Association Analysis in Children Born from Normal and Complicated Pregnancies-Cardiovascular Disease Associated microRNAs and the Incidence of Prehypertension/Hypertension, Overweight/Obesity, Valve Problems and Heart Defects.

The goal was to assess how a history of any kind of pregnancy-related complication altered expression profile of microRNAs played a role in the pathogenesis of diabetes, cardiovascular and cerebrovascular diseases in the peripheral blood leukocytes of children at the age of 3-11 years. The prior exposure to gestational hypertension, preeclampsia, fetal growth restriction, gestational diabetes mellitus, preterm prelabor rupture of membranes or spontaneous preterm birth causes that a significant proportion of children (57.42% to 90.0% specifically) had a substantially altered microRNA expression profile, which might be the origin of a lifelong cardiovascular risk. A total of 23 out of 29 tested microRNAs were upregulated in children born from such complicated gestation. The occurrence of overweight, obesity, valve problems and heart defects even intensified upregulation of microRNAs already present in children exposed to such pregnancy complications. The occurrence of overweight/obesity (miR-92a-3p, and miR-210-3p) and valve problems or heart defects (miR-342-3p) induced microRNA upregulation in children affected with pregnancy complications. Overall, 42.86% overweight/obese children and 27.36% children with valve problems or heart defects had even higher microRNA levels than children with normal clinical findings after complicated pregnancies. In addition, the microRNA expression profile was also able to differentiate between children descending from normal gestation in relation to the occurrence of overweight and obesity. Screening on the base of the combination of 19 microRNAs identified 70.0% overweight/obese children at 90.0% specificity. In general, children after complicated pregnancies, just as children after normal pregnancies, with abnormal findings are at a higher risk of the onset of cardiovascular complications, and their dispensarization, with the aim to implement primary prevention strategies, would be beneficial.

Training-Induced Deactivation of the AT1 Receptor Pathway Drives Autonomic Control and Heart Remodeling During the Transition From the Pre- to Hypertensive Phase in Spontaneously Hypertensive Rats.

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 AT1R gene expression; at 5 weeks, they presented with elevated pressure, increased LV angiotensinogen and ACE mRNA expression, followed by sympathoexcitation (from the 8thweek onwards). Marked AT1R 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-AT1R axis, autonomic control and cardiac remodeling at both the establishment of hypertension and during exercise training reveals the essential role played by the AT1R pathway in driving cardiac remodeling and autonomic modulation during the transition from the pre- to hypertensive phase.

GLP-1-induced renal vasodilation in rodents depends exclusively on the known GLP-1 receptor and is lost in prehypertensive rats.

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.

Prehypertension is real and can be associated with target organ damage.

Prehypertension (systolic blood pressure 120-139 or diastolic blood pressure 80-89 mm Hg) confers a risk of progression to hypertension, impairment of cognitive function, increased left ventricular mass, risk of end-stage renal disease, and an association with arteriosclerosis. Recent studies provide data that could support the rationale for treating prehypertensives subjects with antihypertensive medications in addition to lifestyle modification, especially if they have concomitant cardiovascular risk factors.

Effects of aerobic exercise training on ACE and ADRB2 gene expression, plasma angiotensin II level, and flow-mediated dilation: a study on obese postmenopausal women with prehypertension.

