bluuebunny/crossref_metadata_2025 huggingface dataset:
Coronary Hemodynamic and Ventricular Responses to Angiotensin Type 1 Receptor Inhibition in SHR
Authors: Varagic Jasmina , Susic Dinko , Frohlich Edward D.
Published: June 2012

Abstract
—This study was designed to determine the effects of angiotensin II type 1 (AT
1
) receptor inhibition on coronary hemodynamics and ventricular mass and hydroxyproline content and the additive effects of angiotensin II type 2 (AT
2
) receptor inhibition in spontaneously hypertensive rats (SHR). The selective AT
1
receptor antagonist candesartan (10 mg/kg per day) was administered alone or in combination with the AT
2
receptor antagonist PD 123319 (50 mg/kg per day) for 12 weeks. Control SHR received placebo for the same period. Left and right ventricular coronary blood flow, blood flow reserve, and minimal coronary vascular resistance were determined by using radiomicrospheres in male 35-week-old rats. Mean arterial pressure; total peripheral resistance; left and right ventricular, renal, and aortic weights; and hydroxyproline concentration were also determined. Candesartan reduced mean arterial pressure and left ventricular, renal, and aortic masses, as well as hydroxyproline concentration and minimal coronary vascular resistance of both ventricles. PD 123319 partially prevented the hypotensive effect of AT
1
receptor inhibition and reversed the effect on myocardial hydroxyproline concentration. These data suggest that AT
2
receptors contribute to the hypotensive and antifibrotic effects but not the coronary hemodynamic improvement or reduced left ventricular mass of AT
1
receptor inhibition in these adult SHR.
Relation of Age to Left Ventricular Function and Systemic Hemodynamics in Uncomplicated Mild Hypertension
Authors: Slotwiner David J. , Devereux Richard B. , Schwartz Joseph E. , Pickering Thomas G. , de Simone Giovanni , Roman Mary J.
Published: June 2012

Abstract
—Previous studies in normotensive subjects have shown a slight decline in resting left ventricular pump function and midwall contractility with aging. We examined the relations of age to these variables and to peripheral resistance and vascular stiffness in 272 asymptomatic, unmedicated adults (25 to 80 years old) who had uncomplicated essential hypertension. Cardiac and carotid ultrasound and carotid pressure waveforms were obtained to measure left ventricular dimensions, endocardial and midwall left ventricular shortening, stroke index and cardiac index, end-systolic stress, and pulse pressure/stroke index and β, pressure-dependent and independent measures of vascular stiffness, respectively. Endocardial and midwall stress-corrected left ventricular shortening assessed ventricular performance. Cardiac index and TPRI did not change with age in either gender, with age-related increases in systolic pressure offset by increasingly concentric ventricular geometry in women and enhanced ventricular systolic function in men. In contrast to the lack of age-related change in traditional hemodynamic indexes, pulse pressure/stroke volume and β strongly increased with age (
P
<0.001). Thus, in uncomplicated, relatively mild essential hypertension, neither cardiac index nor peripheral resistance is associated with age. This hemodynamic stability is associated with age-related increased concentricity of ventricular geometry in women and increased ventricular performance indexes in hypertensive men. Vascular stiffness progressively increases with age, independent of change in mean pressure or resistance, possibly contributing to increased rates of cardiovascular events in older individuals.
Vasoactive Drugs Influence Aortic Augmentation Index Independently of Pulse-Wave Velocity in Healthy Men
Authors: Kelly R. P. , Millasseau S. C. , Ritter J. M. , Chowienczyk P. J.
Published: June 2012

Abstract
—Aortic augmentation index, a measure of central systolic blood pressure augmentation arising mainly from pressure-wave reflection, increases with vascular aging. The augmentation index is influenced by aortic pulse-wave velocity (related to aortic stiffness) and by the site and extent of wave reflection. To clarify the relative influence of pulse-wave velocity and wave reflection on the augmentation index, we studied the association between augmentation index, pulse-wave velocity, and age and examined the effects of vasoactive drugs to determine whether altering vascular tone has differential effects on pulse-wave velocity and the augmentation index. We made simultaneous measurements of the augmentation index and carotid-to-femoral pulse-wave velocity in 50 asymptomatic men aged 19 to 74 years at baseline and, in a subset, during the administration of nitroglycerin, angiotensin II, and saline vehicle. The aortic augmentation index was obtained by radial tonometry (Sphygmocor device, PWV Medical) with the use of an inbuilt radial to aortic transfer function. In multiple regression analysis, the aortic augmentation index was independently correlated only with age (
R
=0.58,
P
<0.0001). Nitroglycerin (3 to 300 μg/min IV) reduced the aortic augmentation index from 4.8±2.3% to −11.9±5.3% (n=10,
P
<0.002). Angiotensin II (75 to 300 ng/min IV) increased the aortic augmentation index from 9.3±2.4% to 18.3±2.9% (n=12,
P
<0.001). These drugs had small effects on aortic pulse-wave velocity, producing mean changes from baseline of <1 m/s (each
P
<0.05). In healthy men, vasoactive drugs may change aortic augmentation index independently from aortic pulse-wave velocity.
Mutations in the Na-Cl Cotransporter Reduce Blood Pressure in Humans
Authors: Cruz Dinna N. , Simon David B. , Nelson-Williams Carol , Farhi Anita , Finberg Karin , Burleson Laura , Gill John R. , Lifton Richard P.
Published: June 2012

