The relationship between liver enzymes, prehypertension and hypertension in the Azar cohort population.

BACKGROUND: The incidence of hypertension (HTN) as a worldwide health problem is rising rapidly. Early identification and management of pre-HTN before HTN development can help reduce its related complications. We evaluated the relationship between liver enzymes levels and pre-HTN/HTN in the Azar cohort population. METHOD: This cross-sectional study was based on data from the large Azar cohort study and a total of 14,184 participants were included. Pre-HTN and HTN were defined based on the American Heart Association guideline. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) levels were measured by Pars Azmoon kits. The relationship between pre-HTN/HTN and liver enzyme levels was evaluated by logistic regression. RESULTS: Of 14,184 participants, 5.7% and 39.6% had pre-HTN and HTN, respectively. In the adjusted model, AST levels of 19-23 IU/l were associated with an elevated risk of pre-HTN (OR [95% CI]: 1.24 [1.04-1.48]). A dose-response increase was seen in pre-HTN in relation to ALT, with the highest OR in the third tertile (1.34 [1.09-1.63]). The odds of pre-HTN also increased with GGT in the third tertile (1.25[1.03-1.52]). In addition, the odds of HTN increased with increased levels of AST, ALT, ALP, and GGT, such that the highest ORs were recorded in the third tertile (OR 1.22 [1.09-1.37], 1.51 [1.35-1.70], 1.19 [1.07-1.34], and 1.68 [1.49-1.89], respectively). Among these enzymes, GGT had the highest OR regarding HTN. CONCLUSION: This study indicates that AST, ALT, ALP and GGT levels were associated with pre-HTN (except for ALP) and HTN, independent of known risk factors. Hence, it may be possible to use liver enzymes to predict the incidence of pre-HTN and HTN, empowering primary care providers to make the necessary interventions promptly.

Astaxanthin Ameliorates Blood Pressure in Salt-Induced Prehypertensive Rats Through ROS/MAPK/NF-κB Pathways in the Hypothalamic Paraventricular Nucleus.

Astaxanthin (AST) has a variety of biochemical effects, including anti-inflammatory, antioxidative, and antihypertensive functions. The aim of the present study was to determine whether AST ameliorates blood pressure in salt-induced prehypertensive rats by ROS/MAPK/NF-κB pathways in hypothalamic paraventricular nucleus.To explore the central effects of AST on the development of blood pressure, prehypertensive rats were induced by a high-salt diet (HS, 8% NaCl) and its control groups were treated with normal-salt diet (NS, 0.3% NaCl). The Dahl salt-sensitive (S) rats with HS diet for 6 weeks received AST or vehicle by gastric perfusion for 6 weeks. Compared to those with NS diet, rats with HS diet exhibited increased mean arterial pressure (MAP) and heart rate (HR). These increases were associated with higher plasma level of norepinephrine (NE), interleukin 1ß (IL-1ß), and interleukin 6 (IL-6); elevated PVN level of reactive oxygen species (ROS), NOX2, and NOX4, that of IL-1ß, IL-6, monocyte chemotactic protein 1 (MCP-1), tyrosine hydroxylase (TH), phosphorylation extracellular-signal-regulated kinase (p-ERK1/2), phosphorylation Jun N-terminal kinases (p-JNK), nuclear factor-kappa B (NF-κB) activity; and lower levels of IL-10, superoxide dismutase (SOD), and catalase (CAT) in the PVN. In addition, our data demonstrated that chronic AST treatment ameliorated these changes in the HS but not NS diet rats. These data suggested that AST could alleviate prehypertensive response in HS-induced prehypertension through ROS/MAPK/NF-κB pathways in the PVN.

Inhibition of iNOS augments cutaneous endothelial NO-dependent vasodilation in prehypertensive non-Hispanic Whites and in non-Hispanic Blacks.

