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Hypertension is a pervasive and widespread health condition that poses a significant risk factor for cardiovascular disease, which includes conditions such as heart attack, stroke, and heart failure. Despite its widespread occurrence, the exact cause of hypertension remains unknown, and the mechanisms underlying the progression from prehypertension to hypertension require further investigation. Recent proteomic studies have shown promising results in uncovering potential biomarkers related to disease development. In this study, serum proteomic data collected from Qatar Biobank were analyzed to identify altered protein expression between individuals with normal blood pressure, prehypertension, and hypertension and to elucidate the biological pathways contributing to this disease. The results revealed a cluster of proteins, including the SRC family, CAMK2B, CAMK2D, TEC, GSK3, VAV, and RAC, which were markedly upregulated in patients with hypertension compared to those with prehypertension (fold change ≥ 1.6 or ≤-1.6, area under the curve ≥ 0.8, and q -value < 0.05). Pathway analysis showed that the majority of these proteins play a role in actin cytoskeleton remodeling. Actin cytoskeleton reorganization affects various biological processes that contribute to the maintenance of blood pressure, including vascular tone, endothelial function, cellular signaling, inflammation, fibrosis, and mechanosensing. Therefore, the findings of this study suggest a potential novel role of actin cytoskeleton-related proteins in the progression from prehypertension to hypertension. The present study sheds light on the underlying pathological mechanisms involved in hypertension and could pave the way for new diagnostic and therapeutic approaches for the treatment of this disease.

This study investigated the effects of prehypertension and shear stress on the reendothelialization potential of human early EPCs and explored its potential mechanisms. Early EPCs from the prehypertensive patients showed reduced migration and adhesion in vitro and demonstrated a significantly impaired in vivo reendothelialization capacity. Shear stress pretreatment markedly promoted the in vivo reendothelialization capacity of EPCs. Although basal CXCR4 expression in early EPCs from prehypertensive donors was similar to that from healthy control, SDF-1-induced phosphorylation of CXCR4 was lower in prehypertensive EPCs. Shear stress up-regulated CXCR4 expression and increased CXCR4 phosphorylation, and restored the SDF-1/CXCR4-dependent JAK-2 phosphorylation in prehypertensive EPCs. CXCR4 knockdown or JAK-2 inhibitor treatment prevents against shear stress-induced increase in the migration, adhesion and reendothelialization capacity of the prehypertensive EPCs. Collectively, CXCR4 receptor profoundly modulates the reendothelialization potential of early EPCs. The abnormal CXCR4-mediated JAK-2 signaling may contribute to impaired functions of EPCs from patients with prehypertension., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Angiotensin-converting enzyme 2 (ACE2) or exercise training (ExT) is beneficial to hypertension, but their combined effects remain unknown. In this study, lentivirus containing enhanced green fluorescent protein (eGFP) and ACE2 were microinjected into the paraventricular nucleus (PVN) of young male spontaneous hypertensive rats (SHRs), and SHRs were assigned into five groups: sedentary (SHR), SHR-ExT, SHR-eGFP, ACE2 gene (SHR-ACE2), and ACE2 gene combined with ExT (SHR-ACE2-ExT). Wistar-Kyoto (WKY) rats were used as a control. ACE2 gene or ExT significantly delayed the elevation of blood pressure, and the combined effect prevented the development and progression of prehypertension. Either ACE2 overexpression or ExT improved arterial baroreflex sensitivity (BRS), whereas the combined effect normalized BRS in SHR. Compared with SHR, SHR-ACE2 and SHR-ExT displayed a significantly higher level of ACE2 protein but had lower plasma norepinephrine (NE) and angiotensin II (AngII) as well as angiotensin II type 1 receptor (AT1) protein expression in the PVN. SHR-ACE2-ExT showed the largest decrease in AngII and AT1 protein expression. Reactive oxygen species (ROS) level and NADPH oxidase (NOX2 and NOX4) protein expression in PVN were also decreased in SHR-ACE2-ExT group than in SHR-ACE2 and SHR-ExT groups. It was concluded that the combined effect has effectively prevented prehypertension progression and baroreflex dysfunction in SHR, which is associated with the reduction in AngII/AT1 axis function and oxidative stress in the PVN. NEW & NOTEWORTHY Angiotensin-converting enzyme 2 ( ACE2 ) gene in combination with exercise training (ExT) delayed the progression of hypertension via normalizing the blunted baroreflex sensitivity (BRS) and inhibiting sympathetic nerve activity (SNA). Its underlying mechanism may be related to the inhibition of AngII/AT1 axis function and central oxidative stress in the paraventricular nucleus (PVN) of prehypertensive rats.

Objective: We studied the link of decreased baroreflex sensitivity (BRS) to cardiometabolic risks and prehypertension status in postmenopausal women during their early menopausal phase., Methods: Premenopausal women ( n = 55) and early-postmenopausal women ( n = 50) of age group between 40 and 55 years were recruited for the study, and their anthropometric parameters, complete battery of autonomic function tests (AFT), BRS, hormone levels, and cardiometabolic risk parameters were measured and compared between two groups. Correlation analysis of BRS with various physiological and biochemical parameters in these two groups were performed. Multiple regression analysis of BRS with various other associated factors in postmenopausal subjects and bivariate logistic regression analysis for assessing prediction of prehypertension status by BRS in postmenopausal group were performed., Results: There was a significant difference in AFT and metabolic parameters between premenopausal and postmenopausal women. Sympathovagal imbalance (increased sympathetic and decreased parasympathetic) was prominent in early-postmenopausal women. Decreased BRS, the marker of cardiovascular (CV) risk was found to be significant ( P < .001) and correlated with various cardiometabolic parameters in early-postmenopausal subjects. Multiple regression analysis demonstrated that decreased BRS is independently linked to parameters of decreased vagal activity, inflammation, and oxidative stress in early-postmenopausal group. Decreased BRS could predict prehypertension status in early-postmenopausal subjects as confirmed by bivariate logistic regression analysis., Conclusion: Sympathovagal imbalance, decreased BRS and considerable metabolic derangements were observed in women in their early phase of menopause. Decreased BRS appears to be associated with the cardiometabolic risks in these women. Prehypertension status in early-postmenopausal subjects could be predicted by decreased BRS.

Context: Although dietary potassium and sodium intake may influence calcium-phosphate metabolism and bone health, the effects on bone mineral parameters, including fibroblast growth factor 23 (FGF23), are unclear., Objective: Here, we investigated the effects of potassium or sodium supplementation on bone mineral parameters., Design, Setting, Participants: We performed a post hoc analysis of a dietary controlled randomized, blinded, placebo-controlled crossover trial. Prehypertensive individuals not using antihypertensive medication (n = 36) received capsules containing potassium chloride (3 g/d), sodium chloride (3 g/d), or placebo. Linear mixed-effect models were used to estimate treatment effects., Results: Potassium supplementation increased plasma phosphate (from 1.10 ± 0.19 to 1.15 ± 0.19 mmol/L, P = 0.004), in line with an increase in tubular maximum of phosphate reabsorption (from 0.93 ± 0.21 to 1.01 ± 0.20 mmol/L, P < 0.001). FGF23 decreased (114.3 [96.8-135.0] to 108.5 [93.5-125.9] RU/mL, P = 0.01), without change in parathyroid hormone and 25-hydroxy vitamin D3. Fractional calcium excretion decreased (from 1.25 ± 0.50 to 1.11 ± 0.46 %, P = 0.03) without change in plasma calcium. Sodium supplementation decreased both plasma phosphate (from 1.10 ± 0.19 to 1.06 ± 0.21 mmol/L, P = 0.03) and FGF23 (from 114.3 [96.8-135.0] to 108.7 [92.3-128.1] RU/mL, P = 0.02). Urinary and fractional calcium excretion increased (from 4.28 ± 1.91 to 5.45 ± 2.51 mmol/24 hours, P < 0.001, and from 1.25 ± 0.50 to 1.44 ± 0.54 %, P = 0.004, respectively)., Conclusions: Potassium supplementation led to a decrease in FGF23, which was accompanied by increase in plasma phosphate and decreased calcium excretion. Sodium supplementation reduced FGF23, but this was accompanied by decrease in phosphate and increase in fractional calcium excretion. Our results indicate distinct effects of potassium and sodium intake on bone mineral parameters, including FGF23., Clinical Trial Registration Number: NCT01575041., (© Endocrine Society 2020.)