Abstract
—The relationship between salt homeostasis and blood pressure has remained difficult to establish from epidemiological studies of the general population. Recently, mendelian forms of hypertension have demonstrated that mutations that increase renal salt balance lead to higher blood pressure, suggesting that mutations that decrease the net salt balance might have the converse effect. Gitelman’s syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (
NCCT
), features inherited hypokalemic alkalosis with so-called “normal” blood pressure. We hypothesized that the mild salt wasting of Gitelman’s syndrome results in reduced blood pressure and protection from hypertension. We have formally addressed this question through the study of 199 members of a large Amish kindred with Gitelman’s syndrome. Through genetic testing, family members were identified as inheriting 0 (n=60), 1 (n=113), or 2 (n=26) mutations in
NCCT
, permitting an unbiased assessment of the clinical consequences of inheriting these mutations by comparison of the phenotypes of relatives with contrasting genotypes. The results demonstrate high penetrance of hypokalemic alkalosis, hypomagnesemia, and hypocalciuria in patients inheriting 2 mutant
NCCT
alleles. In addition, the
NCCT
genotype was a significant predictor of blood pressure, with homozygous mutant family members having significantly lower age- and gender-adjusted systolic and diastolic blood pressures than those of their wild-type relatives. Moreover, both homozygote and heterozygote subjects had significantly higher 24-hour urinary Na
+
than did wild-type subjects, reflecting a self-selected higher salt intake. Finally, heterozygous children, but not adults, had significantly lower blood pressures than those of the wild-type relatives. These findings provide formal demonstration that inherited mutations that impair renal salt handling lower blood pressure in humans.
Characterization of the Microglial Response to Cerebral Ischemia in the Stroke-Prone Spontaneously Hypertensive Rat
Authors: Marks Louise , Carswell Hilary V.O. , Peters Elaine E. , Graham David I. , Patterson James , Dominiczak Anna F. , Macrae I. Mhairi
Published: June 2012

Stroke-prone spontaneously hypertensive rats (SHRSP) sustain more ischemic damage after middle cerebral artery occlusion than do their reference strain, the Wistar-Kyoto rat (WKY). The cause of increased stroke sensitivity is still under investigation. In general, SHRSP display a greater response to inflammatory stimuli than do WKY. Because inflammatory cells may influence the extent of damage in experimental stroke, this study has investigated the acute inflammatory response to focal ischemia in SHRSP and WKY. Adult male SHRSP (n=5) and WKY (n=5) were anesthetized and underwent distal middle cerebral artery occlusion. After 24 hours of recovery, infarct volume, neutrophil counts, and activated microglia counts were performed. SHRSP displayed more ischemic damage than did WKY (135±4.7 versus 102±4.7 mm
3
[mean±SEM],
P
<0.005). Brain neutrophil counts were extremely low in both strains. SHRSP displayed significantly more activated microglia than did WKY in the ipsilateral hemisphere (respective SHRSP versus WKY values [mean±SEM] were 88±3.6 versus 51±3.4 per mm
2
for the cortical peri-infarct region [
P
<0.005] and 183±7.9 versus 156±3.7 per mm
2
for the infarct core [
P
<0.05]) and in the contralateral hemisphere (eg, respective SHRSP versus WKY values were 102±3.2 versus 50±3.1 per mm
2
for the sensorimotor cortex [
P
<0.0001]). No neutrophils and very few activated microglia were found within the brains of naive rats. However naive SHRSP possessed more microglia (resting and activated) than did naive WKY. This study demonstrates a more pronounced microglial response to focal ischemia in SHRSP compared with WKY and provides evidence of a potential role for inflammatory processes in response to ischemic damage.
Heritability Estimates of Obesity Measures in Siblings With and Without Hypertension
Authors: Pausova Zdenka , Gossard Francis , Gaudet Daniel , Tremblay Johanne , Kotchen Theodore A. , Cowley Allen W. , Hamet Pavel
Published: June 2012

The goal of the present study was to evaluate mean values and heritability estimates of 3 global and 11 regional obesity measures in siblings with (HPT, n=209) or without (non-HPT, n=91) early-onset (age ≤55 years) hypertension who originated from the same families. Sixty-one sibships, each having at least 2 HPT siblings, were selected from a French-Canadian population with a known founder effect. Comparison of the mean values showed that HPT siblings are more obese than non-HPT siblings and that the body fat of HPT siblings is more centrally distributed. Significant differences were observed in all global obesity measures (
P
=0.009 to 0.0001). Among the regional measures, the most prominent differences were seen in waist circumference (
P
=0.00002), waist/hip ratio (
P
=0.0001), and suprailiac skinfold (
P
=0.00008). Comparison of the heritability estimates derived from sibling/sibling correlations (FCOR program, SAGE) suggested that genetic factors play a greater role in HPT (n=357) than in non-HPT (n=93) sib-pairs in determining most obesity measures. Similar to the mean values, these differences were most apparent in global and upper-body measures, with heritabilities ranging from 40% to 70% (
P
=0.05 to 0.0006) in HPT siblings and from 0% to 32% (
P
=NS) in non-HPT siblings. In summary, the present results suggest that HPT and non-HPT siblings drawn from the same families differ by the degree and distribution of body fat accumulation and that this difference is determined, at least in part, by genetic factors cosegregating with hypertension. This, in turn, suggests that a genetic link exists between obesity and hypertension in these families.
Analysis of Cell-Specific Promoters for Viral Gene Therapy Targeted at the Vascular Endothelium
Authors: Nicklin Stuart A. , Reynolds Paul N. , Brosnan M. Julia , White Steve J. , Curiel David T. , Dominiczak Anna F. , Baker Andrew H.
Published: June 2012

