Sex May Modulate the Effects of Combined Polyphenol Extract and L-citrulline Supplementation on Ambulatory Blood Pressure in Adults with Prehypertension: A Randomized Controlled Trial.

Increased blood pressure (BP), vascular dysfunction and inflammation are involved in the etiology of cardiovascular disease (CVD). Although several dietary components such as polyphenols and L-citrulline may help to control BP, their combined impact on ambulatory BP in individuals at risk of CVD remains unknown. The objective of this research was to investigate the short-term impact of supplementation with a combination of polyphenol extract and L-citrulline on ambulatory BP, endothelial function and inflammation. In a randomized double-blind parallel trial, 73 men and women with prehypertension were supplemented with a placebo (cellulose, n = 34, Plac) or 548 mg/day of polyphenols and 2 g/day of L-citrulline (n = 35, Suppl) for 6 weeks. The primary outcome of this study was the difference between groups in 24-h ambulatory diastolic BP (DBP) at week six. Secondary outcomes were a difference between groups at week six in ambulatory systolic BP (SBP), casual BP, serum lipids and high-sensitivity C-reactive protein (hs-CRP) concentrations and skin advanced glycation end products (AGEs). Potential interaction of treatment with sex was examined. Suppl had no impact on mean ambulatory SBP and DBP (p > 0.10 vs. placebo). Daytime and 24-h SBP were reduced with Suppl in women (p ≤ 0.01), but not in men (p ≥ 0.27). A non-significant reduction in AGEs was observed after Suppl compared to Plac among all participants (p = 0.07) and there was no difference in the concentrations of blood lipids (p > 0.20) or CRP (p = 0.36) between treatments at week six. Therefore, supplementation with polyphenol extract and L-citrulline for 6 weeks has no impact on ambulatory BP, blood lipids and CRP in adults with prehypertension. However, the polyphenol extract/L-citrulline supplement may reduce ambulatory SBP in women, but not in men. These preliminary results need further research efforts towards further documenting this sex-dependent BP response to supplementation with polyphenols and L-citrulline.

Pharmacotherapy for hyperuricaemia in hypertensive patients.

BACKGROUND: This is the second update of this systematic review. High blood pressure represents a major public health problem. Worldwide, approximately one-fourth of the adult population has hypertension. Epidemiological and experimental studies suggest a link between hyperuricaemia and hypertension. Hyperuricaemia affects 25% to 40% of those with untreated hypertension; a much lower prevalence has been reported in those with normotension or in the general population. However, whether lowering serum uric acid (UA) might lower blood pressure (BP), is an unanswered question. OBJECTIVES: To determine whether UA-lowering agents reduce BP in people with primary hypertension or prehypertension, compared with placebo. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to May 2020: the Cochrane Hypertension Specialised Register, CENTRAL 2018, Issue 12, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched LILACS (1982 to May 2020), and contacted authors of relevant papers regarding further published and unpublished work. The searches had no language or date restrictions. SELECTION CRITERIA: To be included in this updated review, the studies had to meet the following criteria: 1) randomised or quasi-randomised, with a group assigned to receive a UA-lowering agent and another group assigned to receive placebo; 2) double-blind, single-blind, or open-label; 3) parallel or cross-over trial design; 4) cross-over trials had to have a washout period of at least two weeks; 5) minimum treatment duration of four weeks; 6) participants had to have a diagnosis of essential hypertension or prehypertension plus hyperuricaemia (serum UA greater than 6 mg/dL in women, 7 mg/dL in men, and 5.5 mg/dL in children or adolescents); 7) outcome measures included change in 24-hour ambulatory systolic or diastolic BP, or both; or clinic-measured systolic or diastolic BP, or both. DATA COLLECTION AND ANALYSIS: The two review authors independently collected the data using a data extraction form, and resolved any disagreements via discussion. We assessed risk of bias using the Cochrane 'Risk of bias' tool. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: In this review update, we screened 722 records, selected 26 full-text reports for evaluation. We identified no ongoing studies and did not add any new studies. We included three randomised controlled trials (RCTs), enrolling 211 people with hypertension or prehypertension, plus hyperuricaemia. Low-certainty evidence from three RCTs found inconclusive results between those who received UA-lowering drugs and placebo, in 24-hour ambulatory systolic (MD -6.2 mmHg, 95% CI -12.8 to 0.5) or diastolic BP (-3.9 mmHg, 95% CI -9.2 to 1.4). Low-certainty evidence from two RCTs found that UA-lowering drugs reduced clinic-measured systolic BP (-8.43 mmHg, 95% CI -15.24 to -1.62) but results for clinic-measured diastolic BP were inconclusive (-6.45 mmHg, 95% CI -13.60 to 0.70). High-certainty evidence from three RCTs found that serum UA levels were reduced by 3.1 mg/dL (95% CI 2.4 to 3.8) in the participants that received UA-lowering drugs. Low-certainty evidence from three RCTs found inconclusive results regarding the occurrence of adverse events between those who received UA-lowering drugs and placebo (RR 1.86, 95% CI 0.43 to 8.10). AUTHORS' CONCLUSIONS: In this updated Cochrane Review, the current RCT data are insufficient to know whether UA-lowering therapy lowers BP. More studies are needed.

