA expression of both ER subtypes in rat tissues by RT-PCR and compared the ligand binding specificity of the ER subtypes. Saturation ligand binding analysis of in vitro synthesized human ER alpha and rat ER beta protein revealed a single binding component for 16 alpha-iodo-17 beta-estradiol with high affinity [dissociation constant (Kd) = 0.1 nM for ER alpha protein and 0.4 nM for ER beta protein]. Most estrogenic substances or estrogenic antagonists compete with 16 alpha-[125I]iodo-17 beta-estradiol for binding to both ER subtypes in a very similar preference and degree; that is, diethylstilbestrol > hexestrol > dienestrol > 4-OH-tamoxifen > 17 beta-estradiol > coumestrol, ICI-164384 > estrone, 17 alpha-estradiol > nafoxidine, moxestrol > clomifene > estriol, 4-OH-estradiol > tamoxifen, 2-OH-estradiol, 5-androstene-3 beta, 17 beta-diol, genistein for the ER alpha protein and dienestrol > 4-OH-tamoxifen > diethylstilbestrol > hexestrol > coumestrol, ICI-164384 > 17 beta-estradiol > estrone, genistein > estriol > nafoxidine, 5-androstene-3 beta, 17 beta-diol > 17 alpha-estradiol, clomifene, 2-OH-estradiol > 4-OH-estradiol, tamoxifen, moxestrol for the ER beta protein. The rat tissue distribution and/or the relative level of ER alpha and ER beta expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ER alpha and prostate, ovary, lung, bladder, brain, uterus, and testis for ER beta. The described differences between the ER subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues.
We examined whether vasodilator responses to beta-agonists in human forearm vasculature are mediated in part through the nitric oxide pathway.
We measured forearm blood flow responses to brachial artery infusions of beta-adrenergic agonists in healthy men. Salbutamol was more than 100 times as potent as dobutamine. Cumulative doses of salbutamol (0.3 to 3.5 nmol.min-1) did not cause tachyphylaxis to an identical repeated infusion after a 24-minute recovery period. Vasodilators were infused with this sequence during coinfusion of saline and NG-monomethyl-L-arginine (L-NMMA, 4 mumol.min-1), an inhibitor of nitric oxide synthase. L-NMMA coinfusion inhibited responses (area under the dose-response curve) to isoproterenol (0.01 to 0.1 nmol.min-1) by 59 +/- 7% (n = 5) and inhibited those to salbutamol (0.3 to 3.5 nmol.min-1) by 52 +/- 6% (n = 8). L-NMMA had no significant effect on vasodilator responses to nitroprusside (2.7 to 11.0 nmol.min-1, n = 8), verapamil (20 to 80 nmol.min-1, n = 8), or prostacyclin (0.08 to 0.24 nmol.min-1, n = 8).
These results suggest that beta-adrenergic vasodilator responses in human forearm vasculature are mediated predominantly through beta 2-adrenergic receptors and are dependent on nitric oxide synthesis.
We sought to assess whether high dose estrogen treatment is associated with enhanced arterial reactivity in genetic males.
Although estrogens have been shown to enhance arterial reactivity in women, and are thereby thought to confer cardiovascular benefit, the vascular effects of long-term estrogen therapy in genetic males is unknown.
We studied the arterial physiology of 30 genetic males--15 male to female transsexuals receiving long-term high dose estrogen therapy and 15 healthy male control subjects matched for age, smoking history and vessel size. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation [EDD]) and after nitroglycerin (GTN), an endothelium-independent dilator. Blood pressure, cholesterol and testosterone levels were also measured in each subject.
Total testosterone and free testosterone index levels were lower in the transsexuals compared with the control subjects (p < 0.001). In contrast, EDD was significantly higher in the transsexuals than in the control males (mean [+/-SD] 7.1 +/- 3.1% vs. 3.2 +/- 2.8%, p = 0.001), as was the GTN response (21.2 +/- 6.7% vs. 14.6 +/- 3.3%, p = 0.002). Total and high density lipoprotein cholesterol, blood pressure levels and baseline vessel size were similar in the two groups. On multivariate analysis, enhanced EDD was associated independently with estrogen therapy (p = 0.02) and with low total cholesterol (p = 0.04). An enhanced GTN response was also significantly associated with estrogen therapy (p = 0.03).
Long-term treatment with high dose estrogens is associated with enhanced arterial reactivity in genetic males, which may be due to the effects of estrogen excess or androgen deprivation, or both.