Abstract—

The use of viral vectors for vascular gene therapy targeted at the endothelium is limited by the promiscuous tropism of vectors and nonspecificity of viral promoters, resulting in high-level transgene expression in multiple tissues. To evaluate suitable endothelial cell (EC)–specific promoters for vascular gene therapy, we directly compared the ability of the
fms
-like tyrosine kinase-1 (FLT-1), intercellular adhesion molecule-2 (ICAM-2), and von Willebrand factor (vWF) promoters to drive EC-restricted transcription after cloning into adenoviral vectors upstream of
lac
Z. Vastly different expression profiles were observed. Whereas both FLT-1 and ICAM-2 promoters generated transgene expression levels similar to cytomegalovirus in ECs in vitro, vWF expression levels were extremely low. Analysis of non-EC types revealed that ICAM-2 but not FLT-1 evoked leaky transgene expression, thus identifying FLT-1 as the most selective promoter. With an ex vivo human gene therapy model, the FLT-1 promoter demonstrated EC-specific transgene expression in intact human vein but no detectable expression from infected exposed smooth muscle cells in EC-denuded vein. Furthermore, when adenoviruses were systemically administered to mice, the FLT-1 promoter demonstrated extremely low-level gene expression in the liver, the major target organ for adenoviral transduction in vivo. This study highlights the potential of using the FLT-1 promoter for local and systemic human gene therapy in hypertension and its complications.
Sodium Sensitivity of Blood Pressure Appearing Before Hypertension and Related to Histological Damage in Immunoglobulin A Nephropathy
Authors: Konishi Yoshio , Okada Noriyuki , Okamura Mikio , Morikawa Takashi , Okumura Michiaki , Yoshioka Katsunobu , Imanishi Masahito
Published: June 2012

Patients with renal parenchymal disease exhibit sodium-sensitive hypertension. We examined patients with immunoglobulin A (IgA) nephropathy to determine whether this sensitivity appears before hypertension begins and whether this sensitivity is related to histological damage. Thirty-eight patients with IgA nephropathy followed a diet with an ordinary sodium level for 1 week and a sodium-restricted diet for 1 week, in random order, and were divided into 3 groups by their systemic blood pressure on the diet with an ordinary sodium level (optimal, <120/<80 mm Hg, n=15; normal to high-normal, 120 to 139/80 to 89 mm Hg, n=18; hypertensive, ≥140/≥90 mm Hg, n=5). The sodium sensitivity index was calculated as the reciprocal of the slope of the pressure-natriuresis curve drawn by linkage of 2 datum points obtained during the different diets. The scores for glomerulosclerosis and tubulointerstitial damage were evaluated semiquantitatively. The sensitivity index, glomerulosclerosis score, and score for tubulointerstitial damage were higher in patients with normal to high-normal blood pressure or hypertension than in patients with optimal pressure. The sensitivity index was significantly correlated with glomerulosclerosis (
P
=0.001) and tubulointerstitial damage (
P
=0.002). In patients with normal to high-normal pressure, sodium restriction lowered blood pressure to the optimal range and decreased proteinuria. In patients with IgA nephropathy, sodium sensitivity of blood pressure related to renal histological damage appears before hypertension.
DASH (Dietary Approaches to Stop Hypertension) Diet Is Effective Treatment for Stage 1 Isolated Systolic Hypertension
Authors: Moore Thomas J. , Conlin Paul R. , Ard Jamy , Svetkey Laura P. ,   for the DASH Collaborative Research Group
Published: June 2012

Use of the DASH (Dietary Approaches to Stop Hypertension) diet, which is rich in fruits, vegetables, and low-fat dairy foods, significantly lowers blood pressure. Among the 459 participants in the DASH Trial, 72 had stage 1 isolated systolic hypertension (ISH) (systolic blood pressure, 140 to 159 mm Hg; diastolic blood pressure, <90 mm Hg). We examined the blood pressure response in these 72 participants to determine whether the DASH diet is an effective treatment for stage 1 ISH. After a 3-week run-in period on a typical American (control) diet, participants were randomly assigned for 8 weeks to 1 of 3 diets: a continuation of the control diet (n=25), a diet rich in fruits and vegetables (n=24), or the DASH diet (n=23). Sodium content was the same in the 3 diets, and caloric intake was adjusted during the trial to prevent weight change. Blood pressure was measured at baseline and at the end of the 8-week intervention period with standard sphygmomanometry. Use of the DASH diet significantly lowered systolic blood pressure compared with the control diet (−11.2 mm Hg; 95% confidence interval, −6.1 to −16.2 mm Hg;
P
<0.001) and the fruits/vegetables diet (−8.0 mm Hg; 95% confidence interval, −2.5 to −13.4 mm Hg;
P
<0.01). Overall, blood pressure in the DASH group fell from 146/85 to 134/82 mm Hg. Similar results were observed with 24-hour ambulatory blood pressure measurements. In the DASH diet group, 18 of 23 participants (78%) reduced their systolic blood pressure to <140 mm Hg, compared with 24% and 50% in the control and fruits/vegetables groups, respectively. Our results indicate that the DASH diet, which is rich in fruits, vegetables, and low-fat dairy foods, is effective as first-line therapy in stage 1 ISH.
Downregulation of Angiotensin II Type 1 Receptors During Sepsis
Authors: Bucher Michael , Ittner Karl-Peter , Hobbhahn Jonny , Taeger Kai , Kurtz Armin
Published: June 2012