OBJECTIVE: The purpose of this study is to determine the effect of 10 weeks of moderate-intensity aerobic exercise training (MIET) on blood pressure (BP), angiotensin-converting enzyme (ACE) and ß2-adrenergic receptor (ADRB2) gene expression in leukocytes, plasma angiotensin II (Ang II), and flow-mediated dilation (FMD) in obese postmenopausal women (PMW) with prehypertension. METHODS: Twenty-four obese prehypertensive PMW (aged 50-70 y; body mass index ≥30 kg/m) randomly assigned to control (n = 12) and exercise (n = 12) groups. Exercise group performed MIET (25-40 min/d, 3 d/wk at 50%-70% of heart rate reserve) for 10 weeks. Control group maintained their normal daily physical activity level. Body composition, VO2max, BP, ACE and ADRB2 gene expression, plasma Ang II, and FMD were measured before and after the training program. RESULTS: After MIET, systolic and diastolic BPs decreased by 4.6% and 2.4%, respectively (P < 0.001). Plasma Ang II level decreased by 45.7%, whereas FMD increased by 86% in the exercise group (P < 0.001). Exercise training resulted in a threefold increase in ADRB2 and a fourfold decrease in ACE gene expressions (P < 0.05). Training-induced changes in BP inversely associated with the changes in FMD and ADRB2 (r values range -0.55 to -0.78), and positively associated with Ang II and ACE (r values range 0.68-0.86) (P < 0.001). CONCLUSIONS: Ten weeks of MIET modulates ACE and ADRB2 gene expression, decreases Ang II plasma levels, and improves endothelial function in obese PMW, and these alterations are associated with reduction in BP.

Endothelial nitric oxide synthase gene polymorphisms are associated with cardiovascular risks in prehypertensives.

Though endothelial nitric oxide synthase (eNOS) gene polymorphism is documented in the causation of hypertension, its role in prehypertension has not been investigated. The present study was conducted in 172 subjects divided into prehypertensives (n = 57) and normotensives (n = 115). Cardiovascular (CV) parameters including baroreflex sensitivity (BRS) by continuous BP variability assessment and sympathovagal imbalance (SVI) by heart rate variability analysis were recorded. Biochemical parameters for insulin resistance (homeostatic model for assessment of insulin resistance), oxidative stress, lipid risk factors, renin, and inflammatory parameters were measured. Genotyping for eNOS polymorphisms rs1799983 (298G>T) and rs2070744 (-786T>C) was performed by polymerase chain reaction-restriction fragment length polymorphism method. Multiple regression analysis was done to assess the association between SVI and metabolic markers, and multivariate logistic regression was done to determine the prediction of prehypertension status by genotype, BRS, and ratio of low-frequency to high-frequency in these subjects. The BP variability, heart rate variability, and biochemical parameters were significantly altered in prehypertensives. The eNOS polymorphisms were found to be associated with prehypertension. BRS, the marker of SVI, was significantly associated with BP, homeostatic model for assessment of insulin resistance, and tumor necrosis factor alpha in 298GG genotype of prehypertensive population. The eNOS gene polymorphisms appear to be associated with prehypertension. 298G>T and -786T>C contribute to SVI in young prehypertensives attributed by insulin resistance and inflammation. The CV risks were associated with prehypertension status in prehypertensives expressing both 298GG and -786TT genotypes. Association of CV risks with SVI appears to be stronger in prehypertensives expressing GG genotype.

Nicotine Mediates CD161a+ Renal Macrophage Infiltration and Premature Hypertension in the Spontaneously Hypertensive Rat.

RATIONALE: Renal inflammation contributes to the pathophysiology of hypertension. CD161a+ immune cells are dominant in the (SHR) spontaneously hypertensive rat and expand in response to nicotinic cholinergic activation. OBJECTIVE: We aimed to phenotype CD161a+ immune cells in prehypertensive SHR after cholinergic activation with nicotine and determine if these cells are involved in renal inflammation and the development of hypertension. METHODS AND RESULTS: Studies used young SHR and WKY (Wistar-Kyoto) rats. Splenocytes and bone marrow cells were exposed to nicotine ex vivo, and nicotine was infused in vivo. Blood pressures, kidney, serum, and urine were obtained. Flow cytometry, Luminex/ELISA, immunohistochemistry, confocal microscopy, and Western blot were used. Nicotinic cholinergic activation induced proliferation of CD161a+/CD68+ macrophages in SHR-derived splenocytes, their renal infiltration, and premature hypertension in SHR. These changes were associated with increased renal expression of MCP-1 (monocyte chemoattractant protein-1) and VLA-4 (very-late antigen-4). LLT1 (lectin-like transcript 1), the ligand for CD161a, was overexpressed in SHR kidney, whereas vascular cellular and intracellular adhesion molecules were similar to those in WKY. Inflammatory cytokines were elevated in SHR kidney and urine after nicotine infusion. Nicotine-mediated renal macrophage infiltration/inflammation was enhanced in denervated kidneys, not explained by angiotensin II levels or expression of angiotensin type-1/2 receptors. Moreover, expression of the anti-inflammatory α7-nAChR (α7-nicotinic acetylcholine receptor) was similar in young SHR and WKY rats. CONCLUSIONS: A novel, inherited nicotinic cholinergic inflammatory effect exists in young SHR, measured by expansion of CD161a+/CD68+ macrophages. This leads to renal inflammation and premature hypertension, which may be partially explained by increased renal expression of LLT-1, MCP-1, and VLA-4.