Effects of Grape Seed Proanthocyanidin Extract on Vascular Endothelial Function in Participants with Prehypertension: A Randomized, Double-Blind, Placebo-Controlled Study.

This study aimed to investigate the effects of grape seed proanthocyanidin extract (GSPE) on blood pressure and vascular endothelial function in middle-aged Japanese adults with prehypertension. We conducted a randomized, double-blind, placebo-controlled study on 6 men and 24 women aged 40-64 years old. The participants were randomized to receive tablets containing either low-dose (200 mg/day) or high-dose (400 mg/day) GSPE, or placebo, for 12 weeks. Systolic and diastolic blood pressures (SBP and DBP, respectively), brachial flow-mediated dilation (FMD), and other cardiovascular parameters were measured before and after 4, 8, and 12 weeks of treatment. The mean SBP in the high-dose group significantly decreased by 13 mmHg after 12 weeks (P = 0.028), although FMD did not change. In an ad hoc analysis of non-smoking participants (n = 21), the mean SBP, DBP, stiffness parameter ß, distensibility, incremental elastic modulus (Einc), and pulse wave velocity (PWV) also significantly improved in the high-dose group after 12 weeks. Changes in Einc and PWV from baseline to 12 weeks were significantly greater in the high-dose group than in the placebo group (Einc, P = 0.023; PWV, P = 0.03). GSPE consumption could help maintain vascular elasticity and normal blood pressure in this population.

Blockade of TLR4 Within the Paraventricular Nucleus Attenuates Blood Pressure by Regulating ROS and Inflammatory Cytokines in Prehypertensive Rats.

BACKGROUND: Toll-like receptor 4 (TLR4) has been implicated in the progression of cardiovascular disease, including hypertension. However, the role of TLR4 in the development of prehypertension is uncertain. METHODS: Prehypertensive rats were treated with 8% salt for 12 weeks to induce prehypertension. These rats were then given either TAK-242 selective TLR4 blocker, or vehicle by bilateral micro-injection to the paraventricular nucleus (PVN). Blood pressure (BP) and renal sympathetic nerve activity were recorded. PVN expression of TLR4, myeloid differentiation factor 88 (Myd88), nuclear factor-kappa B (NF-κB) p65, proinflammation cytokines (PICs), interleukin (IL)-1ß, IL-6, tumor necrosis factor-alpha (TNF-α), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), NADPH oxidase 4 (NOX4), Cu/Zn superoxide dismutase (SOD) level, tyrosine hydroxylase, and 67 kDa isoform of glutamate decarboxylase (GAD67) were tested to determine the influence of TLR4 blockade. RESULTS: TLR4 expression increased significantly in the PVN of high-salt groups with a corresponding increase in reactive oxygen species (ROS) and PICs. TLR4 blockade significantly reduced the signaling molecules downstream TLR4 and the expression of TNF-α, IL-6, IL-1ß, decreased ROS, NOX2, NOX4 level, increased Cu/Zn-SOD, re-balanced neurotransmitters, and regulated sympathetic nerve activity in the PVN of prehypertensive rats. CONCLUSIONS: Salt-induced prehypertension is partly due to the upregulation of TLR4 in PVN. Blockade of TLR4 in the brain reduced salt-induced prehypertension response, possibly through downregulation of ROS and PICs expression, and the restorage of neurotransmitter balance in the PVN.