Our study aimed to characterize the mechanisms underlying the attenuated cardiovascular responsiveness toward the renin-angiotensin system during sepsis. For this purpose, we determined the effects of experimental Gram-negative and Gram-positive sepsis in rats. We found that sepsis led to a ubiquitous upregulation of NO synthase isoform II expression and to pronounced hypotension. Despite increased plasma renin activity and plasma angiotensin (Ang) II levels, plasma aldosterone concentrations were normal, and the blood pressure response to exogenous Ang II was markedly diminished in septic rats. Mimicking the fall of blood pressure during sepsis by short-term infusion of the NO donor sodium nitroprusside in normal rats did not alter their blood pressure response to exogenous Ang II. Therefore, we considered the possibility of an altered expression of Ang II receptors during sepsis. It turned out that Ang II type 1 receptor expression was markedly downregulated in all organs of septic rats. Further in vitro studies with rat renal mesangial cells showed that NO and a combination of proinflammatory cytokines (interleukin-1β, tumor necrosis factor-α, and interferon-γ) downregulated Ang II type 1 receptor expression in a synergistic fashion. In summary, our data suggest that sepsis causes a systemic downregulation of Ang II type 1 receptors that is likely mediated by proinflammatory cytokines and NO. We suggest that this downregulation of Ang II type 1 receptors is the main reason for the attenuated responsiveness of blood pressure and of aldosterone formation to Ang II and, therefore, contributes to the characteristic septic shock.
Aerobic Exercise Training Does Not Modify Large-Artery Compliance in Isolated Systolic Hypertension
Authors: Ferrier Kathryn E. , Waddell Tamara K. , Gatzka Christoph D. , Cameron James D. , Dart Anthony M. , Kingwell Bronwyn A.
Published: June 2012

The present study characterized large-artery properties in patients with isolated systolic hypertension (ISH) and determined the efficacy of exercise training in modifying these properties. Twenty patients (10 male and 10 female) with stage I ISH and 20 age- and gender-matched control subjects were recruited, and large-artery properties were assessed noninvasively. Ten ISH patients (5 male and 5 female) were enrolled in a randomized crossover study comparing 8 weeks of moderate intensity cycling with 8 weeks of sedentary activity. Brachial and carotid systolic, diastolic, mean, and pulse pressures were higher in the ISH group than in the control group. Systemic arterial compliance (0.43±0.04 versus 0.29±0.02 arbitrary compliance units for the control versus ISH groups, respectively;
P
=0.01) was lower, and carotid-to-femoral pulse-wave velocity (9.67±0.36 versus 11.43±0.51 m · s
−1
for the control versus ISH groups, respectively;
P
=0.007), input impedance (2.39±0.19 versus 3.27±0.34 mm Hg · s · cm
−1
for the control versus ISH groups, respectively;
P
=0.04), and characteristic impedance (1.67±0.17 versus 2.34±0.27 mm Hg · s · cm
−1
for the control versus ISH groups, respectively;
P
=0.05) were higher in the ISH group than in the control group. Training increased maximal oxygen consumption by 13±5% (
P
=0.04) and maximum workload by 8±4% (
P
=0.05); however, there was no effect on arterial mechanical properties, blood lipids, or left ventricular mass or function. These results suggest that the large-artery stiffening associated with ISH is resistant to modification through short-term aerobic training.
Role of nNOS in Regulation of Renal Function in Angiotensin II–Induced Hypertension
Authors: Červenka Luděk , Kramer Herbert J. , Malý Jan , Heller Jiří
Published: June 2012

Abstract—

Previous studies have indicated that in normotensive rats, NO produced by neuronal NO synthase (nNOS) plays an important role in modulating tubuloglomerular feedback (TGF)–mediated afferent arteriolar constriction. It has also been shown that in angiotensin (Ang) II–infused hypertensive rats, there is a reduced ability of nNOS-derived NO to counteract this vasoconstriction. The present study was performed to (1) assess in vivo renal functional responses to intrarenal nNOS inhibition in control and Ang II–infused rats and (2) determine whether changes in renal function following nNOS inhibition are mediated by unopposed stimulation of Ang II receptor subtype 1 (AT
1
). Wistar rats were infused with either saline (SAL) or Ang II (80 ng/min) by osmotic minipumps implanted subcutaneously. Mean arterial blood pressure of SAL- and Ang II–infused rats on day 13 after implantation averaged 121±4 (n=28) and 151±5 (n=30), respectively (
P
<0.05). There were no differences in glomerular filtration rate (GFR) (0.68±0.09 versus 0.59±0.09 mL · min
−1
· g
−1
), renal plasma flow (RPF) (2.66±0.31 versus 2.34±0.39 mL · min
−1
· g
−1
), and absolute sodium excretion (0.37±0.07 versus 0.42±0.09 μmol · min
−1
· g
−1
). Intrarenal infusion of SAL did not change GFR, RPF, and sodium excretion in either SAL-infused (n=7) or Ang II–infused rats (n=8). Acute intrarenal administration of the nNOS inhibitor S-methyl-
l
-thiocitrulline (L-SMTC; 0.3 mg/h) decreased GFR, RPF, and sodium excretion in SAL-infused rats (n=9) by 29±4%, 38±4%, and 70±4% compared with control values (
P
<0.05). The pretreatment by the AT
1
receptor antagonist candesartan (750 ng IR) in SAL-infused rats (n=7) effectively prevented the decrease in RPF (−3±3%) elicited by nNOS inhibition and resulted in an increase in GFR (+25±12,
P
<0.05) and a concomitant greater increase in sodium excretion (84±12%,
P
<0.05) compared with control values. In contrast, in Ang II–infused rats (n=10) intrarenal inhibition of nNOS by L-SMTC did not cause significant decreases in GFR, RPF and sodium excretion (−2±2%, −15±10%, and −14±10%, respectively). These results suggest that in normotensive rats nNOS-derived NO counteracts Ang II–mediated vasoconstriction in the pre- and postglomerular microcirculation. Furthermore, Ang II–infused rats exhibit an impaired ability to release NO by nNOS. Decreased nNOS activity is likely to account at least partially for the enhanced TGF responsiveness in Ang II–infused rats and thus may contribute to the maintenance of hypertension in this model.
NF-Y Antagonizes Renin Enhancer Function by Blocking Stimulatory Transcription Factors
Authors: Shi Qi , Gross Kenneth W. , Sigmund Curt D.
Published: June 2012