The purpose of this study was to investigate the effect of race and subclinical elevations in blood pressure (i.e., prehypertension) on cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation. We recruited participants who self-identified as either non-Hispanic black ( n = 16) or non-Hispanic white ( n = 16). Within each group, participants were subdivided as either normotensive ( n = 8 per group) or prehypertensive ( n = 8 per group). Each participant was instrumented with four intradermal microdialysis fibers: 1 ) control (lactated Ringer's), 2 ) 5% lidocaine (sensory nerve inhibition), 3 ) 20 mM N ω -nitro-l-arginine methyl ester (l-NAME) (NO synthase inhibition), and 4 ) lidocaine + l-NAME. Skin blood flow was assessed via laser-Doppler flowmetry, and each site underwent local heating from 33°C to 39°C. At the plateau, 20 mM l-NAME were infused at control and lidocaine sites to quantify NO-dependent vasodilation. Maximal vasodilation was induced via 54 mM sodium nitroprusside and local heating to 43°C. Data are means ± SD. Sensory nerve-mediated cutaneous vasodilation was reduced in prehypertensive non-Hispanic white (34 ± 7%) and both non-Hispanic black groups (normotensive, 20 ± 9%, prehypertensive, 24 ± 15%) relative to normotensive non-Hispanic whites (54 ± 12%). NO-dependent vasodilation was also reduced in prehypertensive non-Hispanic white (41 ± 7%) and both non-Hispanic black groups (normotensive, 44 ± 7%, prehypertensive, 19 ± 7%) relative to normotensive non-Hispanic whites (60 ± 11%). The decrease in NO-dependent vasodilation in prehypertensive non-Hispanic blacks was further reduced relative to all other groups. These data suggest subclinical increases in blood pressure adversely affect sensory-mediated and NO-dependent vasodilation in both non-Hispanic blacks and whites. NEW & NOTEWORTHY Overt hypertension is known to reduce cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation, but the effect of subclinical increases in blood pressure (i.e., prehypertension) is unknown. The combined effect of race and prehypertension is also unknown. In this study, we found that prehypertension reduces cutaneous sensory nerve-mediated and NO-dependent vasodilation in both non-Hispanic white and black populations, with the greatest reductions observed in prehypertensive non-Hispanic blacks.

Background: The effects of hypertension and exercise training (T) on the sequential interplay between renin-angiotensin system (RAS), autonomic control and heart remodeling during the development of hypertension in spontaneously hypertensive rats (SHR), was evaluated., Methods and results: Time course changes of these parameters were recorded in 4-week-old SHR submitted to a T or sedentary (S) protocol. Wistar Kyoto rats served as controls. Hemodynamic recordings were obtained in conscious rats at experimental weeks 0, 1, 2, 4, and 8. The left ventricle (LV) was collected to evaluate RAS gene and protein expression, cardiomyocytes' hypertrophy and collagen accumulation. Pre-hypertensive SHR exhibited augmented AT 1 R gene expression; at 5 weeks, they presented with elevated pressure, increased LV angiotensinogen and ACE mRNA expression, followed by sympathoexcitation (from the 8 th week onwards). Marked AT 1 R protein content, myocytes's hypertrophy, collagen deposition and increased pressure variability were observed in 12-week-old sedentary SHR. In addition to attenuating all these effects, T activated Mas receptor expression augmented parasympathetic modulation of the heart, and delayed the onset and reduced the magnitude, but did not block the development of genetic hypertension., Conclusions: The close temporal relationship between changes in the LV ACE-Ang II-AT 1 R axis, autonomic control and cardiac remodeling at both the establishment of hypertension and during exercise training reveals the essential role played by the AT 1 R pathway in driving cardiac remodeling and autonomic modulation during the transition from the pre- to hypertensive phase.

There are few studies assessing pre-hypertension and an impaired fasting glucose (IFG) and their combined effects on the cancer risk. We investigated the impact of pre-hypertension on cancer risk and IFG, and their combined effects on the cancer risk. This study included 371,762 subjects (≥40 years) who had never been diagnosed with hypertension, diabetes mellitus (DM), and cancer before. During a mean follow-up of 10.06 ± 1.86 years, 35,605 (9.58%) of the subjects developed cancer. In men only, cancer risk was significantly increased with an increase in the blood pressure (BP) (P for trend < 0.001), and were increased in the hypertension range, but not the pre-hypertension range. When analyzing the combination effect of BP and fasting glucose, cancer risks were serially increased with an increase in the fasting glucose in a dose-dependent manner, but not with an increase in BP. These results were more consistently significant in the never-smoker and non-alcohol drinking groups. However, in women, there was no significant difference. In conclusions, increased BP status or the fasting serum glucose level status were associated with cancer risk in men. Furthermore, the combination of both pre-hypertension and IFG also was associated with a cancer risk in men.

For normal-weight population, the management of prehypertension may be more beneficial by identifying insulin resistance (IR) status than relying solely on traditional indicators of obesity. We investigated the association of triglyceride glucose (TyG) index, a simple surrogate marker of IR, and its combination of obesity indices with prehypertension in lean individuals. A total of 105 070 lean adults without hypertension were included in this analysis. Body mass index (BMI), waist circumference (WC), waist-to-height ratio (WtHR), and TyG were calculated according to the corresponding formula; TyG-BMI, TyG-WC, and TyG-WHtR were calculated by multiplying the corresponding two parameters. Gardner-Altman plots, partial correlation, and logistic regression analyses were applied to explore the associations in continuous variables and quartiles. The prehypertensive ones had higher mean values of TyG, TyG-BMI, TyG-WC, and TyG-WHtR than normotensive individuals. All the four indicators showed positive correlations with systolic blood pressure and diastolic blood pressure. After full adjustment, only TyG-BMI and TyG-WC were significantly associated with prehypertension in both genders. Furthermore, TyG-BMI had the highest OR for prehypertension. Our study showed that TyG-BMI might be an accessible and complementary monitor in the hierarchical management of non-obese prehypertensive patients., (© 2020 Wiley Periodicals LLC.)

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate postprandial insulin release. However, GLP-1 also exerts extrapancreatic effects, including renal effects. Some of these renal effects are attenuated in hypertensive rats, where renal expression of GLP-1 receptors is reduced. Here, we assessed the expression and vascular function of GLP-1 receptors in kidneys from young prehypertensive rats. We also examined GLP-1-induced vasodilation in the renal vasculature in wild-type (WT) and GLP-1 receptor knockout mice using wire and pressure myography and the isolated perfused juxtamedullary nephron preparation. We investigated whether GLP-1 and the metabolite GLP-1(9-36)amide had renal vascular effects independent of the known GLP-1 receptor. We hypothesized that hypertension decreased expression of renal GLP-1 receptors. We also hypothesized that GLP-1-induced renal vasodilatation depended on expression of the known GLP-1 receptor. In contrast to normotensive rats, no immunohistochemical staining or vasodilatory function of GLP-1 receptors was found in kidneys from prehypertensive rats. In WT mice, GLP-1 induced renal vasodilation and reduced the renal autoregulatory response. The GLP-1 receptor antagonist exendin 9-39 inhibited relaxation, and GLP-1(9-36)amide had no vasodilatory effect. In GLP-1 receptor knockout mice, no relaxation induced by GLP-1 or GLP-1(9-36)amide was found, the autoregulatory response in afferent arterioles was normal, and no GLP-1-induced reduction of autoregulation was found. We conclude that in prehypertensive kidneys, expression and function of GLP-1 receptors is lost. The renal vasodilatory effect of GLP-1 is mediated exclusively by the known GLP-1 receptor. GLP-1(9-36)amide has no renal vasodilatory effect. GLP-1 attenuates renal autoregulation by reducing the myogenic response.