We tested the hypothesis that inducible nitric oxide synthase (iNOS) contributes to reduced nitric oxide (NO)-dependent vasodilation in non-Hispanic Blacks and prehypertensive non-Hispanic Whites. Twenty Black and twenty White participants (10 normotensive, 10 prehypertensive per group; n = 40 total) participated in this study. Participants were instrumented with two microdialysis fibers, and each site was randomized as control (lactated Ringer) or iNOS inhibition (0.1 mM 1400W). Laser-Doppler flow probes and local heaters were used to measure skin blood flow and heat the skin to induce vasodilation, respectively. Each site was heated from 33°C to 39°C (rate: 0.1°C/s). Once a plateau was established, 20 mM nitro-l-arginine methyl ester (l-NAME), a nonspecific NOS inhibitor, was infused at each site to quantify NO-dependent vasodilation. At control sites, %NO-dependent vasodilation was reduced in prehypertensive Whites (47 ± 10%NO) and in both normotensive and prehypertensive Blacks (39 ± 9%NO and 28 ± 5%NO, respectively) relative to normotensive Whites (73 ± 8%NO; P < 0.0001 for all comparisons). Compared with respective control sites, iNOS inhibition increased NO-dependent vasodilation in prehypertensive Whites (68 ± 8%NO) and in both normotensive and prehypertensive Blacks (78 ± 8%NO and 55 ± 6%NO, respectively; P < 0.0001 for all comparisons). We failed to find an effect for normotensive Whites (77 ± 7%NO). After iNOS inhibition, %NO-dependent vasodilation was similar between normotensive Whites, prehypertensive Whites, and normotensive Blacks. Inhibition of iNOS increased NO-dependent vasodilation to a lesser extent in prehypertensive Blacks. These data suggest that iNOS contributes to reduced NO-dependent vasodilation in prehypertension and in Black participants.NEW & NOTEWORTHY Inducible nitric oxide synthase (iNOS) is typically upregulated in conditions of increased oxidative stress and may have detrimental effects on the vasculature. Endothelial nitric oxide (NO), which is cardioprotective, is reduced in prehypertensive non-Hispanic Whites and in non-Hispanic Blacks. We found that inhibition of iNOS can increase endothelial NO-dependent vasodilation in prehypertensive White participants and in both normotensive and prehypertensive Black participants.Inducible nitric oxide (NO) synthase (iNOS) can be upregulated under conditions of increased oxidative stress and may have detrimental effects on the vasculature. Endothelial NO, which is cardioprotective, is reduced in prehypertensive non-Hispanic Whites and in non-Hispanic Blacks. We found that inhibition of iNOS can increase endothelial NO-dependent vasodilation in prehypertensive White participants and in both normotensive and prehypertensive Black participants.

Activity of lysosomal exoglycosidases in the urine of healthy normotensive and pre-hypertensive children.

PURPOSE: We investigated the relationship between blood pressure (BP) and the activity of lysosomal exoglycosidases: N-acetyl-ß-hexosaminidase (HEX), its isoenzymes A (HEX A) and B (HEX B), α-fucosidase (FUC), ß-galactosidase (GAL), ß-glucuronidase (GLU) and α-mannosidase (MAN) in pre-hypertensive (high normal blood pressure - HNBP) and normal blood pressure (NBP) children. MATERIAL AND METHODS: The study was carried out with urine samples collected from 176 children, aged 6-17.9 years, divided into 2 groups: 42 HNBP and 134 NBP subjects. The children were stratified depending on systolic and diastolic BP (SBP; DBP): HNBP (SBP and/or DBP greater than or equal to the 90th percentile, but less than the 95th percentile) for sex, age, and height; and NBP (SBP and DBP less than the 90th centile). The activities of lysosomal exoglycosidases were determined by the colorimetric method, and expressed in pKat/mL and pKat/µgCr. RESULTS: The activity of urinary HEX A in HNBP group was significantly higher than in NBP (p < 0.05). The HNBP group showed significant positive correlation between HEX, HEX A (pKat/mL) and SBP. AUC for HEX A was 0.616, cut-off value -29.351 pKat/mL (sensitivity 51.2%, specificity 71.8%), and 0.589, cut-off value -0.054 pKat/µgCr (sensitivity 31.7%, specificity 86.3%). CONCLUSIONS: This is the first report of the relationship between BP and the activity of urinary lysosomal exoglycosidases: HEX, HEX A and HEX B, FUC, GAL, GLU, and MAN in healthy children and adolescents. It seems that HEX A (pKat/mL) can be used as a useful tool in identifying children with HNBP.

Associations among oxidative stress, Lp-PLA2 activity and arterial stiffness according to blood pressure status at a 3.5-year follow-up in subjects with prehypertension.