We previously reported that the promoter proximal portion of the mouse renin enhancer contains a binding site for NF-Y (Ea) that overlaps with a positive regulatory element (Eb). In the context of the renin enhancer, NF-Y acts to oppose enhancer activity. We tested the hypothesis that NF-Y acts as a negative regulator by physically blocking the binding of transcription factors to element-b (Eb). Increasing the spacing between the NF-Y binding site (Ea) and Eb by 2, 5, or 10 nucleotides increased activity of the enhancer to the same extent as mutations abolishing NF-Y binding. The increase in transcription caused by increasing the spacing between Ea and Eb was not due to a shift of NF-Y from a negative regulator to a positive regulator because there was no loss of activity when Ea was also mutated. Oligonucleotides containing the normal or increased spacing mutants still allowed the binding of both NF-Y to Ea and transcription factors to Eb. In fact, we present evidence that both NF-Y and the Eb-binding factor(s) can each bind together on the same oligonucleotide containing either a 5- or 10-bp spacing between Ea and Eb. Our data strongly suggest that the mechanism by which NF-Y opposes renin enhancer activity is to sterically block the binding of factors to Eb.
Angiotensin II Type 2 Receptor Inhibits Epidermal Growth Factor Receptor Transactivation by Increasing Association of SHP-1 Tyrosine Phosphatase
Authors: Shibasaki Yasunobu , Matsubara Hiroaki , Nozawa Yoshihisa , Mori Yasukiyo , Masaki Hiroya , Kosaki Atsushi , Tsutsumi Yoshiaki , Uchiyama Yoko , Fujiyama Soichiro , Nose Atsuko , Iba Osamu , Tateishi Eriko , Hasegawa Takamasa , Horiuchi Masatsugu , Nahmias Clara , Iwasaka Toshiji
Published: June 2012

Angiotensin (Ang) II has 2 major receptor isoforms, Ang type 1 (AT
1
) and Ang type (AT
2
). AT
1
transphosphorylates epidermal growth factor receptor (EGFR) to activate extracellular signal–regulated kinase (ERK). Although AT
2
was shown to inactivate ERK, the action of AT
2
on EGFR activation remains undefined. Using AT
2
-overexpressing vascular smooth muscle cells from AT
2
transgenic mice, we studied these undefined actions of AT
2
. Maximal ERK activity induced by Ang II was increased 1.9- and 2.2-fold by AT
2
inhibition, which was abolished by orthovanadate but not okadaic acid or pertussis toxin. AT
2
inhibited AT
1
-mediated EGFR tyrosine phosphorylation by 63%. The activity of SHP-1 tyrosine phosphatase was significantly upregulated 1 minute after AT
2
stimulation and association of SHP-1 with EGFR was increased, whereas AT
2
failed to tyrosine phosphorylate SHP-1. Stable overexpression of SHP-1–dominant negative mutant completely abolished AT
2
-mediated inhibition of EGFR and ERK activation. AT
1
-mediated c-
fos
mRNA accumulation was attenuated by 48% by AT
2
stimulation. Induction of fibronectin gene containing an AP-1 responsive element in its 5′-flanking region was decreased by 37% after AT
2
stimulation, corresponding to the results of gel mobility assay with the AP-1 sequence of fibronectin as a probe. These findings suggested that AT
2
inhibits ERK activity by inducing SHP-1 activity, leading to decreases in AP-1 activity and AP-1–regulated gene expression, in which EGFR dephosphorylation plays an important role via association of SHP-1.
Birth Weight Influences Blood Pressure Values and Variability in Children and Adolescents
Authors: Lurbe Empar , Torro Isabel , Rodríguez Concepción , Alvarez Vicente , Redón Josep
Published: June 2012

The objective of the present study was to assess the relationships between birth weight and the values and variability of ambulatory blood pressure. Six hundred thirty healthy children (369 girls) age 4 to 18 years (mean, 9.9 years) born at term after a normotensive pregnancy were included. The subjects were divided into 5 groups according to birth weight. For each subject, a 24-hour ambulatory blood pressure monitoring was performed according to the protocol designed. Average and variability (estimated as the standard deviation) of ambulatory blood pressure and heart rate were calculated separately for 24-hour, daytime, and nighttime periods. When values were adjusted for gender, current age, weight, and height, children with the lowest birth weights had the highest ambulatory blood pressure values and variability, whereas no differences in heart rate were observed. Multiple regression analysis showed that although current weight was the strongest predictor for 24-hour systolic blood pressure (
P
<0.001), there was also an independent and significant inverse relationship for birth weight (
P
<0.002) after controlling for gender, current age, and height. Likewise, birth weight was independently and inversely correlated with 24-hour systolic blood pressure variability (
P
<0.03). In conclusion, children who had lower birth weights tended to have not only the highest blood pressure values but also the highest blood pressure variability, independent of the increases in ambulatory blood pressure values. Knowing that high blood pressure variability is at least partially independent of blood pressure values, the importance of this variability on further blood pressure rises and/or on vascular damage later in life needs to be assessed in future studies.
Chemokines and Leukocyte Activation in the Fetal Circulation During Preeclampsia
Authors: Mellembakken Jan Roar , Aukrust Pål , Hestdal Kjetil , Ueland Thor , Åbyholm Thomas , Videm Vibeke
Published: June 2012