Early short-term treatment with exogenous hydrogen sulfide postpones the transition from prehypertension to hypertension in spontaneously hypertensive rat.

ABSTACT Hydrogen sulfide (H2S), nitric oxide (NO), and renin-angiotensin system (RAS) are involved in hypertension. We examined whether early treatment with sodium hydrosulfide (NaHS), an exogenous H2S donor, can regulate H2S-generating pathway, NO pathway, and the RAS, to prevent the transition from prehypertension to hypertension in spontaneously hypertensive rats (SHRs). Four-week-old SHRs and control normotensive Wistar-Kyoto (WKY) rats were assigned into three groups: WKY, SHRs, and SHR + NaHS; SHRs were injected intraperitoneally with sodium hydrosulfide (14 µmol/kg/day) for 4 weeks. SHRs exhibited hypertension at 12 weeks of age, which was blocked by early sodium hydrosulfide administration. Concentrations of H2S were increased in the kidney in SHR + NaHS group versus WKY. Sodium hydrosulfide reduces mRNA expression of four H2S-generating enzymes and decreased 3-mercaptopyruvate sulphurtransferase protein level in SHRs. Early administration of sodium hydrosulfide decreases plasma NG monomethyl-l-arginine (l-NMMA, an inhibitor of NO synthase) level and increases plasma NO level in SHRs. Next, sodium hydrosulfide administration reduces renal mRNA expression of Ren, Atp6ap2, Agt, Ace, and Agtr1a in SHRs. We conclude that early short-term sodium hydrosulfide treatment increases renal H2S concentrations, restores NO bioavailability, and blocks the RAS in the kidney, in favor of vasodilatation to prevent the development of hypertension in adult SHRs.

Acute cardiac functional and mechanical responses to isometric exercise in prehypertensive males.

Isometric exercise (IE) training has been shown to reduce resting arterial blood pressure (ABP) in hypertensive, prehypertensive, and normotensive populations. However, the acute hemodynamic response of the heart to such exercise remains unclear. We therefore performed a comprehensive assessment of cardiac structure, function, and mechanics at rest and immediately post a single IE session in 26 male (age 44.8 ± 8.4 years) prehypertensive participants. Conventional echocardiography recorded standard and tissue Doppler measures of left ventricular (LV) structure and function. Speckle tracking echocardiography was used to measure LV global longitudinal, circumferential, and radial strain and strain rate. From this data, apical and basal rotation and rotational velocities, LV twist, systolic twist velocity, untwist velocity, and torsion were determined. IE led to a significant post exercise reduction in systolic (132.6 ± 5.6 vs. 109.4 ± 19.6 mmHg, P < 0.001) and diastolic (77.6 ± 9.4 vs. 58.8 ± 17.2 mmHg, P < 0.001) blood pressure, with no significant change in heart rate (62 ± 9.4 vs. 63 ± 7.5b·min-1, P = 0.63). There were significant reductions in LV end systolic diameter (3.4 ± 0.2 vs. 3.09 ± 0.3 cm, P = 0.002), LV posterior wall thickness (0.99 ± 0.1 vs. 0.9 ± 0.1 cm, P = 0.013), relative wall thickness (0.4 ± 0.06 vs. 0.36 ± 0.05, P = 0.027) estimated filling pressure (E/E' ratio 6.08 ± 1.87 vs. 5.01 ± 0.82, P = 0.006) and proportion of participants with LV concentric remodeling (30.8% vs. 7.8%, P = 0.035), and significant increases in LV ejection fraction (60.8 ± 3 vs. 68.3 ± 4%, P < 0.001), fractional shortening (31.6 ± 4.5 vs. 39.9 ± 5%, P < 0.001), cardiac output (4.3 ± 0.7 vs. 6.1 ± 1L·min-1, P < 0.001), and stroke volume (74.6 ± 11 vs. 96.3 ± 13.5 ml, P < 0.001). In this setting, there were significant increases in global longitudinal strain (-17.8 ± 2.4 vs. -20 ± 1.8%, P = 0.002) and strain rate (-0.88 ± 0.1 vs. -1.03 ± 0.1%, P < 0.001), basal rotation (-5 ± 3.5 vs. -7.22 ± 3.3°, P = 0.047), basal systolic rotational velocity (-51 ± 21.9 vs. -79.3 ± 41.3°·s-1, P = 0.01), basal diastolic rotational velocity (48.7 ± 18.9 vs. 62.3 ± 21.4°·s-1, P = 0.042), LV twist (10.4 ± 5.8 vs. 13.8 ± 5°, P = 0.049), systolic twist velocity (69.6 ± 27.5 vs. 98.8 ± 35.8°·s-1, P = 0.006), and untwist velocity (-64.2 ± 23 vs. -92.8 ± 38°·s-1, P = 0.007). These results suggest that IE improves LV function and mechanics acutely. This may in turn be partly responsible for the observed reductions in ABP following IE training programs and may have important implications for clinical populations.

