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The cytochrome P-450 arachidonic acid metabolite 20-HETE is central to the regulation of vascular tone, renal function, and blood pressure and is synthesized in the rat kidney in response to angiotensin II (ANG II) and endothelin-1 (ET-1). There are very few studies examining the cellular synthesis of 20-HETE in humans. We aimed to measure human neutrophil and platelet 20-HETE levels under basal conditions and after ANG II, ET-1, and calcium ionophore (CaI). 20-HETE was measured in human platelets and neutrophils after saline (control), CaI (2.5 μg/ml), and ANG II or ET-1 (10 nmol/l-1 μmol/l) incubations. The effect of cells, which were preincubated with the ω-hydroxylase inhibitor N-hydroxy-N'-(4-butyl-2-methylphenyl) (HET0016, 10 nM), ANG II types 1 or 2 (AT1 or AT2) receptor inhibition with irbesartan (1 μmol/l) or PD-123319 (1 μmol/l), or endothelin receptor subtypes A or B (ETA or ETB) receptor inhibition with BQ-123 or BQ-778 (100 nmol/l), was studied. Neutrophil and platelet content and release of 20-HETE was significantly increased by CaI and blocked by the ω-hydroxylase inhibitor HET0016. ANG II and ET-1 significantly increased neutrophil and platelet content and release of 20-HETE. ANG II increased 20-HETE via the AT2 receptor. ET-1 increased 20-HETE through the ETB receptor in platelets and both the ETA and ETB receptors in neutrophils. These studies show that human platelets and neutrophils synthesize 20-HETE in response to ANG II and ET-1. 20-HETE synthesis in both cell types was predominantly mediated via the AT2 and ETB receptors. Stimulation via these receptor pathways has generally been thought to be cardioprotective and requires further studies in clinical situations associated with low-grade inflammation or where ANG II and ET-1 are elevated to clarify the role of 20-HETE. [ABSTRACT FROM AUTHOR]

Background. Nitric oxide (NO) is an important vascular signaling molecule that plays a role in vascular homeostasis. A reduction in NO bioavailability is thought to contribute to endothelial dysfunction, an early risk factor for both cardiovascular disease and type 2 diabetes. Dietary nitrate, through the nitrate-nitrite-NO pathway, may provide an alternate source of NO when the endogenous eNOS system is compromised. In addition to a role in the vascular system, NO may also play a role in the metabolic syndrome including obesity and glucose tolerance. Aim. To investigate the effect of long-term dietary nitrate supplementation on development of the metabolic syndrome in mice fed a high-fat diet. Methods. Following 1 week of acclimatisation, male (6–8 weeks) C57BL6 mice were randomly assigned to the following groups (10/group) for 12 weeks: (i) normal chow + NaCl (1 mmol/kg/day), (ii) normal chow + NaNO3 (1 mmol/kg/day), (iii) high-fat diet + NaCl (1 mmol/kg/day), and (iv) high-fat diet + NaNO3 (1 mmol/kg/day). Body weight and food consumption were monitored weekly. A subset of mice (5/group) underwent running wheel assessment. At the end of the treatment period, all mice underwent fasting glucose tolerance testing. Caecum contents, serum, and tissues (liver, skeletal muscle, white and brown adipose, and kidney) were collected, frozen, and stored at −80°C until analysis. Results. Consumption of the high-fat diet resulted in significantly greater weight gain that was not affected by dietary nitrate. Mice on the high-fat diet also had impaired glucose tolerance that was not affected by dietary nitrate. There was no difference in adipose tissue expression of thermogenic proteins or energy expenditure as assessed by the running wheel activity. Mice on the high-fat diet and those receiving dietary nitrate had reduced caecum concentrations of both butyrate and propionate. Conclusions. Dietary nitrate does not prevent development of the metabolic syndrome in mice fed a high-fat diet. This may be due, in part due, to reductions in the concentration of important short-chain fatty acids. [ABSTRACT FROM AUTHOR]