NALP3-Inflammasome-Related Gene Polymorphisms in Patients with Prehypertension and Coronary Atherosclerosis.

Objectives. Prehypertension is an early stage of hypertension that is characterized by inflammatory factors. Inflammation also plays an essential role in the development of coronary atherosclerosis (CAS). The present study evaluated the NALP3-inflammasome and its related genes, NLRP3, NOD2, and CARD8, using SNP linkage and gene haplotypes in prehypertensive patients. Methods. A total of 576 patients with prehypertension and suspected coronary heart disease (CHD) were enrolled. According to coronary angiography, patients were divided into two groups: arterial stenosis <50% of the diameter (control) and arterial stenosis >50% of the diameter (case). Fifteen polymorphisms in the NOD2, NLRP3, and CARD8 genes were analyzed, and serum levels of C-reactive protein (CRP) were measured. Results. When comparing allele frequencies, none of these 15 SNPs in NOD2, CARD8, and NLPR3 genes showed a significant difference using multiple logistic regression. However, the CTACATAA (p = 0.0064) and CCACATAG (p = 0.0126) haplotypes of the NOD2 gene SNPs were significantly different between cases and controls. Conclusions. Although our study excludes a significant association of selected SNPs in these genes with CHD in prehypertension patients, this work suggests that the CTACATAA and CCACATAG haplotypes were associated with CHD in the NOD2 locus. This work suggests that the CTACATAA and CCACATAG haplotypes were associated with CHD in prehypertension patients in the NOD2 locus.

Blood pressure in children and adolescents: current insights.

The available data concerning childhood blood pressure (BP) have increased substantially over the last four decades. Clinicians can use the available pediatric reference BP data to determine whether BP is in the normal range or is at a level that warrants evaluation or preventive intervention. It has also become possible to refine BP-derived parameters and to identify subclinical end organ damage through measures and markers now far more sensitive than those available years ago. The progress to date should provide an impetus for research advances that may translate into clinical practice. Findings that are becoming ready to incorporate into clinical use include data showing the importance of detecting prehypertension or high-normal BP, the meaning of BP obtained out of the clinic setting and the importance of central BP determinations. Furthermore, new information about large and small vessels during the early stages of BP elevation, the clustering of metabolic abnormalities with BP and the relevance of perinatal programming may lead to better strategies for reducing the impact of BP elevation on cardiovascular health.

Prehypertension: Defining the Transitional Phenotype.

More than a simple "transitional stage" defined by covenanted cut points of systolic pressure from 120 to 139 mm of mercury (mm Hg) or a diastolic pressure from 80 to 89 mm Hg, prehypertension should be referred to as a categorical term that defines a specific phenotype in the progression from the "absence of disease" to clinically overt disease. While the currently utilized definition of prehypertension stresses the use of blood pressure cut points to establish the diagnosis, it is of relevance to direct our attention to the structural and functional hemodynamic alterations that occur in response to the two cardinal abnormalities in the development of prehypertension and hypertension: autonomic dysfunction and arterial remodeling. Our current review addresses these aspects of the pathophysiology or prehypertension on its progression to hypertension and suggests a new approach to its classification.

Common Variants in Serum/Glucocorticoid Regulated Kinase 1 (SGK1) and Blood Pressure Responses to Dietary Sodium or Potassium Interventions: A family-Based Association Study.