Pharmacotherapy for hyperuricemia in hypertensive patients.

BACKGROUND: High blood pressure represents a major public health problem. Worldwide, approximately one-fourth of the adult population has hypertension. Epidemiological and experimental studies suggest a link between hyperuricemia and hypertension. Hyperuricemia affects 25% to 40 % of individuals with untreated hypertension; a much lower prevalence has been reported in normotensives or in the general population. However, whether lowering serum uric acid (UA) might lower blood pressure (BP) is an unanswered question. OBJECTIVES: To determine whether UA-lowering agents reduce BP in patients with primary hypertension or prehypertension compared with placebo. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to February 2016: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched LILACS up to March 2016 and contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: To be included in this review, the studies had to meet the following criteria: 1) randomized or quasi-randomized, with a group assigned to receive a UA-lowering agent and another group assigned to receive placebo; 2) double-blind, single-blind or open-label; 3) parallel or cross-over trial; 4) cross-over trials had to have a washout period of at least two weeks; 5) minimum treatment duration of four weeks; 6) participants had to have a diagnosis of essential hypertension or prehypertension, and hyperuricemia (serum UA greater than 6 mg/dL in women, 7 mg/dL in men and 5.5 mg/dL in children/adolescents); 7) outcome measures assessed included change in clinic systolic, diastolic or 24-hour ambulatory BP. DATA COLLECTION AND ANALYSIS: The two review authors independently collected the data using a data extraction form, and resolved any disagreements via discussion. We assessed risk of bias using the Cochrane Collaboration' Risk of bias' tool. MAIN RESULTS: In this review update, we examined the abstracts of 349 identified papers and selected 21 for evaluation. We also identified three ongoing studies, the results of which are not yet available. Three other randomized controlled trials (RCTs) (two new), enrolling individuals with hypertension or prehypertension, and hyperuricemia, met the inclusion criteria for the review and were included in the meta-analysis. Low quality of evidence from three RCTs indicate no reduction in systolic (MD -6.2 mmHg, 95% CI -12.8 to 0.5) or diastolic (-3.9 mmHg, 95% CI -9.2 to 1.4) 24-hour ambulatory BP with UA-lowering drugs compared with placebo. Low quality of evidence from two RCTs reveal a reduction of systolic clinic BP (-8.43 mmHg, 95% CI -15.24 to -1.62) but not diastolic clinic BP (-6.45 mmHg, 95% CI -13.60 to 0.70). High quality of evidence from three RCTs indicates that serum UA levels were reduced by 3.1 mg/dL (95% CI 2.4 to 3.8) in the participants that received UA-lowering drugs. Very low quality of evidence from three RCTs suggests that withdrawals due to adverse effects were not increased with UA-lowering therapy (RR 1.86, 95% CI 0.43 to 8.10). AUTHORS' CONCLUSIONS: In this updated systematic review, the RCT data available at present are insufficient to know whether UA-lowering therapy also lowers BP. More studies are needed.

Effects of Rubus occidentalis extract on blood pressure in patients with prehypertension: Randomized, double-blinded, placebo-controlled clinical trial.