Background: Insulin resistance (IR) is the common pathophysiology of prehypertension and prediabetes. Recognition of IR in one of the two disease states is critical for carrying out preventive strategies of another disease state. This study aimed to explore which simple IR indexes were significantly associated with prehypertension in subjects with normoglycemia. Methods: A total of 108,370 adults without elevated fasting plasma glucose and hypertension were included in this study. The three simple IR indexes [triglycerides to high-density lipoprotein cholesterol ratio, the product of fasting triglycerides and glucose, and metabolic score for IR (METS-IR)] were calculated. Partial correlation was used to analyze the correlation between the three indicators and blood pressure (BP) levels, and logistic regression analysis was used to explore their association with prehypertension. Results: Among the three indicators, only METS-IR had positive correlations with systolic and diastolic blood pressure levels. Furthermore, METS-IR was also significantly associated with prehypertension, irrespective of the categorization of waist circumference (WC). The odds ratios of the highest quartile were 2.223 (95% confidence interval [CI]: 2.044-2.417) in all subjects, 2.022 (95% CI: 1.501-2.725) in elevated WC subgroup, and 1.815 (95% CI: 1.620-2.034) in normal WC subgroup. Conclusions: METS-IR was associated with prehypertension in normoglycemic Chinese subjects, which bypasses the impact of WC and might be valuable for the management of prehypertension and the prevention of prediabetes in different ethnic groups.

Background Previous studies demonstrated that angiotensin (Ang) III , not Ang II , is the predominant endogenous agonist for Ang type-2 receptor ( AT 2 R)-induced natriuresis in normal rats, and that hypertensive 12-week-old spontaneously hypertensive rats ( SHR ) lack natriuretic responses to Ang III . This study tested whether prehypertensive SHR already have defective Ang III -induced natriuresis and determined possible mechanisms. Methods and Results Female and male normotensive 4-week-old SHR and Wistar Kyoto rats were studied after 24-hour systemic AT 1 R blockade. Left kidneys received 30 minute renal interstitial infusions of vehicle followed by Ang III (3.5, 7.0, 14, and 28 nmol/kg per min; each dose for 30 minutes). Right kidneys received vehicle infusions. In 4-week-old Wistar Kyoto rats, renal interstitial Ang III increased urine sodium (Na + ) excretion but failed to induce natriuresis in 4-week-old SHR . Renal Ang III levels were similar between Wistar Kyoto rats and SHR , making increased Ang III degradation as a possible cause for defective natriuresis in SHR unlikely. In Wistar Kyoto rats, renal interstitial Ang III induced translocation of AT 2 Rs to apical plasma membranes of renal proximal tubule cells. Simultaneously, Ang III induced retraction of the major Na + transporter Na + -H + exchanger-3 ( NHE -3) from apical membranes and internalization of Na + /K + ATP ase ( NKA ) from basolateral membranes of renal proximal tubule cells. Consistent with NHE -3 and NKA retraction, Ang III increased pS er 552 - NHE -3 and decreased pS er 23 - NKA . In contrast, in SHR , intrarenal Ang III failed to induce AT 2 R translocation, NHE -3 or NKA retraction, pS er 552 - NHE -3 phosphorylation, or pS er 23 - NKA dephosphorylation. Conclusions These results indicate impaired Ang III / AT 2 R signaling as a possible primary defect in prehypertensive SHR .

Objective: To evaluate whether the berberine treatment can improve endothelial repair capacity of early endothelial progenitor cells (EPCs) from prehypertensive subjects through increasing CXC chemokine receptor 4 (CXCR4) signaling., Methods: EPCs were isolated from prehypertensive and healthy subjects and cultured. In vivo reendothelialization capacity of EPCs from prehypertensive patients with or without in vitro berberine treatment was examined in a nude mouse model of carotid artery injury. The protein expressions of CXCR4/Janus kinase-2 (JAK-2) signaling of in vitro EPCs were detected by Western blot analysis., Results: CXCR4 signaling and alteration in migration and adhesion functions of EPCs were evaluated. Basal CXCR4 expression was significantly reduced in EPCs from prehypertensive patients compared with normal subjects (P<0.01). Also, the phosphorylation of JAK-2 of EPCs, a CXCR4 downstream signaling, was significantly decreased (P<0.01). Berberine promoted CXCR4/JAK-2 signaling expression of in vitro EPCs (P<0.01). Transplantation of EPCs pretreated with berberine markedly accelerated in vivo reendothelialization (P<0.01). The increased in vitro function and in vivo reendothelialization capacity of EPCs were inhibited by CXCR4 neutralizing antibody or pretreatment with JAK-2 inhibitor AG490, respectively (P<0.01)., Conclusion: Berberinemodified EPCs via up-regulation of CXCR4 signaling contributes to enhanced endothelial repair capacity in prehypertension, indicating that berberine may be used as a novel potential primary prevention means against prehypertension-related atherosclerotic cardiovascular disease.

Objective: To examine some anthropometric parameters, arterial stiffness, lipid profile, and soluble adhesion molecules in young adults with reduced physical activity., Material and Methods: The study is carried on 54 healthy young adults aged 20.97 ± 2.04 years. Two groups: 23 with reduced physical activity (INAC) and 31 with optimal physical activity (AC). Body mass index (BMI), basal metabolic rate (BMR), central aortic systolic blood pressure (CSBP, mmHg), plasma atherogenic index (AIP), and serum soluble cell adhesion molecules (sICAM-1, sVCAM-1) are followed up., Results: CSBP [115.56 ± 10.22 vs. 105.13 ± 9.88*], AIP [-0.04 ± 0.18 vs. -0.08 ± 0.08**] and sICAM-1 [362.5 ± 49.95 vs. 281.75 ± 80.39**] are significantly higher, and BMR [1431 ± 297.9 vs. 1674.6 ± 365.57*] is significantly lower in the physically inactive young healthy adults., Conclusions: CSBP, AIP, and sICAM-1 are higher in young adults with reduced physical activity. This plays substantial role in the acceleration of atherogenic process and in long-term perspective could promote cardiovascular diseases.

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)-1β, 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-1β, 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.

Single or combinatorial administration of β-blockers is a mainstay treatment strategy for conditions caused by sympathetic overactivity. Conventional wisdom suggests that the main beneficial effect of β-blockers includes resensitization and restoration of β1-adrenergic signaling pathways in the myocardium, improvements in cardiomyocyte contractility, and reversal of ventricular sensitization. However, emerging evidence indicates that another beneficial effect of β-blockers in disease may reside in sympathetic neurons. We investigated whether β-adrenoceptors are present on postganglionic sympathetic neurons and facilitate neurotransmission in a feed-forward manner. Using a combination of immunocytochemistry, RNA sequencing, Förster resonance energy transfer, and intracellular Ca 2+ imaging, we demonstrate the presence of β-adrenoceptors on presynaptic sympathetic neurons in both human and rat stellate ganglia. In diseased neurons from the prehypertensive rat, there was enhanced β-adrenoceptor-mediated signaling predominantly via β 2 -adrenoceptor activation. Moreover, in human and rat neurons, we identified the presence of the epinephrine-synthesizing enzyme PNMT (phenylethanolamine-N-methyltransferase). Using high-pressure liquid chromatography with electrochemical detection, we measured greater epinephrine content and evoked release from the prehypertensive rat cardiac-stellate ganglia. We conclude that neurotransmitter switching resulting in enhanced epinephrine release, may provide presynaptic positive feedback on β-adrenoceptors to promote further release, that leads to greater postsynaptic excitability in disease, before increases in arterial blood pressure. Targeting neuronal β-adrenoceptor downstream signaling could provide therapeutic opportunity to minimize end-organ damage caused by sympathetic overactivity., (© 2018 The Authors.)

High uric acid (UA) level and high salt intake are reportedly associated with cardiovascular disease. This study investigated the association between UA and urinary sodium excretion, as well as its interaction on the risk of prehypertension. A total of 1869 participants without hypertension were recruited from a previously established cohort in Shaanxi Province, China. The participants were classified as normotensive or prehypertensive on the basis of their blood pressure. Increasing quartiles of sodium excretion were associated with high urinary UA/creatinine levels in prehypertensive participants. Estimated sodium excretion positively correlated with urinary UA/creatinine excretions in the prehypertensive group. In addition, the multivariate-adjusted odds ratios for prehypertension compared with normotension were 1.68 (1.27-2.22) for sodium excretion and 1.71 (1.21-2.42) for serum UA. Increasing sodium excretion and serum UA were associated with higher risk of prehypertension. Compared with the lowest quartiles, the highest sodium excretion and serum UA quartiles entailed 3.48 times greater risk of prehypertension. Sodium excretion is associated with urinary UA excretion in prehypertensive participants. The present study shows that high levels of salt intake and serum UA simultaneously are associated with a higher risk of prehypertension.