BACKGROUND/AIMS: Serum/Glucocorticoid Regulated Kinase 1 (SGK1) plays a significant role in regulating renal Na(+) reabsorption, K(+) secretion, and blood pressure (BP). This study aimed to assess the association of common genetic variants in the SGK1 gene with BP responses to controlled dietary sodium or potassium interventions. METHODS: A total of 334 subjects from 124 families were recruited from the rural areas of northern China. After a three-day baseline observation, they were sequentially maintained a seven-day low-sodium diet (3g/day of NaCl or 51.3 mmol/day of sodium), a seven-day high-sodium diet (18 g/day of NaCl or 307.8 mmol/day of sodium) and a seven-day high-sodium plus potassium supplementation intervention (4.5 g/day of KCl or 60 mmol/day of potassium). Six single-nucleotide polymorphisms (SNPs) in the SGK1 gene were selected. RESULTS: After adjustment for multiple testing, SNP rs9376026 was significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) responses to low-sodium intervention (P = 0.018 and 0.022, respectively). However, the associations between selected SNPs in the SGK1 gene and BP responses to high-sodium or high-sodium plus potassium-supplementation intervention did not reach statistical significance. In addition, SNP rs9389154 and two other SNPs (rs1763509 and rs9376026) were associated respectively with systolic BP (SBP) and DBP at baseline (P = 0.040, 0.032, and 0.031, respectively). SNP rs3813344 was significantly associated with SBP, DBP, and MAP (P = 0.049, 0.015 and 0.018, respectively). CONCLUSION: Our study indicates that the genetic polymorphism in the SGK1 gene is significantly associated with BP responses to dietary sodium intervention.

Effect of electro-acupuncture on gene expression in heart of rats with stress-induced pre-hypertension based on gene chip technology.

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.

Blood pressure interacts with APOE ε4 to predict memory performance in a midlife sample.

OBJECTIVE: Elevated blood pressure and the Apolipoprotein ε4 allele (APOE ε4) are independent risk factors for Alzheimer's disease. We sought to determine whether the combined presence of the APOE ε4 allele and elevated blood pressure is associated with lower cognitive performance in cognitively healthy middle-aged adults. METHODS: A total of 975 participants aged 30-54 (mean age = 44.47) were genotyped for APOE. Cardiometabolic risk factors including blood pressure, lipids, and glucose were assessed and cognitive function was measured using the Trail Making Test and the Visual Reproduction and Logical Memory subtests from the Wechsler Memory Scale. RESULTS: Multivariable regression analysis showed that the association between APOE ε4 and episodic memory performance varied as a function of systolic blood pressure (SBP), such that elevated SBP was predictive of poorer episodic memory performance only in APOE ε4 carriers (ß = -.092; t = -2.614; p = .009). Notably, this association was apparent at prehypertensive levels (≥130 mmHg), even after adjusting for physical activity, depression, smoking, and other cardiometabolic risk factors. CONCLUSIONS: The joint presence of APOE ε4 and elevated SBP, even at prehypertensive levels, is associated with lower cognitive performance in healthy, middle-aged adults. Results of this study suggest that the combination of APOE ε4 and elevated SBP may synergistically compromise memory function well before the appearance of clinically significant impairments. Interventions targeting blood pressure control in APOE ε4 carriers during midlife should be studied as a possible means to reduce the risk of cognitive decline in genetically susceptible samples.

Progress in aldosteronism: a review of the prevalence of primary aldosteronism in pre-hypertension and hypertension.