BACKGROUND AND AIMS: We aimed to determine changes in oxidative stress, lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and arterial stiffness in subjects with persistent prehypertensive symptoms during a 3.5-year follow-up period. METHODS: We divided 254 subjects with prehypertension according to their blood pressure (BP) status at 3.5 years of follow-up into three groups: reversed normotensive, persistent prehypertensive and developed hypertensive group. BP, serum lipid profile, oxidized LDL (ox-LDL), Lp-PLA2 activity and brachial-ankle pulse wave velocity (ba-PWV) were measured at baseline and the 3.5-year follow-up. RESULTS: The reversed normotensive group showed a significant reduction in average BP (14.7/10.1 mmHg), whereas the developed hypertensive group showed a significant increase in average BP (15.2/11.5 mmHg). The persistent prehypertensive group showed increases in serum lipid profiles, circulating levels of Lp-PLA2 activity, ox-LDL and arterial stiffness as measured by ba-PWV at 3.5 years. The persistent prehypertensive and developed hypertensive groups showed greater increases in ox-LDL than the reversed normotensive group. The developed hypertensive group showed greater increases in Lp-PLA2, 8-epi-PGF2α, and ba-PWV than those observed in the reversed normotensive and persistent prehypertensive groups. In all subjects, changes (Δ) in systolic blood pressure (SBP) positively correlated with Δ Lp-PLA2, Δ ox-LDL, Δ urinary 8-epi-PGF2α and Δ ba-PWV. CONCLUSIONS: This study indicates that in persistent prehypertension, increased ox-LDL hydrolysis by Lp-PLA2 enhances arterial stiffness without an age-related increase in BP.

Paraoxonase and arylesterase activities in dipper and non-dipper prehypertensive subjects.

Paraoxonase-1, a high-density lipoprotein linked enzyme complex, was shown to be decreased in several cardiovascular diseases. We aimed to explore whether serum paraoxonase and arylesterase activities differ in dipper and non-dipper prehypertensive subjects compared to healthy controls.Sixty prehypertensive subjects and 30 controls were enrolled. All subjects underwent echocardiographic assessment and 24-hour ambulatory blood pressure monitoring (ABPM). According to the blood pressure (BP) course on ABPM, prehypertensive subjects were categorized into two: non-dipper prehypertensive (NDPH) and dipper prehypertensive (DPH) groups. Serum paraoxonase and arylesterase activities were detected spectrophotometrically.Paraoxonase and arylesterase activities were significantly lower in patients with NDPH compared to both DPH and control groups. Both paraoxonase and arylesterase activities showed significant negative correlations with BP and left ventricular mass index.We have demonstrated that NDPH subjects have lower paraoxonase and arylesterase activities compared to DPH subjects and normotensives. Further prospective studies are needed to clarify the role of paraoxonase and arylesterase activities in the development of overt hypertension in prehypertensive subjects.

Rho-Kinase activity and cutaneous vasoconstriction is upregulated in essential hypertensive humans.

Essential hypertension (HT) is associated with endothelial dysfunction augmented vasoconstriction (VC) which may be secondary to increased Rho/Rho-Kinase (ROCK)-dependent mechanisms. Our aim was to assess the in vivo magnitude of cutaneous VC to local cooling as a ROCK specific stimulus, and in vitro evaluate ROCK activity in the skin from HT humans. Four microdialysis fibers were placed in the forearm of 9 pre- to stage I hypertensive (MAP: 106±3 mm Hg) and 11 normotensive (NT; 86±1 mm Hg) men and women: Ringers (control), 3mM fasudil (ROCK inhibited), 5mM yohimbine+1mM proprananol (α- and ß-adrenoceptor inhibited; Y+P), Y+P+3mM fasudil (ROCK and adrenocepor inhibited). Skin blood flow was measured during local cooling (Tskl 24°C) and ROCK activity in the skin biopsy samples was determined with western blot. In vitro phosphorylated myosin phosphatase target subunit 1 (pMYPT-1)/ROCK was increased in the HT skin samples (p=0.0018). Functionally, no difference in basal vasomotor tone (Tskl 34°C) was observed between the groups (HT: 0.36±0.07 vs. NT: 0.31±0.07 CVC), nor at the control site during local cooling. Pre- to stage 1 hypertensives show greater ROCK-mediated vasoconstriction at early (1-5 min; HT: -0.8±0.2 versus NT: -0.3±0.2 ΔCVC baseline 1; P<0.0001) and late (36-40 min; HT: -0.9±0.1 versus NT: -0.5±0.2 ΔCVC baseline 1; P<0.0001) phases of local cooling. These data suggest that the magnitude of cutaneous vasoconstriction to local cooling does not differ in normotensive and pre- to stage I essential hypertensive humans; however, ROCK activity is increased and functional vasoconstriction is increasingly dependent upon Rho/ROCK mechanisms with essential hypertension.