Estrogen therapy is associated with a 50% reduction in the clinical manifestations of coronary artery disease in postmenopausal women. Attenuation of coronary vasomotor dysfunction may contribute to estrogen's cardioprotective effects. We hypothesized that conjugated estrogens, which contain several vasoactive estrogenic compounds, may favorably influence the vasomotor response to acetylcholine in men. Twenty men, 56 +/- 5 years of age, referred for clinically indicated coronary angiography, participated in this study. Acetylcholine-induced changes in coronary flow were measured by quantitative coronary angiography and intracoronary Doppler ultrasonography before and 15 minutes after intravenous administration of conjugated estrogens (0.625 mg) in 12 men and placebo in 8 men. Initial acetylcholine infusion resulted in no significant increase in coronary blood flow. However, 15 minutes after estrogen administration repeat acetylcholine infusion caused a mean 32% increase in coronary blood flow from 41 +/- 5 to 54 +/- 8 ml/min (p = 0.02). Acetylcholine-induced change in flow after estrogen was significantly different from that before estrogen (p = 0.03). Placebo administration did not affect acetylcholine-induced changes in coronary flow. Thus, intravenous conjugated estrogens favorably modulate acetylcholine-induced changes in coronary hemodynamics in men. This suggests that novel nonfeminizing estrogenic compounds may have anti-ischemic effects in men.
At physiological concentrations, 17beta-estradiol selectively enhances endothelium-dependent coronary vasodilation by an unknown mechanism in postmenopausal women.
To assess the contribution of nitric oxide (NO) to the vascular effects of estradiol, we measured coronary epicardial and microvascular responses to intracoronary acetylcholine (range, 3 to 300 microg/min for 2 minutes) before and after intracoronary estradiol 75 ng/min for 15 minutes in 20 estrogen-deficient women, 16 of whom had angiographic evidence of atherosclerosis or risk factors for atherosclerosis. This testing was repeated after inhibition of NO synthesis with intracoronary N(G)-monomethyl-L-arginine (L-NMMA) 64 micromol/min for 5 minutes. Estradiol increased acetylcholine-stimulated coronary flow from 54+/-48% (mean+/-SD) above baseline values before estradiol infusion to 100+/-63% above baseline values (P=.007) and decreased coronary resistance from 32+/-21% to 46+/-15% below baseline values (P=.007) at a coronary sinus estradiol concentration of 1725+/-705 pmol/L (470+/-192 pg/mL). Estradiol also tended to lessen the severity of acetylcholine-induced epicardial coronary artery vasoconstriction from 8+/-11% to 3+/-11% below baseline values (P=.123). However, during L-NMMA infusion, estradiol no longer potentiated the effects of acetylcholine on coronary flow dynamics; coronary flow increased 39+/-46% above baseline values and coronary resistance decreased 19+/-30% below baseline values (both P<.001 versus pre-L-NMMA responses). The epicardial diameter decreased 8+/-11% below baseline values (P=.06 versus pre-L-NMMA response).
The effects of estradiol at physiological concentrations on endothelium-dependent coronary vasodilator responsiveness in postmenopausal women are mediated by enhanced bioavailability of NO, which may be responsible in part for the cardioprotective effects of estrogen.
Transplant-associated coronary arteriopathy is manifested in its early stages by paradoxical coronary artery constriction in response to endothelium-dependent vasodilator stimuli such as the cold pressor test (CPT) and is a major cause of death or retransplantation. Estrogen has vasoactive properties that abolish coronary artery endothelial dysfunction in native hearts. We hypothesized that estrogen attenuates inappropriate coronary artery constriction in cardiac allografts.
Coronary artery diameter and systemic hemodynamic responses to a 90-second CPT were measured before and 15 minutes after double-blind, randomized administration of intravenous conjugated estrogens (1.25 mg) or placebo in men with male cardiac allografts. Before estrogen, 9 men exhibited an abnormal 15.1 +/- 3.0% CPT-induced decrease in coronary artery diameter. However, repeat CPT did not induce significant coronary artery constriction when performed 15 minutes after estrogen. CPT responses before and after estrogen were significantly different (P=.02). Placebo did not influence coronary artery responses to CPT in 6 men. Systemic hemodynamic responses to CPT were not influenced by estrogen or placebo. Estrogen was the only significant determinant of changes in coronary artery responses to CPT.
Conjugated estrogens acutely abolish abnormal CPT-induced coronary artery constriction in male cardiac allografts. This favorable vasomotor effect suggests that estrogen may prevent inappropriate coronary artery constriction in men with cardiac transplants.