Primary aldosteronism (PA) secondary to excessive and/or autonomous aldosterone secretion from the renin-angiotensin system accounts for ∼10% of cases of hypertension and is primarily caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenomas (APAs). Although the diagnosis has traditionally been supported by low serum potassium levels, normokalaemic and even normotensive forms of PA have been identified expanding further the clinical phenotype. Moreover, recent evidence has shown that serum aldosterone correlates with increased blood pressure (BP) in the general population and even moderately raised aldosterone levels are linked to increased cardiovascular morbidity and mortality. In addition, aldosterone antagonists are effective in BP control even in patients without evidence of dysregulated aldosterone secretion. These findings indicate a higher prevalence of aldosterone excess among hypertensive patients than previously considered that could be attributed to disease heterogeneity, aldosterone level fluctuations related to an ACTH effect or inadequate sensitivity of current diagnostic means to identify apparent aldosterone excess. In addition, functioning aberrant receptors expressed in the adrenal tissue have been found in a subset of PA cases that could also be related to its pathogenesis. Recently a number of specific genetic alterations, mainly involving ion homeostasis across the membrane of zona glomerulosa, have been detected in ∼50% of patients with APAs. Although specific genotype/phenotype correlations have not been clearly identified, differential expression of these genetic alterations could also account for the wide clinical phenotype, variations in disease prevalence and performance of diagnostic tests. In the present review, we critically analyse the current means used to diagnose PA along with the role that ACTH, aberrant receptor expression and genetic alterations may exert, and provide evidence for an increased prevalence of aldosterone dysregulation in patients with essential hypertension and pre-hypertension.

Relationship between serum gamma-glutamyltransferase levels and prehypertension in Chinese adults: the cardiometabolic risk in Chinese study.

The authors aimed to investigate the relationship between serum gamma-glutamyltransferase (GGT) and prehypertension, as well as the modification of other metabolic risk factors in a large cohort of Chinese individuals. The data were collected via a community-based health examination survey in central China. Blood pressure, body mass index (BMI), and levels of GGT, fasting blood glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lipid indicators were measured. In total, data from 18,302 patients with available biomarkers were included in the present study. Elevated blood pressure was associated with increased GGT concentration (P<.001). After adjusting for age, sex, BMI, fasting blood glucose, lipid indicators, AST, and family history of hypertension, the association between GGT levels and prehypertension remained significant (P=.021). The adjusted odds ratios (95% confidence interval) for prehypertension across quintiles of GGT level were 1.00, 1.057 (1.012-1.334), 1.068 (0.916-1.254), 1.024 (0.851-1.368), and 1.272 (1.027-1.593), respectively. In stratified analyses, the association between GGT levels and prehypertension was significant in women but was not significant in men. Moreover, additive effect of BMI and age on the effect of GGT levels on prehypertension (both P for interaction <.001) was observed. In summary, GGT levels were positively associated with prehypertension in women, independent of other metabolic factors. Furthermore, BMI and age may amplify the effects of GGT levels on prehypertension. These findings suggest that monitoring the levels of GGT could help in the diagnosis and monitoring of prehypertension.

The AGT and the GNB3 polymorphisms and insulin resistance in prehypertension.

OBJECTIVE: This study surveyed the frequencies of single nucleotide polymorphisms (SNPs) M235T AGT and C825T GNB3, and their association with insulin resistance, other biochemical markers and qualitative variables in subjects with high normal blood pressure and/or prehypertension in the Greek population. DESIGN: 330 men and women of Greek origin were divided into 3 groups: a) hypertensive, b) prehypertensive and c) control group. These groups were genetically tested for these polymorphisms and insulin resistance with the HOMA index. RESULTS: No statistically significant differences were found among the polymorphisms of the compared groups. However, the ? allele carriers (CT/TT vs. CC) of the C825T polymorphism were associated with an increased BMI in all 3 groups (p=0.004). The HOMA index was higher in the hypertensive (p=0.006) and prehypertensive (p=0.016) versus the control group, and similar results were found for insulin (hypertensive vs. control p=0.012, prehypertensive vs. control p=0.001) without statistical significance between the first 2 groups (p=0.522). Additionally, there was a statistically significant difference between the control group and the hypertensive and prehypertensive groups regarding cholesterol (control vs. hypertensive p=0.001, control vs. prehypertension p=0.018) and triglycerides (control vs. hypertensive p=0.0001, control vs. prehypertension p=0.007). Differences were also noted between the control and the hypertensive group regarding the value of HDL (p=0.005) and LDL (p=0.013). CONCLUSION: This study failed to demonstrate a correlation between specific SNPs, blood pressure and insulin resistance in the 3 groups. However, T allele carriers of the polymorphism C825T were found to have an increased BMI. Similarly, increased insulin resistance and lipidemia were more common in the hypertensive and prehypertensive populations.