We aimed to elucidate the role of autonomic dysfunction in the context of complex metabolic and cardiovascular changes in subjects with prehypertension. We identified 556 asymptomatic subjects without hypertension who underwent comprehensive cardiovascular exams. We obtained heart rate recovery (HRR) after peak exercise to quantitatively measure autonomic dysfunction. Of the 556 participants, 279 individuals had prehypertension and the remaining 277 had optimal BP. HRR was significantly lower in the prehypertension group (36.0 ± 14.5 bpm) than in the optimal BP group (39.3 ± 14.7 bpm, P = .009). The prehypertension group more frequently demonstrated features of metabolic disturbances and subclinical target organ damage. Among the various baseline cardiovascular and metabolic factors assessed, resting systolic BP and high-density lipoprotein cholesterol level were independent determinants of HRR (both P < .05). Autonomic dysfunction coexists with prehypertension and is closely linked to changes in systolic BP and lipid metabolism., (©2018 Wiley Periodicals, Inc.)

Intermittent fasting is a phenomenon which can be observed in most humans. The effect of intermittent fasting on blood pressure variability (BPV) has not previously been investigated. The purpose of this study was to assess the effect of fasting on blood pressure (BP) (with office, home, central, and ambulatory blood pressure monitoring [ABPM]) and on BPV. Sixty individuals were included in the study. Office, home, ABPM, and central BP measurements were performed before and during intermittent fasting. Standard deviation and coefficient variation were used for office and home BPV measurement, while the smoothness index was used to calculate ABPM variability. Patients' BP and BPV values before and during intermittent fasting were then compared. Intermittent fasting resulted in a significant decrease in office BP values and ABPM measurements but caused no significant change in home and central BP measurements. Twenty-four hour urinary sodium excretion decreased. Smoothness values obtained from ABPM measurements were low; in other words, BPV was greater. BPV was higher in patients who woke up to eat before sunrise, but BPV was low in patients with high body mass index. Intermittent fasting produced a significant decrease in BP values in terms of office and ABPM measurements in this study but caused no significant change in central BP and home measurements. We also identified an increase in BPV during intermittent fasting, particularly in patients who rose before sunrise., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

ABSTACT Hydrogen sulfide (H 2 S), nitric oxide (NO), and renin-angiotensin system (RAS) are involved in hypertension. We examined whether early treatment with sodium hydrosulfide (NaHS), an exogenous H 2 S donor, can regulate H 2 S-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 H 2 S were increased in the kidney in SHR + NaHS group versus WKY. Sodium hydrosulfide reduces mRNA expression of four H 2 S-generating enzymes and decreased 3-mercaptopyruvate sulphurtransferase protein level in SHRs. Early administration of sodium hydrosulfide decreases plasma N G 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 H 2 S concentrations, restores NO bioavailability, and blocks the RAS in the kidney, in favor of vasodilatation to prevent the development of hypertension in adult SHRs.

The aim of this study was to investigate the effects of urinary sodium and sodium to potassium ratio on inflammatory cytokines, hypertension, and cardiovascular disease in patients with prehypertension. The authors observed 627 patients with prehypertension in the General Hospital of Shenyang Military Region. Rank correlation analysis revealed that interleukin 6 expression exhibited significant positive correlations with urinary sodium (R = .13) and sodium to potassium ratio (R = .13). The multivariate-adjusted hazard ratio of 24-hour urinary sodium was 1.01 (95% confidence interval, 1.00 - 1.01) for hypertension and 1.01 (95% confidence interval, 1.00 - 1.02) for cardiovascular disease, whereas the hazard ratio for 24-hour urinary sodium to potassium ratio was 1.13 (95% confidence interval, 1.08 - 1.19) for hypertension and 1.10 (95% confidence interval, 1.04 - 1.17) for cardiovascular disease. The study suggests that a high-salt diet may lead to increased interleukin 6 levels and may contribute to hypertension. In addition, a high sodium to potassium ratio and high sodium levels are associated with increased risks of cardiovascular disease and hypertension in patients with prehypertension., (©2017 Wiley Periodicals, Inc.)

The effect of age to modify the relationship between insulin resistance and hypertension is unclear. In this retrospective, cross-sectional study, median age was used to create two age groups (<52 vs. ≥52 years), and comparisons were made of metabolic characteristics, including steady-state plasma glucose (SSPG) concentrations measured during the insulin suppression test to quantify insulin resistance. Individuals were stratified into SSPG tertiles and categorized as having normal blood pressure (BP), prehypertension, or hypertension. SSPG concentrations were similar in the two age groups (161 vs. 164 mg/dL). In the most insulin-resistant tertile, distribution of normal BP, prehypertension, and hypertension was equal in those aged <52 years, whereas in those aged ≥52 years, prevalence of hypertension was increased approximately fivefold compared with those with normal BP. Multivariate regression analysis demonstrated significant interaction between age and SSPG in predicting systolic BP (P = .023). In stratified analysis, SSPG, but not age, was an independent predictor of systolic BP and diastolic BP in ≥52 years group, whereas the reverse was true in the younger group. The adverse impact of insulin resistance on BP was accentuated in older individuals and may have a greater impact than further aging., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Uric acid is the end product of purine metabolism. Metabolic disorders of uric acid are associated with many disease states. Substantial evidence suggests the possible role of uric acid as a mediator of high blood pressure. Elevated uric acid is closely associated with new onset essential hypertension in adolescents and prehypertension; and urate-lowering agents can significantly improve these early stages of hypertension. Uric acid also influences salt sensitivity of blood pressure through two phases. Local renin-angiotensin-aldosterone system activation initiates renal damage, arteriolopathy, and endothelium dysfunction, which is followed by the dysregulation of sodium homeostasis, thereby leading to increased salt sensitivity. In this review we summarize the available evidence to contribute to a better understanding of the casual relationship between uric acid and early or intermediate stages of hypertension. We hope our review can contribute to the prevention of hypertension or provide new insights into a treatment that would slow the progression of hypertension.