Soy is a unique dietary source of the isoflavones, genistein and daidzein. It has been part of the Southeast Asian diet for nearly five millenia, whereas consumption of soy in the United States and Western Europe has been limited to the 20th century. Heavy consumption of soy in Southeast Asian populations is associated with reduction in the rates of certain cancers and cardiovascular disease. Recent experimental evidence suggests that phytochemicals in soy are responsible for its beneficial effects, which may also include prevention of osteoporosis, a hereditary chronic nose bleed syndrome, and autoimmune diseases. Exposure of soy formula-fed infants to the potential estrogenizing effects of the isoflavones is limited by the first pass effect of the liver following the uptake of isoflavones from the gut. Several mechanisms of action of isoflavones have been proposed-both through estrogen-dependent and estrogen-independent pathways.
A fast, precise and selective diode array HPLC method is presented for the extraction and analysis of soy isoflavonoids from foods and from human urine, plasma, and breast milk in support of mechanistic and epidemiologic studies assessing the potential cancer protective role of soya or isoflavones. Solid phase or solvent extraction was chosen for isolation, and enzymatic or acid hydrolysis procedures were used for aglycone production depending on the matrix to be analyzed. C-18 reversed-phase HPLC was applied to selectively separate and quantitate daidzein (1), glycitein (3), and genistein (4), including their malonyl (a) and acetyl (b) esters, and their mammalian metabolites equol (6) and O-desmethylangolensin (7), as well as formononetin (2), biochanin-A (5), and coumestrol (8) using a gradient elution system. UV absorbance scans and authentic standards were applied for identification purposes, additional to fluorometric monitoring, electrochemical detection, and GC/ MS analysis after trimethyl silylation. Detection limits of 20-microl injections were found to be 1.09, 0.53, 3.28, and 1.00 pmoles for daidzein, genistein, equol, and O-desmethylangolensin (DMA), respectively, by monitoring at the individual compound's absorption maximum. The proposed method was applied to monitor isoflavone levels in soy foods and in human plasma, urine and breast milk after challenge with roasted soybeans. Implications of the presented results on the potential activity of isoflavones to prevent cancer by exposing newborn infants to these agents are discussed.
Improvement in endothelial function may be an important mechanism by which estrogen replacement therapy protects postmenopausal women against coronary artery disease. However, combined hormone replacement therapy is more frequently used owing to the risk of uterine cancer with estrogen-only therapy. Concurrent progesterone treatment may attenuate the beneficial effects of estrogens not only on the lipid profile but also on the endothelium.
We studied endothelial vasomotor function in 100 healthy postmenopausal women aged 53.3+/-2.9 years randomized to either combined hormone replacement therapy (n=46) or no substitution (n=54) 2.9+/-0.5 years earlier. In addition, 30 healthy premenopausal women aged 30.3+/-4.2 years were studied. With external ultrasound, brachial artery diameter was measured at rest, during reactive hyperemia (with increased flow causing endothelium-dependent dilation), and after sublingual nitroglycerin (causing endothelium-independent dilation). Compared with premenopausal women, flow-mediated dilation was significantly reduced in both postmenopausal groups. In the postmenopausal women, total cholesterol was lower in the treated women (5.66+/-0.83 versus 6.13+/-0.92 mmol/L; P=.025), whereas HDL cholesterol was similar (1.91+/-0.53 versus 1.85+/-0.46 mmol/L; P=NS). Dilation to flow and to nitroglycerin was similar in the two postmenopausal groups (flow: 2.5+/-2.9% versus 2.2+/-2.2%, P=NS; nitrate: 18.7+/-5.9% versus 17.2+/-6.2%, P=NS).
Long-term combined oral hormone replacement therapy is without beneficial effects on endothelial vasomotor function in healthy postmenopausal women. This supports the view that progesterone may attenuate the beneficial effects of unopposed estrogen replacement.
Estrogen exerts direct effects on vascular endothelial and smooth muscle cells that are important for vascular protection. Estrogen receptor-alpha (ERalpha) is expressed in vascular cells from males and females and may mediate some of the effects of estrogen on vascular tissue. However, we recently found that estrogen is able to protect against vascular injury in ovariectomized female ERalpha knockout mice. These mice express the newly described estrogen receptor-beta (ERbeta) in their aortas, suggesting that ERbeta may also mediate some of the direct effects of estrogen on the vasculature. In this study, the level of expression of ERalpha and ERbeta mRNA in male rat aortas was examined before and after vascular injury using en face (Häutchen) preparations and in situ hybridization. Little or no change in ERalpha expression was observed after vascular injury in either vascular endothelial or smooth muscle cells at any time point. In contrast, ERbeta mRNA was found to be expressed markedly after balloon injury. In endothelial cells, ERbeta was increased by 2 days after injury, and high levels of expression were maintained at 8 and 14 days. Furthermore, ERbeta expression was high in luminal smooth muscle cells at 8 and 14 days after injury and had decreased to low levels by 28 days after injury. These data demonstrate the presence of ERbeta in male vascular tissues and the induction of ERbeta mRNA expression after vascular injury, supporting a role for ERbeta in the direct vascular effects of estrogen.