OBJECTIVE: Black raspberry (Rubus occidentalis) is known for improving vascular function. However, there has been no study evaluating its effects on 24-h systolic and diastolic blood pressure in prehypertensive patients. The aim of this study was to examine those effects. METHODS: Patients with prehypertension (N = 45) were prospectively randomized into a moderate-dose black raspberry group (n = 15, 1500 mg/d), a high-dose black raspberry group (n = 15, 2500 mg/d), or a placebo group (n = 15) during an 8-wk follow-up period. Raspberries were consumed in the form of a dried powder extract that was fashioned into capsules. The capsules contained 187.5 and 312.5 mg of raspberry powder, which was equivalent to 1500 and 2500 mg raspberries. Ambulatory 24-h blood pressure (BP); central BP; pulse-wave velocity; abdominal visceral fat; serum renin; angiotensin-converting enzyme; and inflammatory cytokines such as interleukin-6, tumor necrosis factor-α, C-reactive protein, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and plasminogen activator inhibitor-1 were measured at baseline and at 8-wk follow-up. RESULTS: High-dose black raspberry significantly reduced 24-h systolic blood pressure (SBP; 3.3 ± 10 mm Hg versus -6.7 ± 11.8 mm Hg; P < 0.05) and nighttime SBP (5.4 ± 10.6 mm Hg versus -4.5 ± 11.3 mm Hg; P < 0.05) compared with controls during the 8-wk follow-up. Black raspberry powder did not produce any significant changes in most of the parameters other than BP. CONCLUSION: The use of black raspberry significantly lowered 24-h BP in prehypertensive patients during the 8-wk follow-up. Black raspberry used as a dietary supplement could be beneficial in reducing SBP in prehypertensive patients.

Effects of grape seed extract beverage on blood pressure and metabolic indices in individuals with pre-hypertension: a randomised, double-blinded, two-arm, parallel, placebo-controlled trial.

The aim of the present study was to test grape seed extract (GSE) as a functional ingredient to lower blood pressure (BP) in individuals with pre-hypertension. A single-centre, randomised, two-arm, double-blinded, placebo-controlled, 12-week, parallel study was conducted in middle-aged adults with pre-hypertension. A total of thirty-six subjects were randomised (1:1) to Placebo (n 18) or GSE (n 18) groups; twenty-nine of them completed all the protocol-specified procedures (Placebo, n 17; GSE, n 12). Subjects consumed a juice (167 kJ (40 kcal)) containing 0 mg (Placebo) or 300 mg/d GSE (150 mg) twice daily for 6 weeks preceded by a 2-week Placebo run-in and followed by 4-week no-beverage follow-up. Compliance was monitored. BP was measured at screening, 0, 6 and 10 weeks of intervention and blood samples were collected at 0, 3, 6 and 10 weeks of intervention. GSE significantly reduced systolic BP (SBP) by 5·6 % (P=0·012) and diastolic BP (DBP) by 4·7 % (P=0·049) after 6 weeks of intervention period, which was significantly different (SBP; P=0·03) or tended to be different (DBP; P=0·08) from Placebo. BP returned to baseline after the 4-week discontinuation period of GSE beverage. Subjects with higher initial BP experienced greater BP reduction; nearly double the effect size. Fasting insulin and insulin sensitivity tended to improve after 6 weeks of GSE beverage supplementation (P=0·09 and 0·07, respectively); no significant changes were observed with fasting plasma lipids, glucose, oxidised LDL, flow-mediated dilation or vascular adhesion molecules. Total plasma phenolic acid concentrations were 1·6 times higher after 6 weeks of GSE v. Placebo. GSE was found to be safe and to improve BP in people with pre-hypertension, supporting the use of GSE as a functional ingredient in a low-energy beverage for BP control.

Effects of a quercetin-rich onion skin extract on 24 h ambulatory blood pressure and endothelial function in overweight-to-obese patients with (pre-)hypertension: a randomised double-blinded placebo-controlled cross-over trial.

The polyphenol quercetin may prevent CVD due to its antihypertensive and vasorelaxant properties. We investigated the effects of quercetin after regular intake on blood pressure (BP) in overweight-to-obese patients with pre-hypertension and stage I hypertension. In addition, the potential mechanisms responsible for the hypothesised effect of quercetin on BP were explored. Subjects (n 70) were randomised to receive 162 mg/d quercetin from onion skin extract powder or placebo in a double-blinded, placebo-controlled cross-over trial with 6-week treatment periods separated by a 6-week washout period. Before and after the intervention, ambulatory blood pressure (ABP) and office BP were measured; urine and blood samples were collected; and endothelial function was measured by EndoPAT technology. In the total group, quercetin did not significantly affect 24 h ABP parameters and office BP. In the subgroup of hypertensives, quercetin decreased 24 h systolic BP by -3·6 mmHg (P=0·022) when compared with placebo (mean treatment difference, -3·9 mmHg; P=0·049). In addition, quercetin significantly decreased day-time and night-time systolic BP in hypertensives, but without a significant effect in inter-group comparison. In the total group and also in the subgroup of hypertensives, vasoactive biomarkers including endothelin-1, soluble endothelial-derived adhesion molecules, asymmetric dimethylarginine, angiotensin-converting enzyme activity, endothelial function, parameters of oxidation, inflammation, lipid and glucose metabolism were not affected by quercetin. In conclusion, supplementation with 162 mg/d quercetin from onion skin extract lowers ABP in patients with hypertension, suggesting a cardioprotective effect of quercetin. The mechanisms responsible for the BP-lowering effect remain unclear.