Background: Prehypertension has a high risk of progression to hypertension, and intensive lifestyle modification including regular exercise is recommended for the management of prehypertensive individuals. However, data on the association between exercise capacity and hypertension status are limited. Therefore, we aimed 1) to define the characteristics of prehypertension, focusing on metabolic aspects and exercise capacity, and 2) to elucidate determinants of exercise capacity in healthy individuals without hypertension., Methods: We retrospectively identified 741 normotensive healthy subjects (mean age, 52.6±8.8years; 57.9% men) who underwent consecutive cardiopulmonary exercise testing. The participants were categorized into two groups: the optimal blood pressure (BP) (systolic BP<120mmHg and diastolic BP<80mmHg, n=364) and prehypertension (systolic BP 120-139mmHg and/or diastolic BP 80-89mmHg, n=377) groups. Exercise capacity was assessed with peak oxygen consumption., Results: The prehypertension group showed metabolic syndrome characteristics, and had increased left ventricular mass index and impaired diastolic function. However, no significant differences in exercise capacity were found between the optimal BP and prehypertension groups (peak VO 2 , 25.3±7.2 vs. 25.8±7.3mL/kg/min, p=0.327). Age, resting heart rate, and fat percentage were identified as independent determinants of exercise capacity (p<0.001 for all)., Conclusions: Prehypertension is associated with metabolic disarrangement and preclinical target organ damage but not with exercise capacity. Exercise capacity is determined by age, resting heart rate, and body composition in relatively healthy individuals who do not have hypertension., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Increased matrix metalloproteinase (MMP)-2 is implicated in the vascular remodeling of hypertension. Calponin-1 is a contractile protein, and its absence is associated with vascular smooth muscle cell (VSMC) phenotype switch, which leads to migration and remodeling. We evaluated whether increased MMP-2 activity precedes chronic vascular remodeling by decreasing calponin-1 and inducing VSMC proliferation. Sham or two kidney-one clip (2K1C) rats were treated with doxycycline at 30mg/kg/day. Systolic blood pressure was increased in the 2K1C rats after 1 and 2weeks post-surgery, and doxycycline was effective to reduce it only at 2weeks of hypertension (p<0.05). Increased activity of MMP-2 was observed in aortas from 2K1C at 1 and 2weeks of hypertension, followed by increased VSMC proliferation, and those effects were abolished by treating 2K1C rats with doxycycline (p<0.05). Increased aortic media to lumen ratio started to emerge in 2K1C rats at 1week of hypertension, and it was established by 2weeks. MMP-2 and calponin-1 co-localized in the cytosol of VSMC. Aortas from 2K1C rats showed a significant reduction in calponin-1 levels at 1week of hypertension, and doxycycline prevented its loss (p<0.05). However, at 2weeks of hypertension, calponin-1 was upregulated in 2K1C (p<0.05 vs. Sham groups). The mRNA levels of calponin-1 were not altered in the aortas of 2K1C at 1week of hypertension. MMP-2 may contribute to the post-translational decrease in calponin-1, thus culminating in hypertension-induced maladaptive arterial remodeling., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Diet rich in fruits, vegetables, and dairy products, known as the Dietary Approaches to Stop Hypertension (DASH) diet, is known to reduce blood pressure (BP) in hypertensive patients. More recently, the DASH diet was shown to reduce oxidative stress in hypertensive and nonhypertensive humans. However, the main nutritional components responsible for these beneficial effects of the DASH diet remain unknown. Because the DASH diet is rich in potassium (K), magnesium (Mg), and alkali, we performed a randomized, double-blinded, placebo-controlled study to compare effects of potassium magnesium citrate (KMgCit), potassium chloride (KCl), and potassium citrate (KCit) to allow dissociation of the three components of K, Mg, and citrate on 24-hour ambulatory BP and urinary 8-isoprostane in hypertensive and prehypertensive subjects, using a randomized crossover design. We found that KCl supplementation for 4 weeks induced a significant reduction in nighttime SBP compared with placebo (116 ± 12 vs 121 ± 15 mm Hg, respectively, p <0.01 vs placebo), whereas KMgCit and KCit had no significant effect in the same subjects (118 ± 11 and 119 ± 13 mm Hg, respectively, p >0.1 vs placebo). In contrast, urinary 8-isoprostane was significantly reduced with KMgCit powder compared with placebo (13.5 ± 5.7 vs 21.1 ± 10.5 ng/mgCr, respectively, p <0.001), whereas KCl and KCit had no effect (21.4 ± 9.1 and 18.3 ± 8.4, respectively, p >0.1 vs placebo). In conclusion, our study demonstrated differential effects of KCl and KMgCit supplementation on BP and the oxidative stress marker in prehypertensive and hypertensive subjects. Clinical significance of the antioxidative effect of KMgCit remains to be determined in future studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Diet plays a crucial role in maintaining healthy blood pressure. Functional foods are increasingly popular among health-conscious consumers to reduce cardiovascular risk factors and improve vascular health. In particular, dietary polyphenols represent an extraordinary inventory of structurally different compounds that may represent promising candidate chemical entities to prevent or delay the onset of hypertension. In recent years, it has been recognized that prehypertension may be a predictor of clinical hypertension and consequently of cardiovascular risk. Moreover, prehypertension status is associated with increased levels of several inflammatory markers and it is also characterized by structural changes, including endothelial dysfunction and arteriolar hypertrophy. Despite the low bioavailability of polyphenols and the lack of clinical data from nutritional intervention studies, the antihypertensive role of polyphenols to control blood pressure and reduce inflammation and endothelial dysfunction has been subject of recent debate. The purpose of this article is to discuss the potential benefits of dietary polyphenols as a promising and effective nutritional strategy for the management of prehypertension.

Sex disparity in hypertension prevalence is well established in developed nations; however, there is paucity of data on the distribution of hypertension prevalence between the sexes in developing countries. Therefore, the authors examined sex differences in hypertension prevalence and cardiovascular risk factors in a sample of 352 healthy hospital workers in Nigeria. The mean ages of the men and women were 37.2±7.9 and 44.7±9.1 years, respectively. Thirty-five percent of participants were hypertensive, with 54% on treatment and 70% with controlled blood pressure. Men had a higher prevalence of hypertension (38.4% vs 33.0%) and prehypertension (37.6% vs 29.7%). Women had significantly higher odds of developing hypertension and of being on treatment. Mean blood pressure and fasting plasma glucose values were higher in men, while women were more often older, obese, and dyslipidemic and had a lower mean estimated glomerular filtration rate (P<.0001). These findings indicate sex disparity in blood pressure among hospital employees. Sex-focused management of hypertension is therefore advocated for hospital employees., (© 2015 Wiley Periodicals, Inc.)

Background: Poor diet and physical inactivity strongly affect the growing epidemic of cardiovascular disease worldwide. Mobile phone-based health interventions (mHealth) have been shown to help promote weight loss and increase physical activity and are an attractive approach for health-care systems with limited resources. We aimed to assess whether mHealth with advice for lifestyle improvements would reduce blood pressure, promote weight loss, and improve diet quality and physical activity in individuals with prehypertension living in low-resource urban settings in Latin America., Methods: In this parallel-group, randomised controlled trial, we recruited individuals (aged 30-60 years) with systolic blood pressure between 120 and 139 mm Hg, diastolic blood pressure between 80 and 89 mm Hg, or both from health-care centres, workplaces, and community centres in low-resource urban settings in Argentina, Guatemala, and Peru. Participants were randomly assigned to receive either monthly motivational counselling calls and weekly personalised text messages to their mobile phones about diet quality and physical activity for 12 months, or usual care. Randomisation was stratified by country, and we applied minimisation by sex and age groups. Study personnel collecting and analysing data were masked to group assignment. The primary outcomes were mean between-group differences in the changes in systolic and diastolic blood pressure from baseline to 12 months in an intention-to-treat analysis of all participants who completed assessments at 12 months. Secondary outcome measures were changes in bodyweight, waist circumference, and self-reported target behaviours from baseline to 12 months. The trial is registered with ClinicalTrials.gov, number NCT01295216., Findings: Between March 1, 2012, and Nov 30, 2012, we randomly assigned 637 participants to receive intervention (n=316) or usual care (n=321). 266 (84%) participants in the intervention group and 287 (89%) in the control group were assessed at 12 months. The intervention did not affect change in systolic blood pressure (mean net change -0·37 mm Hg [95% CI -2·15 to 1·40]; p=0·43) or diastolic blood pressure (0·01 mm Hg [-1·29 to 1·32]; p=0·99) compared with usual care. However, we noted a significant net reduction in bodyweight (-0·66 kg [-1·24 to -0·07]; p=0·04) and intake of high-fat and high-sugar foods (-0·75 [-1·30 to -0·20]; p=0·008) in the intervention group compared with the control group. In a prespecified subanalysis, we found that participants in the intervention group who received more than 75% of the calls (nine or more, from a maximum of 12) had a greater reduction of bodyweight (-4·85 [-8·21 to -1·48]) and waist circumference (-3·31 [-5·95 to -0·67]) than participants in the control group. Additionally, participants in the intervention group had an increase in the intake of fruits and vegetables and a decrease in diets high in sodium, fat, and simple sugars relative to participants in the control group. However, we found no changes in systolic blood pressure, diasatolic blood pressure, or physical activity in the group of participants who received more than 75% of the calls compared with the group who received less than 50% of the calls., Interpretation: Our mHealth-based intervention did not result in a change in blood pressure that differed from usual care, but was associated with a small reduction in bodyweight and an improvement in some dietary habits. We noted a dose-response effect, which signals potential opportunities for larger effects from similar interventions in low-resource settings. More research is needed on mHealth, particularly among people who are poor and disproportionally affected by the cardiovascular disease epidemic and who need effective and affordable interventions to help bridge the equity gap in the management of cardiometabolic risk factors., Funding: National Heart, Lung, and Blood Institute (US National Institutes of Health) and the Medtronic Foundation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Adulthood hypertension can be programmed in response to a suboptimal environment in early life. However, developmental plasticity also implies that one can prevent hypertension in adult life by administrating appropriate compounds during early development. We have termed this reprogramming. While the risk of hypertension has been assessed in many mother-child cohorts of human developmental programming, interventions necessary to prove causation and provide a reprogramming strategy are lacking. Since the developing kidney is particularly vulnerable to environmental insults and blood pressure is determined by kidney function, renal programming is considered key in developmental programming of hypertension. Common pathways, whereby both genetic and acquired developmental programming converge into the same phenotype, have been recognized. For instance, the same reprogramming interventions aimed at shifting nitric oxide (NO)-reactive oxygen species (ROS) balance, such as perinatal citrulline or melatonin supplements, can be protective in both genetic and developmentally programmed hypertension. Furthermore, a significantly increased expression of gene Ephx2 (soluble epoxide hydrolase) was noted in both genetic and acquired animal models of hypertension. Since a suboptimal environment is often multifactorial, such common reprogramming pathways are a practical finding for translation to the clinic. This review provides an overview of potential clinical applications of reprogramming strategies to prevent programmed hypertension. We emphasize the kidney in the following areas: mechanistic insights from human studies and animal models to interpret programmed hypertension; identified risk factors of human programmed hypertension from mother-child cohorts; and the impact of reprogramming strategies on programmed hypertension from animal models. It is critical that the observed effects on developmental reprogramming in animal models are replicated in human studies.