Effects of gender on sympathovagal imbalance, prehypertension status, and cardiovascular risks in first-degree relatives of type 2 diabetics.

BACKGROUND: Although cardiovascular (CV) risks are reported in first-degree relatives (FDRs) of type 2 diabetics, effects of gender on sympathovagal imbalance (SVI) and CV risks in these subjects have not been investigated. METHODS: Body mass index (BMI), blood pressure variability parameters including baroreflex sensitivity (BRS), spectral indices of heart rate variability, autonomic function tests, insulin resistance, lipid profile, inflammatory markers (interleukin 6, high-sensitivity C-reactive protein, tumor necrosis factor α) and oxidative stress (OS) marker were measured and analyzed in control group (without family history of diabetes; 65 women, 60 men) and study group (FDRs of type 2 diabetics; 52 women, 49 men) subjects. RESULTS: BMI, heart rate, blood pressure, rate-pressure product, stroke volume, left-ventricular ejection time, cardiac output, total peripheral resistance, homeostatic model of insulin resistance, lipid profile, inflammatory and OS markers, and ratio of low-frequency to high-frequency power of heart rate variability (LF-HF ratio), a sensitive marker of SVI, were significantly increased, and BRS was significantly decreased in study group men compared with women. SVI was more intense in men and was due to concomitant sympathetic activation and vagal inhibition. There was no SVI in control subjects. Multiple regression analysis demonstrated independent contribution of BMI, homeostatic model of insulin resistance, atherogenic index, inflammatory and OS markers, and BRS to LF-HF ratio. Logistic regression analysis demonstrated significant prediction of prehypertension status and rate-pressure product (markers of CV risk) by LF-HF, which was more prominent in men. CONCLUSIONS: SVI is more intense in male FDRs of type 2 diabetics, and SVI is associated with increased CV risk due to insulin resistance, dyslipidemia, inflammation, and oxidative stress in these subjects.

Targeted neuronal nitric oxide synthase transgene delivery into stellate neurons reverses impaired intracellular calcium transients in prehypertensive rats.

Hypertension is associated with the early onset of cardiac sympathetic hyperresponsiveness and enhanced intracellular Ca(2+) concentration [Ca(2+)](i) in sympathetic neurons from both prehypertensive and hypertensive, spontaneously hypertensive rats (SHRs). Oxidative stress is a hallmark of hypertension, therefore, we tested the hypothesis that the inhibitory action of the nitric oxide-cGMP pathway on [Ca(2+)](i) transients is impaired in cardiac sympathetic neurons from the SHR. Stellate ganglia were isolated from young prehypertensive SHRs and age-matched normotensive Wistar-Kyoto rats. [Ca(2+)](i) was measured by ratiometric fluorescence imaging. Neurons from the prehypertensive SHR ganglia had a significantly higher depolarization evoked [Ca(2+)](i) transient that was also associated with decreased expression of neuronal nitric oxide synthase (nNOS), ß1 subunit of soluble guanylate cyclase and cGMP when compared with the Wistar-Kyoto rat ganglia. Soluble guanylate cyclase inhibition or nNOS inhibition increased [Ca(2+)](i) in the Wistar-Kyoto rats but had no effect in SHR neurons. A nitric oxide donor decreased [Ca(2+)](i) in both sets of neurons, although this was markedly less in the SHR. A novel noradrenergic cell specific vector (Ad.PRSx8-nNOS/Cherry) or its control vector (Ad.PRSx8-Cherry) was expressed in sympathetic neurons. In the SHR, Ad.PRSx8-nNOS/Cherry-treated neurons had a significantly reduced peak [Ca(2+)](i) transient that was associated with increased tissue levels of nNOS protein and cGMP concentration compared with gene transfer of Ad.PRSx8-Cherry alone. nNOS inhibition significantly increased [Ca(2+)](i) after Ad.PRSx8-nNOS/Cherry expression. We conclude that artificial upregulation of stellate sympathetic nNOS via targeted gene transfer can directly attenuate intracellular Ca(2+) and may provide a novel method for decreasing enhanced cardiac sympathetic neurotransmission.