Preeclampsia is a potentially life-threatening disease for both mother and fetus. Endothelial dysfunction is pivotal in the pathogenesis of this disorder, possibly reflecting a state of persistent inflammation. In the present study, we examined whether signs of inflammation with production of chemokines and leukocyte activation were present in the fetal circulation during preeclampsia. Venous cord blood was sampled during cesarean sections from 36 neonates born after uncomplicated pregnancies and from 35 born after severe preeclamptic pregnancies with premature newborns. The expression of adhesion molecules on neutrophils and monocytes was analyzed by flow cytometry, and plasma levels of chemokines and soluble adhesion molecules were analyzed by enzyme immunoassay. Newborns of preeclamptic mothers had increased expression of CD15s (
P
=0.003), CD49d/CD29 (
P
=0.01/0.005), and CD31 (
P
=0.007) on neutrophils and CD15s (
P
<0.001), CD11c (
P
=0.009), and CD54 (
P
=0.001) on monocytes. This activation of neutrophils and monocytes was accompanied by raised plasma levels of the CXC chemokines interleukin-8 (
P
=0.007) and growth-related oncogene-α (
P
=0.01) and decreased plasma levels of soluble E-selectin (
P
=0.001) and L-selectin (
P
=0.002). Although raised levels of adhesion molecules on leukocytes or decreased levels of soluble adhesion molecules in plasma were not related to prematurity or the degree of preeclampsia, raised interleukin-8 levels were found only in neonates of preeclamptic mothers with the highest blood pressures. Our findings suggest the activation of neutrophils and monocytes in the fetus during preeclampsia involving enhanced chemokine activation, possibly contributing to the fetal morbidity of this disorder.
Left Ventricular Systolic Dysfunction in a Biracial Sample of Hypertensive Adults
Authors: Devereux Richard B. , Bella Jonathan N. , Palmieri Vittorio , Oberman Albert , Kitzman Dalane W. , Hopkins Paul N. , Rao D.C. , Morgan Derek , Paranicas Mary , Fishman Dawn , Arnett Donna K.
Published: June 2012

To determine the prevalence and correlates of left ventricular systolic dysfunction in hypertensive patients in a biracial population-based sample, clinical evaluation and echocardiography were performed in 2086 participants in the Hypertension Genetic Epidemiology Network (HyperGEN) examination; 86% had normal ejection fraction (>54%), 10% had mild ventricular dysfunction (ejection fraction 41% to 54%), and 4% had severe ventricular dysfunction (ejection fraction ≤40%). Prevalences of mild and severe ventricular dysfunction were higher in men than women (14% versus 8% and 7% versus 3%,
P
<0.001) and, weakly, in diabetics than nondiabetics (13% versus 10% and 6% versus 4%,
P
=0.07). Patients with severe ventricular dysfunction were older than those with mild dysfunction or normal function (mean, 58 versus 54 and 54 years, respectively;
P
=0.005) and had higher mean creatinine (1.20 versus 1.05 and 1.00 mg/dL) and uric acid (6.9 versus 6.3 and 6.1 mg/dL) levels (both
P
<0.001). Those with severe ventricular dysfunction, compared with those with mild dysfunction or normal ejection fraction, had greater mean ventricular internal dimension (6.2 versus 5.6 and 5.1 cm) and mass (61 versus 50 and 43 g/m
2.7
) and lower relative wall thickness (0.31 versus 33 and 0.35; all
P
<0.0001). Severe and mild ventricular dysfunction was associated with lower myocardial contractility (mean stress-corrected midwall shortening, 68% versus 94% versus 106% of predicted;
P
<0.0001). In regression analyses, lower ejection fraction as a continuous variable was independently and positively associated with male gender, diabetes, uric acid level, and body mass index. With the addition of echocardiographic variables, lower ejection fraction was associated with male gender, black race, prior myocardial infarction, and higher ventricular mass and lower relative wall thickness, pulse pressure, and body mass index. In a population-based sample of hypertensive patients, left ventricular systolic dysfunction was related to male gender, black race, diabetes, and elevated uric acid levels, as well as higher ventricular mass and lower relative wall thickness.
Lesions of the Commissural Nucleus of the Solitary Tract Reduce Arterial Pressure in Spontaneously Hypertensive Rats
Authors: Akemi Sato Monica , Vanderlei Menani José , Ubríaco Lopes Oswaldo , Colombari Eduardo
Published: June 2012