Even though several studies have implicated the role of inflammation in the pathogenesis of hypertension and other cardiovascular disease, there are only limited studies about inflammatory markers in prehypertension. The objective of the present article was to review the role of markers like C-reactive protein, interleukin-6, tumor necrosis factor-α and sialic acid in prehypertension. An extensive literature search was made in Pubmed (http://www.ncbi.nlm.nih.gov/pubmed/) using phrases such as prehypertension, inflammation, C-reactive protein, cardiovascular disease, cytokines and sialic acid. Several investigators have reported increased inflammatory markers like C-reactive protein, interleukin-6, tumor necrosis factor-α and sialic acid in prehypertension indicating the role of inflammation in the pathogenesis of prehypertension and its complications. Elevated inflammatory markers may enhance the risk for cardiovascular disease in subjects with prehypertension., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The concept of enhancing structural integrity of mitochondria has emerged as a novel therapeutic option for cardiovascular disease. Flow-induced increase in laminar shear stress is a potent physiological stimulant associated with exercise, which exerts atheroprotective effects in the vasculature. However, the effect of laminar shear stress on mitochondrial remodeling within the vascular endothelium and its related functional consequences remain largely unknown. Using in vitro and in vivo complementary studies, here, we report that aerobic exercise alleviates the release of endothelial microparticles in prehypertensive individuals and that these salutary effects are, in part, mediated by shear stress-induced mitochondrial biogenesis. Circulating levels of total (CD31(+)/CD42a(-)) and activated (CD62E(+)) microparticles released by endothelial cells were significantly decreased (∼40% for both) after a 6-mo supervised aerobic exercise training program in individuals with prehypertension. In cultured human endothelial cells, laminar shear stress reduced the release of endothelial microparticles, which was accompanied by an increase in mitochondrial biogenesis through a sirtuin 1 (SIRT1)-dependent mechanism. Resveratrol, a SIRT1 activator, treatment showed similar effects. SIRT1 knockdown using small-interfering RNA completely abolished the protective effect of shear stress. Disruption of mitochondrial integrity by either antimycin A or peroxisome proliferator-activated receptor-γ coactivator-1α small-interfering RNA significantly increased the number of total, and activated, released endothelial microparticles, and shear stress restored these back to basal levels. Collectively, these data demonstrate a critical role of endothelial mitochondrial integrity in preserving endothelial homeostasis. Moreover, prolonged laminar shear stress, which is systemically elevated during aerobic exercise in the vessel wall, mitigates endothelial dysfunction by promoting mitochondrial biogenesis., (Copyright © 2015 the American Physiological Society.)

Purpose: Previously, we found that the pressor response to muscle metaboreflex activation is enhanced in prehypertension and associated with peripheral vasoconstriction. However, mechanisms underlying this exaggerated response are not clear. Therefore, we tested the hypothesis that activation of this reflex is augmented owing to increased production of muscle metabolites (i.e., lactate, K, and H)., Methods: Twenty-two men (11 normotensive and 11 prehypertensive) were studied. Changes in cardiac output (Q˙), mean arterial pressure (MAP), and total peripheral resistance (TPR) were compared between the two groups during static exercise (SE) and postexercise muscular ischemia (PEMI). Subjects completed 2 min of SE at 50% of maximal voluntary contraction (MVC) followed by 2 min of PEMI. Venous blood samples for determination of metabolites and hormones (catecholamines, vasopressin, and plasma renin activity) were taken from the exercising and nonexercising arm, respectively., Results: Mean arterial pressure responses to SE (39 ± 3 vs 31 ± 2 mm Hg) and PEMI (24 ± 3 vs 19 ± 3 mm Hg) were significantly higher in the prehypertensive group. Increases in lactate and decreases in pH during PEMI were seen in both groups. However, changes in these variables were greater in the prehypertensive group (lactate, 50.1 ± 6.2 vs 32.8 ± 7.6 mg·dL; pH, -0.06 ± 0.02 vs -0.01 ± 0.01) (P < 0.05). Postexercise muscular ischemia did not evoke increases in hormones in either group., Conclusions: Compared to the normotensive group, the augmented pressor response to the metaboreflex in the prehypertensive group was associated with greater production of muscle metabolites that activate its afferent arm. The augmented response was not associated with activation of the vasopressin and renin-angiotensin systems and greater activation of the sympathetic nervous system was not apparent. Consequently, additional factors specific to prehypertension, such as arterial stiffness, may have been involved.

Prehypertension (blood pressure (BP) 120-139/80-89 mm Hg) is associated with an increased risk for future atherothrombotic events. Although the mechanisms underlying this elevated risk are not completely understood, one possibility is that prehypertension is associated with impaired endothelial fibrinolytic capacity. We tested the hypothesis that vascular endothelial release of tissue-type plasminogen activator (t-PA) is impaired in prehypertensive men. Net endothelial release of t-PA was determined, in vivo, in response to intrabrachial infusions of bradykinin (12.5, 25, 50 ng per 100 ml tissue per min) and sodium nitroprusside at (1.0, 2.0, 4.0 μg per 100 ml tissue per min) in 42 middle-age and older men: 16 normotensive (BP range: 100-119/57-79 mm Hg); 16 prehypertensive (BP range: 120-139/76-89 mm Hg); and 10 hypertensive (BP range: 140-150/74-100 mm Hg). Net release of t-PA antigen was ~25% lower (P<0.05) in the prehypertensive (-0.9 ± 0.8 to 42.4 ± 5.3 ng per 100 ml tissue per min) compared with the normotensive (0.5 ± 1.0 to 53.9 ± 6.5 ng per 100 ml tissue per min) men. There was no significant difference in t-PA release between the hypertensive (-1.8 ± 1.6 to 40.8 ± 6.6 ng per 100 ml tissue per min) and prehypertensive groups. Sodium nitroprusside did not significantly alter the t-PA release in any group. These data indicate that endothelial t-PA release is diminished in prehypertensive men. Further, the level of impairment in t-PA release seen with clinical hypertension is already apparent in the prehypertensive state. Impaired endothelial fibrinolytic function may underlie the increased atherothrombotic risk associated with BP in the prehypertensive range.

Objective: To explore electro-acupuncture's (EA's) effect on gene expression in heart of rats with stress-induced pre-hypertension and try to reveal its biological mechanism based on gene chip technology., Methods: Twenty-seven Wistar male rats were randomly divided into 3 groups. The stress-induced hypertensive rat model was prepared by electric foot-shocks combined with generated noise. Molding cycle lasted for 14 days and EA intervene was applied,on rats in model + EA group during model preparation. Rat Gene 2.0 Sense Target Array technology was used for the determination of gene expression profiles and the screened key genes were verified by real-time quantitative polymerase chain reaction (RT-PCR) method., Results: Compared with blank control group, 390 genes were changed in model group; compared with model control group, 330 genes were changed in model+EA group. Significance analysis of gene function showed that the differentially expressed genes are those involved in biological process, molecular function and cellular components. RT-PCR result of the screened key genes is consistent with that of gene chip test., Conclution: EA could significantly lower blood pressure of stress-induced pre-hypertension rats and affect its gene expression profile in heart. Genes that related to the contraction of vascular smooth muscle may be involved in EA's anti-hypertensive mechanism.