Six weeks daily ingestion of whole blueberry powder increases natural killer cell counts and reduces arterial stiffness in sedentary males and females.

Evidence suggests that berries contain bioactive compounds, which reduce certain cancers and hypertension. Our hypothesis was that daily blueberry (BB) consumption would increase natural killer (NK) cells and plasma redox capacity and reduce blood pressure, augmentation index (AIx), central pulse wave velocity, and aortic systolic pressures (ASPs). Twenty-five men and postmenopausal women aged 18 to 50 years were recruited and randomized to BB (n, 13) or placebo groups (n, 12). Participants were provided with BB (equivalent to 250 g berries) or placebo powders each day for 6 weeks. Blood pressure, vascular performance testing, and blood samples were taken at baseline (presupplementation). Participants returned after 6 weeks and repeated all procedures. Presupplementation to postsupplementation comparisons for the main effects of treatment, time, and treatment-time interaction were made using a 2 (treatment) × 2 (times) repeated-measures analysis of variance for all vascular measures, redox status, and NK cell counts. Anthropometric measures were compared using t tests. Body mass, composition, and overall blood pressures were not affected in either group. Overall, AIx and ASPs were decreased in BB (treatment effect, P = .024 and P = .046, respectively). Plasma redox was not affected. Absolute NK cells were increased in BB (time, P = .001 and interaction, P = .012). Subjects (n, 9) with prehypertensive pressures (≥120/80 mm Hg, respectively) were examined as a subset using t tests and exhibited significant reductions in diastolic pressure (P = .038) from presupplementation to postsupplementation in BB. We conclude that BB ingestion for 6 weeks increases NK cells and reduces AIx, ASP, and diastolic pressures in sedentary males and females.

Long-term prehypertension treatment with losartan effectively prevents brain damage and stroke in stroke-prone spontaneously hypertensive rats.

Prehypertension has been associated with adverse cerebrovascular events and brain damage. The aims of this study were to investigate ⅰ) whether short­ and long-term treatments with losartan or amlodipine for prehypertension were able to prevent blood pressure (BP)-linked brain damage, and ⅱ) whether there is a difference in the effectiveness of treatment with losartan and amlodipine in protecting BP-linked brain damage. In the present study, prehypertensive treatment with losartan and amlodipine (6 and 16 weeks treatment with each drug) was performed on 4-week­old stroke-prone spontaneously hypertensive rats (SHRSP). The results showed that long-term (16 weeks) treatment with losartan is the most effective in lowering systolic blood pressure in the long term (up to 40 weeks follow-up). Additionally, compared with the amlodipine treatment groups, the short­ and long-term losartan treatments protected SHRSP from stroke and improved their brains structurally and functionally more effectively, with the long-term treatment having more benefits. Mechanistically, the short­ and long-term treatments with losartan reduced the activity of the local renin-angiotensin-aldosterone system (RAAS) in a time-dependent manner and more effectively than their respective counterpart amlodipine treatment group mainly by decreasing AT1R levels and increasing AT2R levels in the cerebral cortex. By contrast, the amlodipine treatment groups inhibited brain cell apoptosis more effectively as compared with the losartan treatment groups mainly through the suppression of local oxidative stress. Taken together, the results suggest that long-term losartan treatment for prehypertension effectively protects SHRSP from stroke-induced brain damage, and this protection is associated with reduced local RAAS activity than with brain cell apoptosis. Thus, the AT1R receptor blocker losartan is a good candidate drug that may be used in the clinic for long-term treatment on prehypertensive populations in order to prevent BP-linked brain damage.

Effect of polyphenol-rich grape seed extract on ambulatory blood pressure in subjects with pre- and stage I hypertension.