Age-dependent regulation of renal vasopressin V(1A) and V2 receptors in rats with genetic hypertension: implications for the treatment of hypertension.

The role of arginine vasopressin (AVP) as a hypertensive hormone remains controversial. We have previously reported that intervention with a V(1A) receptor antagonist in 6-week-old prehypertensive spontaneously hypertensive rats (SHR) for 4 weeks attenuated the subsequent development of hypertension in adult SHR. This study assessed the age-dependent regulation of plasma AVP levels and kidney V(1A) and V2 receptor expression during the development of hypertension in SHR and in normotensive Sprague Dawley rats. Systolic blood pressure (SBP), plasma AVP, and plasma renin activity (PRA) and kidney V(1A) and V2 receptor expression were assessed. SHR were studied at three ages: prehypertensive (6 weeks), developed hypertension (10 weeks), and established hypertension (16 weeks). SBP increased with age in SHR (P < .01) and both plasma AVP (P < .01) and PRA (P < .05) were increased in 10-week-old SHR. Renal medulla V(1A) receptor gene expression decreased in 10-week and 16-week-old SHR (P < .01), with a reduction in V(1A) receptor protein in the inner medulla of 16-week-old SHR (P < .05) compared with young SHR. There was no change in V2 receptor expression during the development of hypertension. In normotensive rats, plasma AVP, PRA, and kidney V(1A) and V2 receptor expression were unchanged over time. These data suggest that in SHR, activation of plasma AVP and the renal V(1A) receptor occurs during developing hypertension, with downregulation when hypertension is established. The use of V(1A) receptor antagonists in prehypertension may provide a unique opportunity for the prevention of hypertension in high-risk individuals.

Upregulation of junctional adhesion molecule-A is a putative prognostic marker of hypertension.

AIMS: Establishing biochemical markers of pre-hypertension and early hypertension could help earlier diagnostics and therapeutic intervention. We assess dynamics of junctional adhesion molecule-A (JAM-A) expression in rat models of hypertension and test whether JAM-A expression could be driven by angiotensin (ANG) II and whether JAM-A contributes to the progression of hypertension. We also compare JAM-A expression in normo- and hypertensive humans. METHODS AND RESULTS: In pre-hypertensive and spontaneously hypertensive rats (SHRs), JAM-A protein was overexpressed in the brainstem microvasculature, lung, liver, kidney, spleen, and heart. JAM-A upregulation at early and late stages was even greater in the stroke-prone SHR. However, JAM-A was not upregulated in leucocytes and platelets of SHRs. In Goldblatt 2K-1C hypertensive rats, JAM-A expression was augmented before any increase in blood pressure, and similarly JAM-A upregulation preceded hypertension caused by peripheral and central ANG II infusions. In SHRs, ANG II type 1 (AT(1)) receptor antagonism reduced JAM-A expression, but the vasodilator hydralazine did not. Body-wide downregulation of JAM-A with Vivo-morpholinos in juvenile SHRs delayed the progression of hypertension. In the human saphenous vein, JAM-A mRNA was elevated in hypertensive patients with untreated hypertension compared with normotensive patients but reduced in patients treated with renin-angiotensin system antagonists. CONCLUSION: Body-wide upregulation of JAM-A in genetic and induced models of hypertension in the rat precedes the stable elevation of arterial pressure. JAM-A upregulation may be triggered by AT(1) receptor-mediated signalling. An association of JAM-A with hypertension and sensitivity to blockers of ANG II signalling were also evident in humans. We suggest a prognostic and possibly a pathogenic role of JAM-A in arterial hypertension.