Background: Maternal protein restriction in rats increases the risk of adult offspring arterial hypertension through unknown mechanisms., Objectives: The aims of the study were to evaluate the effects of a low-protein (LP) diet during pregnancy and lactation on baseline sympathetic and respiratory activities and peripheral chemoreflex sensitivity in the rat offspring., Methods: Wistar rat dams were fed a control [normal-protein (NP); 17% protein] or an LP (8% protein) diet during pregnancy and lactation, and their male offspring were studied at 30 d of age. Direct measurements of baseline arterial blood pressure (ABP), heart rate (HR), and respiratory frequency (Rf) as well as peripheral chemoreflex activation (potassium cyanide: 0.04%) were recorded in pups while they were awake. In addition, recordings of the phrenic nerve (PN) and thoracic sympathetic nerve (tSN) activities were obtained from the in situ preparations. Hypoxia-inducible factor 1α (HIF-1α) expression was also evaluated in carotid bifurcation through a Western blotting assay., Results: At 30 d of age, unanesthetized LP rats exhibited enhanced resting Rf (P = 0.001) and similar ABP and HR compared with the NP rats. Despite their similar baseline ABP values, LP rats exhibited augmented low-frequency variability (∼91%; P = 0.01). In addition, the unanesthetized LP rats showed enhanced pressor (P = 0.01) and tachypnoeic (P = 0.03) responses to peripheral chemoreflex activation. The LP rats displayed elevated baseline tSN activity (∼86%; P = 0.02) and PN burst frequency (45%; P = 0.01) and amplitude (53%; P = 0.001) as well as augmented sympathetic (P = 0.01) and phrenic (P = 0.04) excitatory responses to peripheral chemoreflex activation compared with the NP group. Furthermore, LP rats showed an increase of ∼100% in HIF-1α protein density in carotid bifurcation compared with NP rats., Conclusion: Sympathetic-respiratory overactivity and amplified peripheral chemoreceptor responses, potentially through HIF-1α-dependent mechanisms, precede the onset of hypertension in juvenile rats exposed to protein undernutrition during gestation and lactation., (© 2015 American Society for Nutrition.)

This study investigated the effect of sex differences on circulating endothelial progenitor cells (EPCs) in prehypertension and its underlying mechanism. The authors found that premenopausal women show increased number and activity of circulating EPCs when compared with men, which was similar to enhanced nitric oxide (NO) level in plasma or culture medium. There was no difference in the number and activity of circulating EPCs and NO level between normotensive and prehypertensive premenopausal women. There was also no difference seen in levels of vascular endothelial growth factor and granulocyte macrophage colony-stimulating factor. Both number and activity of circulating EPCs were correlated with the level of NO. The present study firstly demonstrated that the number and activity of circulating EPCs were preserved in prehypertensive premenopausal women, which was related to the restoration of NO production. The sex differences in EPCs in prehypertension may be involved in the mechanism underlying vascular protection in premenopausal women., (© 2015 Wiley Periodicals, Inc.)

Prehypertension is an important phenotype for cardiovascular risk and development of established hypertension. To better understand the early circulatory changes in this group, the authors studied 34 patients with prehypertension (blood pressure 120-139/80-89 mm Hg) using digital plethysmography for measurement of blood flow and reactive hyperemic index (RHI). Arterial augmentation index (AI) was also measured. Because prehypertension is associated with endothelial dysfunction and decreased availability of nitric oxide (NO), indices of arginine metabolism (l-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, and l-citrulline) were measured. Nebivolol (5 mg/d), a vasodilating β1 -antagonist with β3 -agonist activity, was studied in a double-blind fashion for 8 weeks. Nebivolol increases the bioavailability of NO. Prehypertension was associated with normal RHI and baseline digital blood flow. AI was abnormal and associated with diastolic blood pressure. ADMA concentration was increased at baseline. After 8 weeks of nebivolol therapy, RHI, ADMA, symmetric dimethylarginine, and AI showed no significant change, but digital blood flow and l-citrulline levels were significantly increased. Prehypertension is associated with increased ADMA and evidence of increased arterial stiffness and preserved RHI. Nebivolol therapy is associated with digital vasodilation and increased NO production, as depicted by increased levels of l-citruline and mean digital blood flow., (© 2014 Wiley Periodicals, Inc.)

Background: Study suggested that elevated homocysteine showed a multiplicative effect on cardiovascular diseases in hypertensive subjects. It was reported that elevated homocysteine level was independently associated with increased arterial stiffness in prehypertensives. It remains unclear whether prehypertensives combined with elevated homocysteine have adverse cardiovascular risk factors. We aimed to compare cardiometabolic risk profile between prehypertensives with hyperhomocysteinaemia and those without either condition., Methods: Plasma total homocysteine and risk profile were determined among 874 Chinese non-hypertension individuals in Tianjin. They were subdivided into four groups: prehypertension with hyperhomocysteinaemia (≥10 μmol/L), prehypertension with normal homocysteine (<10 μmol/L), normotension with hyperhomocysteinaemia, normotension with normol homocysteine, respectively., Results: In 874 participants, 22.5% of them were male, mean age was 56.8 years. In multiple comparisons, after adjustment for age, gender, smoking, alcohol, exercise, education prehypertensives had higher body mass index (BMI) and high sensitive C reactive protein (hs-CRP) than normotensives (p < 0.05, respectively); Only prehypertensive subjects with hyperhomocysteinaemia had higher triglyceride and serum uric acid compared to normotensive subjects, and lower HDL cholesterol than normotensives with normal homocysteine (p < 0.05, respectively). However, the significance of higher hs-CRP, uric acid and lower HDL cholesterol were abolished when further adjustment was made for BMI., Conclusion: The combination of prehypertension and hyperhomocusteinaemia increases the likelihood of having adverse cardiometabolic risk profile. Strict lipid management and weigh control may be needed in prehypertensives with elevated homocysteine.

Objective: The progression from prehypertensive to hypertensive state in spontaneous hypertensive rats (SHRs) is accompanied by a significant increase in membrane expression of Na-K-2Cl co-transporter isoform 2 (NKCC2), suggesting that the altered NKCC2 trafficking and activity are directly related with the development of hypertension in this strain. The aim of this work is to gain insights on the molecular mechanism that underlies this phenomenon., Methods: We performed a comparative analysis of NKCC2 multiprotein complexes (MPCs) in the kidney of SHRs versus Wistar Kyoto rats by Blue Native difference gel electrophoresis combined with mass spectrometry., Results: We found that the recruitment of the β-subunit isoform 1 of the Na(+)-K(+)-ATPase (β1NK) in NKCC2 MPCs was significantly increased in the kidneys of SHR compared with Wistar Kyoto rat control strain. Co-immunoprecipitation experiments showed that β1NK actually interacts with NKCC2 in the native tissue. The analysis of the physiological role of β1NK-NKCC2 interaction in human embryonic kidney cells showed that β1NK increased the steady-state membrane expression and activity of NKCC2 enhancing NKCC2 trafficking toward the plasma membrane., Conclusion: We identify a new NKCC2-interacting partner involved in the modulation of NKCC2 intracellular trafficking and possibly involved in the regulation of blood pressure.

Prehypertension is a risk factor for atherosclerosis. We investigated alterations in plasma metabolites that are associated with prehypertension. A group of 53 individuals was identified who remained within the range of prehypertension during repeated measurements in a 3-year period. This group was compared with the control group of 53 normotensive subjects who were matched for age and gender. Metabolomic profiles were analyzed with UPLC-LTQ-Orbitrap mass spectrometry. The prehypertensive group showed higher levels of lysophosphatidylcholines (lysoPCs) containing C14:0, C16:1, C16:0, C18:2, C18:1, C18:0, C20:5, C20:4, C20:3, and C22:6, higher circulating Lp-PLA2 activity, oxidized LDL (ox-LDL), interleukin 6 (IL-6), urinary 8-epi-PGF2α, and higher brachial-ankle pulse wave velocity (ba-PWV), before and after adjusting for BMI, WHR, smoking, alcohol consumption, serum lipid profiles, glucose, and insulin. LysoPC (16:0) was the most important plasma metabolite for evaluating the difference between control and prehypertensive groups, with a variable important in the projection (VIP) value of 17.173, and it showed a positive and independent association with DBP and SBP. In the prehypertensive group, the levels of lysoPC (16:0) positively and significantly correlated with ox-LDL, Lp-PLA2 activity, 8-epi-PGF2α, ba-PWV, and IL-6 before and after adjusting for confounding variables. Prehypertension-associated elevations in lysoPCs, Lp-PLA2 activity, ox-LDL, urinary 8-epi-PGF2α, IL-6, and ba-PWV could indicate increased oxidative stress from Lp-PLA2-catalyzed PC hydrolysis during increased LDL oxidation, thereby enhancing proinflammation and arterial stiffness.