Decreased erythrocyte NA+,K+-ATPase activity and increased plasma TBARS in prehypertensive patients.

The essential hypertension has been associated with membrane cell damage. The aim of the present study is investigate the relationship between erythrocyte Na(+),K(+)-ATPase and lipoperoxidation in prehypertensive patients compared to normotensive status. The present study involved the prehypertensive patients (systolic: 136 ± 7 mmHg; diastolic: 86.8 ± 6.3 mmHg; n = 8) and healthy men with normal blood pressure (systolic: 110 ± 6.4 mmHg; diastolic: 76.1 ± 4.2 mmHg; n = 8) who were matched for age (35 ± 4 years old). The venous blood samples of antecubital vein (5 mL) were collected into a tube containing sodium heparin as anticoagulant (1000 UI), and erythrocyte ghosts were prepared for quantifying Na(+),K(+)-ATPase activity. The extent of the thiobarbituric acid reactive substances (TBARS) was determined in plasma. The statistical analysis was carried out by Student's t-test and Pearson's correlation coefficient. A P < 0.05 was considered significant. The Na(+),K(+)-ATPase activity was lower in prehypertensive patients compared with normotensive subjects (4.9 versus 8.0 nmol Pi/mg protein/min; P < 0.05). The Na(+),K(+)-ATPase activity correlated negatively with TBARS content (r = -0.6; P < 0.05) and diastolic blood pressure (r = -0.84; P < 0.05). The present study suggests that Na(+),K(+)-ATPase activity reduction and elevation of the TBARS content may underlie the pathophysiological aspects linked to the prehypertensive status.

Possible modulation of glycated protein levels in prehypertension by lipid peroxides.

Glycation and lipid peroxidation are two important processes known to play a key role in complications of many pathophysiological processes. Malondialdehyde (MDA) has been reported to play a possible role in the genesis of glycated proteins. This study was undertaken to unravel the possible association of MDA with glycated hemoglobin and fructosamine in prehypertensive patients. A case-control study was performed on 42 prehypertensive and 30 control subjects. Plasma glucose, MDA, fructosamine, and glycated hemoglobin were analyzed in both the groups. Partial correlation analysis was performed to predict the independent association of MDA and fasting glucose on fructosamine and glycated hemoglobin. Plasma of prehypertensive subjects revealed significantly higher concentrations of lipid peroxides and fructosamine than in controls. Glycated hemoglobin concentrations were also found to be significantly increased in test group when compared with healthy controls. When the effects of fasting glucose on the concentrations of glycated hemoglobin and fructosamine were refuted by partial correlation analysis, MDA was found to be a significant determinant of glycated hemoglobin and fructosamine in subjects with prehypertension. These data also support the premise that lipid peroxides per se could play a role in the glycation of hemoglobin and plasma proteins in prehypertension.

Association between γ-glutamyltransferase and prehypertension.

Researchers have identified an association between baseline γ-glutamyltransferase (GGT) and prehypertension. However, data from China are limited. A cross-sectional study was performed among 2,205 subjects from Heilongjiang Province in China. Multiple logistic regression analyses revealed a significant association between baseline GGT and prehypertension [1.59, 95% confidence interval (CI), 1.18-2.16], comparing quartile 4 to quartile 1. Subgroup analyses showed a stronger association between GGT and prehypertension in Koreans; men, current alcohol drinkers and subjects with pre-diabetes. Receiver operating characteristics (ROC) analysis demonstrated that when GGT was higher than 20 U/l, the risk of developing prehypertension increased. Serum GGT is used as a biochemical liver test, but our findings suggest that baseline values may also predict prehypertension in Chinese.