Dietary polyphenols, such as those from grape products, may exert beneficial effects on cardiovascular health, including anti-hypertensive effects. We investigated the effect of a specific grape seed extract (GSE) rich in low-molecular-weight polyphenolic compounds on ambulatory blood pressure (ABP) in untreated subjects with pre- and stage I hypertension. In addition, potential mechanisms that could underlie the hypothesised effect of GSE on blood pressure (BP), and platelet aggregation, were explored. The study was designed as a double-blind, placebo-controlled, randomised, parallel-group intervention study including seventy healthy subjects with systolic BP between 120 and 159 mmHg. A 1-week run-in period was followed by an 8-week intervention period, during which subjects consumed capsules containing either 300 mg/d of GSE or a placebo (microcrystalline cellulose). Before and after the intervention, daytime ABP readings, 24 h urine samples and fasting and non-fasting blood samples were taken. The mean baseline systolic BP was 135.8 (SE 1.3) mmHg and diastolic BP was 81.5 (SE 0.9) mmHg. BP values were modestly, but not significantly, affected by the polyphenol-rich GSE treatment v. placebo with an effect of - 3.0 mmHg for systolic BP (95% CI - 6.5, 0.5) and - 1.4 mmHg for diastolic BP (95% CI - 3.5, 0.6). Vasoactive markers including endothelin-1, NO metabolites and asymmetric dimethylarginine, plasma renin activity and platelet aggregation were not affected by the GSE intervention. Our findings show that consumption of polyphenol-rich GSE does not significantly lower ABP in untreated subjects with pre- and stage I hypertension.

Effects of anthocyanins on cardiovascular risk factors and inflammation in pre-hypertensive men: a double-blind randomized placebo-controlled crossover study.

High intake of fruits and vegetables is associated with reduced cardiovascular risk. A number of fruits and vegetables are rich in anthocyanins, which constitute a subgroup of the flavonoids. Anthocyanins have demonstrated anti-inflammatory and anti-oxidative properties, and anthocyanin-rich interventions have indicated beneficial effects on blood pressure and other cardiovascular risk factors. We assessed whether a purified anthocyanin supplement improves cardiovascular metabolic risk factors and markers of inflammation and oxidative stress in prehypertensive participants, and whether plasma polyphenols are increased 1-3 h following intake. In all, 31 men between 35-51 years with screening blood pressure >140/90 mm Hg without anti-hypertensive or lipid-lowering medication, were randomized in a double-blinded crossover study to placebo versus 640 mg anthocyanins daily. Treatment durations were 4 weeks with a 4-week washout. High-density lipoprotein (HDL)-cholesterol and blood glucose were significantly higher after anthocyanin versus placebo treatment (P=0.043 and P=0.024, respectively). No effects were observed on inflammation or oxidative stress in vivo, except for von Willebrand factor, which was higher in the anthocyanin period (P=0.007). Several plasma polyphenols increased significantly 1-3 h following anthocyanin intake. The present study strengthens the evidence that anthocyanins may increase HDL-cholesterol levels, and this is demonstrated for the first time in prehypertensive and non-dyslipidemic men. However, no other beneficial effects in the short term were found on pathophysiological markers of cardiovascular disease.

Fish oil and neurovascular control in humans.

The antihypertensive influence of fish oil is controversial, and the mechanisms remain unclear. Because the inverse relation between fish oil and hypertension appears to be partially dependent on the degree of hypertension, we tested the hypothesis that fish oil would elicit more dramatic reductions in mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA) in prehypertensive (PHT) compared with normotensive (NT) subjects. Resting MAP, MSNA, and heart rate (HR) were examined before and after 8 wk of fish oil (9 g/day; 1.6 g eicosapentaenoic acid and 1.1 g docosahexaenoic acid) or placebo (olive oil; 9 g/day) in 38 NT (19 fish oil; 19 placebo) and 29 PHT (15 fish oil; 14 placebo) volunteers. Fish oil did not alter resting MAP, MSNA, or HR in either NT (80 ± 1 to 80 ± 1 mmHg; 11 ± 2 to 10 ± 1 bursts/min; 71 ± 2 to 71 ± 2 beats/min) or PHT (88 ± 2 to 87 ± 1 mmHg; 11 ± 2 to 10 ± 2 bursts/min; 73 ± 2 to 73 ± 2 beats/min) subjects. When NT and PHT groups were consolidated, analysis of covariance confirmed that pretreatment resting MAP was not associated with changes in MSNA after fish oil. In contrast, pretreatment resting HR was correlated with changes in MSNA (r = 0.47; P = 0.007) and MAP (r = 0.42; P < 0.007) after fish oil but not placebo. In conclusion, fish oil did not alter sympathetic neural control in NT or PHT subjects. However, our findings suggest that fish oil is associated with modest sympathoinhibition in individuals with higher resting heart rates, a finding that is consistent with a recent meta-analysis examining the relations among fish oil, HR, and the risk of cardiovascular disease.