Background -- Oxidative stress may contribute to the pathogenesis of hypertension and endothelial dysfunction via increased production of free radicals in the arterial wall. Objective -- To investigate the effect of water-soluble antioxidants, vitamin C and polyphenols, on blood pressure (BP), endothelial function and oxidative stress in hypertensive individuals. Methods -- 69 treated hypertensive individuals with a mean 24hr ambulatory systolic BP ≥125 mmHg were involved in a randomised, double blind, placebo-controlled factorial trial. Following a 3-week washout, participants received either 500 mg/d vitamin C, 1000 mg/d grape-seed polyphenols, both vitamin C and polyphenols, or neither, for 6-weeks. At baseline and post-intervention, 24hr ambulatory BP, ultrasound assessed endothelium dependent and independent vasodilation of the brachial artery, and markers of oxidative damage, including plasma and urinary isoprostanes, oxidised low density lipoproteins and plasma tocopherols, were measured. Results -- A significant interaction was observed, therefore results could not be analysed for main effects. In comparison to placebo, vitamin C lowered systolic BP (-1.8±0.8 mmHg, p=0.03), polyphenols did not significantly alter BP, but the combination of vitamin C and polyphenols significantly increased systolic (4.8±0.9 mmHg, p<0.0001), and diastolic (2.7±0.6 mmHg, p<0.0001) BP. Endothelium-dependent and independent vasodilation, and markers of oxidative damage were not significantly altered. Conclusion -- The combination of vitamin C and polyphenols significantly increased BP, but the mechanism remains to be elucidated. [ABSTRACT FROM AUTHOR]

Isoflavonoids are a class of flavonoids that are derived in the human diet mainly from soybean-based foods. The major dietary isoflavonoids, genistein and daidzein, have estrogen-like activity and are classed as phytoestrogens. Because estrogens can lower serum LDL cholesterol and raise HDL cholesterol, the objective of this study was to determine if isoflavonoids could improve serum lipids in healthy subjects. Forty-six men and 13 postmenopausal women not receiving hormone replacement therapy completed a randomized, double-blind, placebo-controlled trial of two-way parallel design and 8 wk duration. One tablet containing 55 mg of isoflavonoids (predominantly in the form of genistein) or one placebo tablet was taken daily with the evening meal. Subjects maintained their usual diet and physical activity, which were unchanged throughout the intervention. Measurement of isoflavonoids and their metabolites in 24-h urine samples provided an assessment of compliance and of isoflavonoid metabolism. Serum total, LDL, HDL and HDL subclass cholesterol, triglycerides and lipoprotein (a) were assessed at baseline and during the last week of intervention. After adjustment for baseline values, no significant differences in postintervention serum lipid and lipoprotein (a) concentrations between groups were identified. Further adjustment for age, gender and weight change did not alter the results. In addition, changes in urinary isoflavonoids were not significantly correlated with changes in serum lipids and lipoprotein (a). Therefore, this study does not support the hypothesis that isoflavonoid phytoestrogens can improve the serum lipids, at least in subjects with average serum cholesterol concentrations. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To test the hypothesis that the hepatic secretion of very-low-density lipoprotein (VLDL) apolipoprotein B100 (apoB) is increased in men with visceral obesity and to examine whether the oversecretion of this apolipoprotein is related to insulin resistance and increased hepatic availability of lipid substrates. SUBJECTS: 16 obese men (body mass index (BMI) > 30 kg/m², waist circumference > 100 cm) and 16 non-obese, age matched men, were studied. MEASUREMENTS: The hepatic secretion of VLDL apoB was measured using a primed (1 mg/kg), constant (1 mg/kg/ h), intravenous infusion of 1-[[sup 13]C]-Ieucine. Isotopic enrichment of VLDL apoB was determined using gas-chromatography mass spectrometry and a multi-compartmental model (SAAM-II) was used to estimate the fractional turnover rate of VLDL apoB. RESULTS: Plasma concentrations of total cholesterol, triglyceride, glucose, insulin, mevalonic acid and lathosterol, as well as dietary fat intake, were significantly higher (P < 0.05) in obese than control subjects. The obese subjects had significantly lower high-density-lipoprotein cholesterol (P < 0.01). VLDL apoB pool size and hepatic secretion rate (mg/ kg fat free mass/d) were significantly higher in the obese than non-obese subjects (P < 0.02). The fractional catabolic rate of VLDL apoB was lower in the obese subjects compared with controls, but the difference did not attain conventional significance (P=0.053). In pooled analysis, there was a significant positive association (P<0.05) between VLDL apoB secretion rate (mg/kg fat free mass/d) and waist-to-hip ratio (WHR), waist circumference, and fasting plasma triglyceride, insulin and glucose concentrations. In multiple linear regression analysis, the association between VLDL apoB secretion and fasting insulin concentration was independent of age, apolipoprotein E (apoE) genotype, mevalonic acid concentration, free fatty acid concentration and fat intake. CONCLUSION: Our findings are consistent with... [ABSTRACT FROM AUTHOR]