Epidemiological studies indicate that estrogen replacement therapy decreases the risk of cardiovascular events in postmenopausal women. Estrogen may confer cardiovascular protection by improving endothelial function because it increases endothelium-dependent vasodilation. It is not known whether progesterone attenuates the beneficial effects of estrogen on endothelial function.
Seventeen postmenopausal women with mild hypercholesterolemia were enrolled in a placebo-controlled, crossover trial to evaluate the effect of transdermal estradiol, with and without vaginal micronized progesterone, on endothelium-dependent vasodilation in a peripheral conduit artery. Brachial artery diameter was measured with high-resolution B-mode ultrasonography. To assess endothelium-dependent vasodilation, brachial artery diameter was determined at baseline and after a flow stimulus induced by reactive hyperemia. To assess endothelium-independent vasodilation, brachial artery diameter was measured after administration of sublingual nitroglycerin. During estradiol therapy, reactive hyperemia caused an 11.1+/-1.0% change in brachial artery diameter compared with 4. 7+/-0.6% during placebo therapy (P<0.001). Progesterone did not significantly attenuate this improvement. During combined estrogen and progesterone therapy, flow-mediated vasodilation of the brachial artery was 9.6+/-0.8% (P=NS versus estradiol alone). Endothelium-independent vasodilation was not altered by estradiol therapy, either with or without progesterone, compared with placebo. There was a modest decrease in total and LDL cholesterol during treatment both with estradiol alone and when estradiol was combined with progesterone (all P<0.001 versus placebo). In a multivariate analysis that included serum estradiol, progesterone, total and LDL cholesterol concentrations, blood pressure, and heart rate, only the estradiol level was a significant predictor of endothelium-dependent vasodilation.
The addition of micronized progesterone does not attenuate the favorable effect of estradiol on endothelium-dependent vasodilation. The vasoprotective effect of hormone replacement therapy may extend beyond its beneficial actions on lipids.
Estrogen is an important vasoprotective molecule that causes the rapid dilation of blood vessels by activating endothelial nitric oxide synthase (eNOS) through an unknown mechanism. In studies of intact ovine endothelial cells, 17beta-estradiol (E2) caused acute (five-minute) activation of eNOS that was unaffected by actinomycin D but was fully inhibited by concomitant acute treatment with specific estrogen receptor (ER) antagonists. Overexpression of the known transcription factor ERalpha led to marked enhancement of the acute response to E2, and this was blocked by ER antagonists, was specific to E2, and required the ERalpha hormone-binding domain. In addition, the acute response of eNOS to E2 was reconstituted in COS-7 cells cotransfected with wild-type ERalpha and eNOS, but not by transfection with eNOS alone. Furthermore, the inhibition of tyrosine kinases or mitogen-activated protein (MAP) kinase kinase prevented the activation of eNOS by E2, and E2 caused rapid ER-dependent activation of MAP kinase. These findings demonstrate that the short-term effects of estrogen central to cardiovascular physiology are mediated by ERalpha functioning in a novel, nongenomic manner to activate eNOS via MAP kinase-dependent mechanisms.
The recent discovery of a second estrogen receptor subtype, estrogen receptor-beta, may significantly advance our understanding of tissue specific effects of estrogenic compounds, both natural and synthetic. Although specific effects mediated by estrogen receptor beta in vivo remain to be elucidated, hypothetically the existence of two estrogen receptor subtypes (differing in both tissue distribution and biological activity) may help to explain the curious pharmacological behaviour of many estrogenic and antiestrogenic compounds, including the naturally occurring dietary phytoestrogens.
This article has no abstract; the first 100 words appear below.
The incidence of cardiovascular disease differs significantly between men and women, in part because of differences in risk factors and hormones.¹ The incidence of atherosclerotic diseases is low in premenopausal women, rises in postmenopausal women, and is reduced to premenopausal levels in postmenopausal women who receive estrogen therapy.¹–³ Until recently, the atheroprotective effects of estrogen were attributed principally to the hormone's effects on serum lipid concentrations. However, estrogen-induced alterations in serum lipids account for only approximately one third of the observed clinical benefits of estrogen.³–⁵ Reviews of the data suggest that the direct actions of estrogen on blood . . .