Genetic variations in CYP17A1, CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China.

OBJECTIVES: Two large-scale genome-wide association studies (GWAs) have identified multiple variants associated with blood pressure (BP) or hypertension. The present study was to investigate whether some variations were associated with BP traits and hypertension or even prehypertension in adult She ethnic minority of China. METHODS: The population of the present study comprised 4460 (1979 males and 2481 females, respectively) unrelated she ethnic minority based on a cross-sectional study from Ningde City in Fujian province of China. There were 1692 hypertensives, 1600 prehypertensives and 1168 normotensive controls, respectively. We genotyped 7 variants in CYP17A1, PLEKHA7, CACNB2, ATP2B1, TBX3-TBX5, CSK-ULK3 and SH2B3 reported by the previous GWAs on Europeans. All analyses were performed in an additive genetic model. RESULTS: As the minor allele of rs653178 in/near SH2B3 was very rare with the frequency of 0.018, we excluded this single nucleotide polymorphism (SNP) in the further analyses. Of the other 6 loci, linear regression analyses revealed that rs11191548 in CYP17A1 and rs11014166 in CACNB2 were significantly associated with systolic BP (ß = -1.17, P = 0.002 and ß = -0.50, P = 0.006, respectively), while only SNP rs11191548 was significantly associated with diastolic BP (ß = -0.56, P=0.002) after adjusted by age, sex and BMI. Two variants in CACNB2 and PLEKHA7 were found to be significantly related to hypertension (odds ratios [OR] and (95% confidence interval [CI]): 0.79 (0.65-0.97) and 1.19 (1.01-1.41), respectively) in logistic regression analyses after adjusted by age, sex and BMI. In addition, we found that combined risk alleles of the 6 SNPs increased risk of hypertension in a stepwise fashion (P for trend < 0.001). However, none of the 6 SNPs was significantly associated with BMI or prehypertension status. While logistic analysis showed that subjects with cumulative risk alleles more than 9 had significantly higher risk for prehypertension (adjusted OR: 3.10, P < 0.001) compared with those with risk alleles less than 4. CONCLUSIONS: We replicated that variations in CYP17A1, CACNB2 and PLEKHA7 were related to BP traits and/or hypertension in She population. In addition, although we failed to observe single gene associated with prehypertension, we first found that conjoint effect of multiple risk alleles on BP might increase the risk of progressing to prehypertension.

Elevated serum neutrophil elastase is related to prehypertension and airflow limitation in obese women.

BACKGROUND: Neutrophil elastase level/activity is elevated in a variety of diseases such as atherosclerosis, systolic hypertension and obstructive pulmonary disease. It is unknown whether obese individuals with prehypertension also have elevated neutrophil elastase, and if so, whether it has a deleterious effect on pulmonary function. OBJECTIVES: To determine neutrophil elastase levels in obese prehypertensive women and investigate correlations with pulmonary function tests. METHODS: Thirty obese prehypertensive women were compared with 30 obese normotensive subjects and 30 healthy controls. The study groups were matched for age. MEASUREMENTS: The following were determined: body mass index, waist circumference, blood pressure, lipid profile, high sensitivity C-reactive protein, serum neutrophil elastase, and pulmonary function tests including forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio. RESULTS: Serum neutrophil elastase concentration was significantly higher in both prehypertensive (405.8 ± 111.6 ng/ml) and normotensive (336.5 ± 81.5 ng/ml) obese women than in control non-obese women (243.9 ± 23.9 ng/ml); the level was significantly higher in the prehypertensive than the normotensive obese women. FEV1, FVC and FEV1/FVC ratio in both prehypertensive and normotensive obese women were significantly lower than in normal controls, but there was no statistically significant difference between the prehypertensive and normotensive obese women. In prehypertensive obese women, there were significant positive correlations between neutrophil elastase and body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, low density lipoprotein cholesterol, high sensitivity C-reactive protein and negative correlations with high density lipoprotein cholesterol, FEV1, FVC and FEV1/FVC. CONCLUSION: Neutrophil elastase concentration is elevated in obese prehypertensive women along with an increase in high sensitivity C-reactive protein which may account for dyslipidemia and airflow dysfunction in the present study population.