Background -- Oxidative stress is thought to play a role in the development of diabetes, hypertension and endothelial dysfunction. Vitamin E, a major lipid-soluble dietary antioxidant, occurs in a number of structurally related forms. Although many studies have examined a-tocopherol, another major dietary form, γ-tocopherol has largely been overlooked. Objective -- To investigate the effect of α-tocopherol and γ-tocopherol supplementation on blood pressure (BP), vascular function and oxidative stress in people with type 2 diabetes. Design -- 55 individuals were randomised in a double blind, placebo-controlled trial. Participants received either 500 mg/d α-tocopherol, 500 mg/d mixed tocopherols (60% γ-tocopherol), or placebo, for 6-weeks. At baseline and postintervention, 24hr ambulatory BP, endothelium dependent and independent vasodilation and plasma and urinary F2- isoprostanes were measured. Outcomes -- Treatment with α-tocopherol significantly increased systolic BP (7.0 ± 0.9 mmHg, P <0.0001), diastolic BP (5.3 ± 0.6 mm Hg, P <0.0001), pulse pressure (1.79 ± 0.61 mm Hg, P <0.005) and heart rate (2.0 ± 0.7 bpm, P <0.005) versus placebo. Treatment with g-tocopherol significantly increased systolic BP (6.8±1.0 mm Hg, P <0.0001), diastolic BP (3.6±0.7 mm Hg, P <0.0001), pulse pressure (3.20 ± 0.63 mm Hg, P <0.0001) and heart rate (1.8±0.7 bpm, P <0.01) versus placebo. Treatment with α-tocopherol or γ-tocopherol significantly reduced plasma F2-isoprostanes versus placebo, but had no effect on urinary F2-isoprostanes. Endothelium-dependent and independent vasodilation were not significantly altered. Conclusion -- Treatment with either α- or γ-tocopherol significantly increases BP, pulse pressure and HR in type 2 diabetes, independent of changes in vascular function or oxidative stress. [ABSTRACT FROM AUTHOR]

Introduction - Oxidative stress has been implicated in a number of disease processes. There is evidence suggesting that vitamin C, a major water-soluble antioxidant, may reduce oxidative stress. The effects of dietary polyphenols, watersoluble compounds with potent antioxidant activity in vitro, on oxidative stress are unclear. Objectives - The objectives of this study were to investigate the effect of supplementation with grape-seed polyphenols on oxidative stress, and to compare any effects to those of vitamin C. Design- Following a 3-week washout, participants were randomised to receive (i) 500mg/day vitamin C + matched placebo (n = 19), (ii) 1000mg/day polyphenols + matched placebo (n = 16), (iii) 500mg/day vitamin C + 1000mg/day polyphenols (n = 16), or (iv) matched placebos (n = 18). Plasma and urinary F2-isoprostanes and oxidised low-density lipoproteins were analysed as markers of oxidative damage. Outcomes - Supplementation with grape-seed polyphenols resulted in a significant increase in urinary excretion of specific phenolic acids (3-hydroxyphenylproprionic acid), but did not alter F2-isoprostane concentrations or oxidised low-density lipoproteins. The phenolic acid metabolites, markers of exposure to grape-seed polyphenols, were not related to changes in markers of oxidative stress. Plasma vitamin C levels increased significantly following supplementation. Plasma F2-isoprostane concentrations fell following supplementation with vitamin C (p=0.056). There was no change in urinary F2-isoprostane concentrations or oxidised low-density lipoproteins. There was no relationship between increases in plasma vitamin C and changes in markers of oxidative stress. Conclusions - These results support the suggestion that supplementation with vitamin C may reduce in vivo lipid peroxidation. However, supplementation with grape-seed polyphenols and exposure to phenolic acid metabolites had no effect on in vivo lipid peroxidation. [ABSTRACT FROM AUTHOR]