Supported in part by grants (HL61298, HL55309, HL56069, and HL59953) from the National Institutes of Health. Dr. Mendelsohn is an Established Investigator of the American Heart Association.
We are indebted to Drs. Myles Brown, Jan-Ake Gustafsson, Ken Korach, Bert O'Malley, and Phil Shaul for many helpful discussions and to Ms. Patricia Nayak for expert preparation of the manuscript. This review is dedicated to Robert S. Mendelsohn, M.D.
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From the Molecular Cardiology Research Institute and the Department of Medicine, New England Medical Center and Tufts University School of Medicine, Boston.
Address reprint requests to Dr. Mendelsohn at the Molecular Cardiology Research Institute, Tufts University School of Medicine, New England Medical Center, 750 Washington St., No. 80, Boston, MA 02111, or at michael.mendelsohn@es.nemc.org.
The endothelium plays a key role in vascular homeostasisthrough the release of a variety of autocrine and paracrinesubstances (1). In addition to vasodilation, a healthy endo-thelium is antiatherogenic because of effects that includeinhibition of platelet aggregation and adhesion, smoothmuscle cell proliferation and leukocyte adhesion. Dysfunc-tion of endothelial cells is a systemic process and theinitiating event in atherosclerosis, and is important in theischemic manifestations of the disease process as well.Endothelial cell dysfunction occurs in the presence ofatherosclerosis or its risk factors, particularly hypercholes-terolemia (2). Over the past five years, new methodology hasallowed more widespread assessment of endothelium-dependent vasodilation in patients in a variety of researchsettings. This review will focus on the assessment ofendothelial function in humans and the therapeutic optionsthat are now available for treating abnormalities in vascularfunction.
In the present study, confluent bovine aortic endothelial cells (BAECs) were used to study the rapid nongenomic effects of 17beta-estradiol and the membrane impermeable conjugated 17beta-estradiol (E(2)BSA) on the activation of endothelial nitric oxide synthase (eNOS) and mitogen activated protein kinase (MAPK). eNOS activation was assessed in whole cells by measuring [(3)H]L-arginine conversion to [(3)H]L-citrulline. MAPK activity was determined by Western blotting. The results obtained show that the addition of various concentrations of E(2) (0.001-1 micromol/L) resulted in 122+/-29, 186+/-17, 83+/-20 and 157+/-29% increases in eNOS activity, respectively, in BAECs within 15 min of exposure to the hormone. E(2) (0.01 mol/L)-stimulated eNOS activity was detectable during 5-, 15- and 30- min incubation which yielded increases of 37+/-6, 56+/-9 and 38+/-8%, respectively. The increase reached a plateau from 15 through 30 min and rapidly declined thereafter. E(2)BSA 17.5 ng/ml also enhanced eNOS activity by an increase of 35+/-9% above the basal activity. The effect of E(2) and E(2)BSA on eNOS activation was unaffected by actinomycin D 25 microg/ml but was obviously inhibited by tamoxifen (0.1 micromol/L) and PD98059 (50 micromol/L). Compared with control E(2) and E(2)BSA stimulation of BAECs for 15 min caused an increase in MAPK activity by 428+/-17 and 360+/-14% respectively. This effect was blocked by tamoxifen. These results suggest that there might be the membrane estrogen receptor localized on BAECs, which mediates the rapid nongenomic effect of estrogen on eNOS activation through MAPK pathways.
This paper describes an electrically calibrated plethysmograph which may be used with all lengths of mercury-in-rubber strain gauges. Due to the very low resistance of these strain gauges, electrical calibration of previously available plethysmographs has suffered from errors caused by lead-wire resistance. The present instrument eliminates lead-wire errors by a design which effectively places the strain gauge at the corners of the measurement bridge. Linearity of the output for large changes in gauge resistance has been insured by the incorporation of a constant-current bridge supply.
Estrogen increases Ca 2 efflux from female porcine coronary arterial smooth muscle Gilligan DM, Quyyumi AA, Cannon RO III. Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women
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Prakash YS, Togaibayeva AA, Kannam MS, et al. Estrogen increases Ca 2 efflux from female porcine coronary arterial smooth muscle. Am J Physiol. 1999;276:H926 –H934. 14. Gilligan DM, Quyyumi AA, Cannon RO III. Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation. 1994;89:2545–2551.