Abstract
—

— It has been suggested that increased sympathetic activity and arterial chemoreceptors are important for the high blood pressure in spontaneously hypertensive rats (SHR). Electrolytic lesions of the commissural nucleus of the solitary tract (commNTS) abolish (1) the cardiovascular responses to chemoreflex activation with potassium cyanide (KCN) in normotensive rats and (2) the hypertension that follows acute aortic baroreceptor denervation in rats. Therefore, in this study we investigated the effects of electrolytic lesions of the commNTS on basal mean arterial pressure (MAP), baroreflex, and chemoreflex in SHR and in normotensive control Wistar-Kyoto (WKY) and Wistar rats. CommNTS lesions elicited a dramatic fall in MAP to normal levels during the period of study (from the first to fourth day following lesions) in SHR and almost no changes in WKY and Wistar rats. The pressor responses to chemoreflex activation with KCN tested in the days 1 and 4 after commNTS lesions were abolished in SHR and in normotensive strains. The reflex tachycardia induced by sodium nitroprusside was also attenuated in days 1 and 4 after commNTS lesions in SHR, WKY, and Wistar rats. The data suggest that the integrity of commNTS is important for the maintenance of high blood pressure in SHR and for the reflex responses dependent on sympathetic activation either in SHR or in normotensive strains.
Treatment of Obesity Hypertension and Diabetes Syndrome
Authors: Zanella Maria Teresa , Kohlmann Osvaldo , Ribeiro Artur Beltrame
Published: June 2012

Abstract
—

— Obesity has been shown to be an independent risk factor for coronary heart disease. The insulin resistance associated with obesity contributes to the development of other cardiovascular risk factors, including dyslipidemia, hypertension, and type 2 diabetes. The coexistence of hypertension and diabetes increases the risk for macrovascular and microvascular complications, thus predisposing patients to cardiac death, congestive heart failure, coronary heart disease, cerebral and peripheral vascular diseases, nephropathy, and retinopathy. Body weight reduction increases insulin sensitivity and improves both blood glucose and blood pressure control. Metformin therapy also improves insulin sensitivity and has been associated with decreases in cardiovascular events in obese diabetic patients. Antihypertensive treatment in diabetics decreases cardiovascular mortality and slows the decline in glomerular function. However, pharmacological treatment should take into account the effects of the antihypertensive agents on insulin sensitivity and lipid profile. Diuretics and β-blockers are reported to reduce insulin sensitivity and increase triglyceride levels, whereas calcium channel blockers are metabolically neutral and ACE inhibitors increase insulin sensitivity. For the high-risk hypertensive diabetic patients, ACE inhibition has proven to confer additional renal and vascular protection. Because hypertension and glycemic control are very important determinants of cardiovascular outcome in obese diabetic hypertensive patients, weight reduction, physical exercise, and a combination of antihypertensive and insulin sensitizers agents are strongly recommended to achieve target blood pressure and glucose levels.
Relation of Cellular Potassium to Other Mineral Ions in Hypertension and Diabetes
Authors: Resnick Lawrence M. , Barbagallo Mario , Dominguez Ligia J. , Veniero Joseph M. , Nicholson J. P. , Gupta Raj K.
Published: June 2012

Abstract
—

— To investigate the role of intracellular potassium (K
i
)and other ions in hypertension and diabetes, we utilized
39
K-,
23
Na-,
31
P-, and
19
F-nuclear magnetic resonance (NMR) spectroscopy to measure K
i
, intracellular sodium (Na
i
), intracellular free magnesium (Mg
i
), and cytosolic free calcium (Ca
i
), respectively, in red blood cells of fasting normotensive nondiabetic control subjects (n=10), untreated (n=13) and treated (n=14) essential hypertensive subjects, and diabetic subjects (n=5). In 12 subjects (6 hypertensive and 6 normotensive controls), ions were also measured before and after the acute infusion of 1 L of normal saline. Compared with those in controls (K
i
=148±2.0 mmol/L), K
i
levels were significantly lower in hypertensive (132.2±2.9 mmol/L, sig=0.05) and in type 2 diabetic subjects (121.2±6.8 mmol/L, sig=0.05). K
i
was higher in treated hypertensives than in untreated hypertensives (139±3.1 mmol/L, sig=0.05) but was still lower than in normals. Although no significant relation was observed between basal K
i
and Na
i
values, saline infusion elevated Na
i
(
P
<0.01) and reciprocally suppressed K
i
levels (142±2.4 to 131±2.2 mmol/L,
P
<0.01). K
i
was strongly and inversely related to Ca
i
(
r
=−0.846,
P
<0.001), and was directly related to Mg
i
(
r
=0.664,
P
<0.001). We conclude that (1) K
i
depletion is a common feature of essential hypertension and type 2 diabetes, (2) treatment of hypertension at least partially restores K
i
levels toward normal, and (3) fasting steady-state K
i
levels are closely linked to Ca
i
and Mg
i
homeostasis. Altogether, these results emphasize the similar and coordinate nature of ionic defects in diabetes and hypertension and suggest that their interpretation requires an understanding of their interaction.
Predictable Blood Pressure Variability in Healthy and Complicated Pregnancies
Authors: Hermida Ramón C. , Ayala Diana E. , Iglesias Manuel
Published: June 2012