Ambulatory blood pressure monitoring in prehypertensive subjects.

BACKGROUND: Although treatment of prehypertensives is feasible and effective, it is unclear how to define those who may benefit. We hypothesized that ambulatory blood pressure monitoring (ABPM) might be a tool for selecting prehypertensive subjects, classified according to the JNC 7, who later develop drug-treated hypertension. METHODS: Prehypertensives (n=107; 62 M, 45 F; age 50 ± 14 years) with or without cardiovascular risk factors were assessed for drug-treated hypertension development. They underwent ABPM at entry examination and were clinically followed-up for an average of 99 ± 42 months. Thereafter, subjects were divided into 2 groups according to the development of drug-treated hypertension. Stepwise logistic regression (LR) analysis was performed to assess the role of factors contributing independent prediction of outcome (i.e. drug-treated hypertension onset). RESULTS: In LR analysis body mass index [odds ratio (OR)=1.29, confidence intervals (CI)95% 1.03-1.62], female gender (OR=11.10, CI95% 2.66-46.30), total cholesterol (OR=1.03, CI95% 1.01-1.05), smoking (OR=3.90, CI95% 0.94-16.20), daytime SBP (OR=1.10, CI95% 1.01-1.19) and 24h DBP (OR=1.23, CI95% 1.08-1.41) predicted the development of hypertension. The criteria combining BP and clinical variables were superior to BP or clinical criteria alone in the correct classification of true positives and true negatives. Altogether there was an improvement of 14.02% (p < 0.01) in comparison to only clinical criteria. CONCLUSIONS: In the setting of global cardiovascular risk assessment, ABPM, in the early diagnosis of hypertension in prehypertensive individuals, appears as a useful tool, both diagnostically and prognostically, to index subjects who are suspected to be masked hypertensives.

Antihypertensive and antioxidant effects of dietary black sesame meal in pre-hypertensive humans.

BACKGROUND: It has been known that hypertension is an independent risk factor for cardiovascular disease (CVD). CVD is the major cause of morbidity and mortality in developed and developing countries. Elevation of blood pressure (BP) increases the adverse effect for cardiovascular outcomes. Prevention of increased BP plays a crucial role in a reduction of those outcomes, leading to a decrease in mortality. Therefore, the purpose of this study was to investigate the effects of dietary black sesame meal on BP and oxidative stress in individuals with prehypertension. METHODS: Twenty-two women and eight men (aged 49.8 ± 6.6 years) with prehypertension were randomly divided into two groups, 15 subjects per group. They ingested 2.52 g black sesame meal capsules or placebo capsules each day for 4 weeks. Blood samples were obtained after overnight fasting for measurement of plasma lipid, malondialdehyde (MDA) and vitamin E levels. Anthropometry, body composition and BP were measured before and after 4-week administration of black sesame meal or a placebo. RESULTS: The results showed that 4-week administration of black sesame meal significantly decreased systolic BP (129.3 ± 6.8 vs. 121.0 ± 9.0 mmHg, P < 0.05) and MDA level (1.8 ± 0.6 vs. 1.2 ± 0.6 µmol/L, P < 0.05), and increased vitamin E level (29.4 ± 6.0 vs. 38.2 ± 7.8 µmol/L, P < 0.01). In the black sesame meal group, the change in SBP tended to be positively related to the change in MDA (R = 0.50, P = 0.05), while the change in DBP was negatively related to the change in vitamin E (R = -0.55, P < 0.05). There were no correlations between changes in BP and oxidative stress in the control group. CONCLUSIONS: These results suggest the possible antihypertensive effects of black sesame meal on improving antioxidant status and decreasing oxidant stress. These data may imply a beneficial effect of black sesame meal on prevention of CVD.