Prehypertension is associated with reduced conduit artery endothelial function and perturbation of oxidant/antioxidant status. It is unknown whether endothelial dysfunction persists to resistance arteries and whether exercise training affects oxidant/antioxidant balance in young prehypertensives. We examined resistance artery function using venous occlusion plethysmography measurement of forearm (FBF) and calf blood flow (CBF) at rest and during reactive hyperaemia (RH), as well as lipid peroxidation (8-iso-PGF2α) and antioxidant capacity (Trolox-equivalent antioxidant capacity; TEAC) before and after exercise intervention or time control. Forty-three unmedicated prehypertensive and 15 matched normotensive time controls met screening requirements and participated in the study (age: 21.1±0.8 years). Prehypertensive subjects were randomly assigned to resistance exercise training (PHRT; n=15), endurance exercise training (PHET; n=13) or time-control groups (PHTC; n=15). Treatment groups exercised 3 days per week for 8 weeks. Peak and total FBF were lower in prehypertensives than normotensives (12.7±1.2 ml min(-1) per100 ml tissue and 89.1±7.7 ml min(-1) per 100 ml tissue vs 16.3±1.0 ml min(-1) per 100 ml tissue and 123.3±6.4 ml min(-1) per 100 ml tissue, respectively; P<0.05). Peak and total CBF were lower in prehypertensives than normotensives (15.3±1.2 ml min(-1) per 100 ml tissue and 74±8.3 ml min(-1) per 100 ml tissue vs 20.9±1.4 ml min(-1) per 100 ml tissue and 107±9.2 ml min(-1) per 100 ml tissue, respectively; P<0.05). PHRT and PHET improved humoral measures of TEAC (+24 and +30%) and 8-iso-PGF2α (-43 and -40%, respectively; P < or = 0.05). This study provides evidence that young prehypertensives exhibit reduced resistance artery endothelial function and that short-term (8 weeks) resistance or endurance training are effective in improving resistance artery endothelial function and oxidant/antioxidant balance in young prehypertensives.

Little information is available on temporal trends in sodium intake in the U.S. population using urine sodium excretion as a biomarker. Our aim was to assess 1988-2010 trends in estimated 24-h urine sodium (24hUNa) excretion among U.S. adults (age 20-59 y) participating in the cross-sectional NHANES. We used subsamples from a 1988-1994 convenience sample, a 2003-2006 one-third random sample, and a 2010 one-third random sample to comply with resource constraints. We estimated 24hUNa excretion from measured sodium concentrations in spot urine samples by use of calibration equations (for men and women) derived from the International Cooperative Study on Salt, Other Factors, and Blood Pressure study. Estimated 24hUNa excretion increased over the 20-y period [1988-1994, 2003-2006, and 2010; means ± SEMs (n): 3160 ± 38.4 mg/d (1249), 3290 ± 29.4 mg/d (1235), and 3290 ± 44.4 mg/d (525), respectively; P-trend = 0.022]. We observed significantly higher mean estimated 24hUNa excretion in each survey period (P < 0.001) for men compared with women (31-33%) and for persons with a higher body mass index (BMI; 32-35% for obese vs. normal weight) or blood pressure (17-26% for hypertensive vs. normal blood pressure). After adjusting for age, sex, and race-ethnicity, temporal trends in mean estimated 24hUNa excretion remained significant (P-trend = 0.004). We observed no temporal trends in mean estimated 24hUNa excretion among BMI subgroups, nor after adjusting for BMI. Although several limitations apply to this analysis (the use of a convenience sample in 1988-1994 and using estimated 24hUNa excretion as a biomarker of sodium intake), these first NHANES data suggest that mean estimated 24hUNa excretion increased slightly in U.S. adults over the past 2 decades, and this increase may be explained by a shift in the distribution of BMI.

In humans uric acid (UA) is the end product of degradation of purines. The handling of UA by the renal system is a complex process which is not fully understood. To date, several urate transporters in the renal proximal tubule have been identified. Among them, urate transporter 1 (URAT1) and a glucose transporter 9 (GLUT9) are considered of greater importance, as potential targets for treatment of hyperuricemia and the potential associated cardio-metabolic risk. Therefore, the recognition of the metabolic pathway of UA and elucidation of occurrence of hyperuricemia may provide important insights about the relationship between UA, pre-hypertension (preHT) and the metabolic syndrome (MetS). We also review the available clinical studies in this field, including experimental studies dealing with the mechanisms of UA transport via different transporters, as well as current treatment options for hyperuricemia in patients with MetS, preHT or cardiovascular risk factors.

To investigate the effects of losartan and amlodipine on cell apoptosis in the cerebral cortex of stroke-prone spontaneously hypertensive rats (SHRSP) from the onset of prehypertension or hypertension. SHRSP were randomly divided into five experimental groups that were administered losartan, amlodipine (n=8 in each group; 4 weeks old or 10 weeks old), or vehicle, respectively. Wistar-Kyoto rats were used as control animals. Systolic blood pressure was measured using the tail-cuff method every 2 weeks. At 20 weeks of age, apoptosis was analyzed by TdT-mediated dUTP-biotin nick end labeling, and the level of angiotensin II was measured by radioimmunoassay. Protein expressions of gp91(phox), superoxide dismutase, and angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors in the cerebral cortex were detected by western blot. Losartan and amlodipine effectively delayed the progression of systolic blood pressure elevation, especially from the onset of prehypertension, and they had no obvious effects on the level of angiotensin II. In addition, treatment with losartan or amlodipine significantly decreased cell apoptosis, downregulated the protein expression of gp91(phox), and upregulated the protein expression of superoxide dismutase. The protein expressions of AT1R and AT2R were decreased by the administration of both drugs. No difference was found in the expression of AT1R among the drug treatment groups, whereas the expression of AT2R was increased in rats with increased blood pressure. Amlodipine, especially from the onset of prehypertension, was more effective than losartan in reducing apoptosis in the cerebral cortex in SHRSP. This may be related to the antioxidative stress properties of amlodipine.

Potassium and sodium share a yin/yang relationship in the regulation of blood pressure (BP). BP is directly associated with the total body sodium and negatively correlated with the total body potassium. Epidemiologic, experimental, and clinical studies have shown that potassium is a significant regulator of BP and further improves cardiovascular outcomes. Hypertensive cardiovascular damage, stroke, and stroke-related death are accelerated by salt intake but might be curbed by increasing dietary potassium intake. The antihypertensive effect of potassium supplementation appears to occur through several mechanisms that include regulation of vascular sensitivity to catecholamines, promotion of natriuresis, limiting plasma renin activity, and improving endothelial function. In the absence of chronic kidney disease, the combined evidence suggests that a diet rich in potassium content serves a vasculoprotective function, particularly in the setting of salt-sensitive hypertension and prehypertension., (Copyright © 2013 American Society of Hypertension. All rights reserved.)

Background: Hypertension, one of the modifiable risk factors for cardiovascular disease (CVD), is known to be associated with increased oxidative stress and reduced cardiovagal modulation. Similar to hypertension, prehypertension is associated with increased risk of adverse cardiovascular (CV) events. We planned this study to find the association between prehypertension, cardiovagal modulation, oxidative stress, and associated CV risk factors., Methods: We recruited 178 subjects through hypertension screening camps conducted in Puducherry, India. Subjects were grouped into prehypertensive (n = 97) and normotensive (n = 81) groups. They were further subdivided, based on age, as young (20-39 years) and middle-aged (40-60 years) adults. We measured basal physiological parameters, heart rate variability, oxidative stress (thiobarbituric acid reactive substance and total antioxidant capacity (TAC)), and CV risk factors., Results: We found significant increase in oxidative stress in prehypertensive subjects of both age groups but the cardiovagal modulation decreased significantly in young prehypertensive subjects when compared with normotensive subjects. Correlation of TAC with root mean square of the sum of successive R wave to R wave (RR) interval differences (RMSSD), a cardiovagal modulation parameter (r = 0. 437; P < 0.001), and mean arterial pressure (MAP) (r = -0.318; P < 0.001) was significant even after adjusting for CV risk factors. The correlation between MAP and RMSSD (r = 0.199; P = 0.009) was reduced after adjusting for CV risk factors., Conclusions: Prehypertension in young adults is associated with increased oxidative stress and altered cardiovagal modulation. The risk factors for CVDs in prehypertensive young adults were found to be equivalent to that of middle-aged adults who are in the twilight zone for developing CV dysfunctions.