Abstract
—

— With the aim of describing the predictable pattern of blood pressure (BP) variability during gestation, we analyzed 2430 BP series systematically sampled by ambulatory monitoring for 48 consecutive hours every 4 weeks from the first obstetric visit (usually within the first trimester of pregnancy) until delivery in 235 normotensive women, 128 women who developed gestational hypertension, and 40 women who had a final diagnosis of preeclampsia. The pattern of variation along gestation of the 24-hour means of BP and heart rate was established for each group of women by polynomial regression analysis. For normotensive women, results indicate a steady decrease in BP up to 20 weeks of pregnancy, followed by an increase in BP up to the day of delivery, with an average 8% BP increase between the middle of gestation and delivery. In complicated pregnancies, BP is stable until the 22nd week of gestation and then increases linearly for the remainder of the pregnancy. Complicated pregnancies are characterized by a 9% and 13% increase in systolic and diastolic BPs, respectively, during the second half of gestation. Results also indicate that during the first half of pregnancy, systolic but not diastolic BP is slightly elevated in women who developed preeclampsia compared with those who developed gestational hypertension. During the second half of gestation, the linear trend of increasing BP for women who developed preeclampsia has a significantly higher slope than the trend for women with gestational hypertension. For both healthy and complicated pregnancies, heart rate increases until the end of the second trimester and slightly decreases thereafter. This study of women systematically sampled by 48-hour ambulatory BP monitoring throughout gestation confirms the predictable pregnancy-associated variability in BP and provides proper information for the establishment of reference limits for BP to be used in the early diagnosis of hypertensive complications in pregnancy. Those limits should be developed as a function of gestational age, taking into account the trends in BP throughout pregnancy demonstrated here.
Effect of Angiotensin II Synthesis Blockade on the Hypertensive Response to Chronic Reductions in Uterine Perfusion Pressure in Pregnant Rats
Authors: Alexander Barbara T. , Cockrell Kathy , Cline Farrah D. , Llinas Maria T. , Sedeek Mona , Granger Joey P.
Published: June 2012

Abstract
—

— The purpose of this study was to examine the role of the renin-angiotensin system in mediating the hypertension in response to chronic reductions in uterine perfusion pressure (RUPP) in conscious chronically instrumented pregnant rats. Mean arterial pressure was significantly higher in pregnant rats with chronic RUPP (125±3.0 mm Hg,
P
<0.01, n=12) than in pregnant rats (100±2.3 mm Hg, n=17). Plasma renin activity in pregnant rats with chronic RUPP was 17.1±2.5 nmol angiotensin I · L
−1
· h
−1
compared with 21.9±3.5 nmol angiotensin I · L
−1
· h
−1
in pregnant rats. Chronic oral administration of a converting-enzyme inhibitor (enalapril, 250 mg/L for 6 days) decreased mean arterial pressure to a similar extent in pregnant rats with chronic RUPP (109±4.2 mm Hg,
P
<0.01, n=9) and in normal pregnant (81±1.8 mm Hg,
P
<0.01, n=9) rats. Blockade of the renin-angiotensin system, however, had no significant effect on the blood pressure response to chronic RUPP as differences were similar in control (Δ25 mm Hg) and converting-enzyme inhibitor-treated (Δ27 mm Hg) groups. These findings suggest that the renin-angiotensin system does not play a major role in mediating the hypertension produced by chronic RUPP in pregnant rats.
Acute responses to arterial pressure and plasma renin activity to converting enzyme inhibition (SQ 20,881) in serially studied dogs with neonatally-induced coarctation hypertension.
Authors: Bagby S P
Published: June 2012

In six inbred dogs with neonatally-induced coarctation hypertension, and in seven littermate controls, acute responses of proximal arterial pressure and plasma renin activity (PRA) to converting enzyme inhibitor (CEI; SQ 20,881, 0.5 mg/kg i.v.) were serially examined. Studies were performed at 2, 6, and 12 months post-aortic banding under sodium-replete and -deplete conditions. Both in normotensive controls and in coarcted dogs, depressor responses (pre- minus post-CEI values) were positively correlated, not only with initial (pre-CEI) PRA, but also independently with initial blood pressure. Although absolute depressor responses in coarcted dogs exceeded those of the control group, there were no significant group differences when, by analysis of covariance, depressor responses were adjusted for the physiologic influence of initial pressure. Similarly, depressor responses expressed as a percent of initial pressure were comparable in coarcted and control groups. Initial PRA and PRA response to CEI in coarcted dogs were also comparable to control dogs; the PRA response correlated with initial PRA in both groups. CEI did not significantly diminish the magnitude of blood-pressure difference between coarcted and control dogs. Thus, in neonatally-induced coarctation hypertension, under both sodium replete- and -deplete conditions: 1) acute depressor and PRA responses to CEI are modulated by the same factors that influence responses of normotensive controls; 2) larger absolute depressor responses to CEI appear to be a physiologic function of higher initial pressure; and 3) blood pressure excess over littermate controls is largely sustained by CEI-resistant factors, potentially including the known volume excess in coarcted dogs.
Abnormal sodium efflux in erythrocytes of patients with essential hypertension.
Authors: Walter U , Distler A
Published: June 2012

Erythrocyte sodium efflux as well as sodium, potassium, and water content were studied in 12 untreated men with uncomplicated essential hypertension and in 18 normotensive control subjects. In the patients with essential hypertension, the rate constant for total sodium efflux was significantly lower than in the normotensives (5.96.10(-3) +/- 0.45.10(-3) min-1 vs 6.69.10(-3) +/- 0.49.10(-3) min-1; p less than 0.005), which was due to a reduced ouabain-sensitive sodium efflux rate constant. Significant differences in total sodium efflux and ouabain-sensitive sodium efflux, however, could not be demonstrated, since intracellular sodium concentrations, although insignificant, were higher in the patients with essential hypertension (6.11 +/- 0.74 mmole/liter vs 5.97 +/- 0.66 mmole/liter. The rate constants for ouabain-insensitive sodium efflux, for ouabain-insensitive furosemide-sensitive sodium efflux, and for passive (ouabain-insensitive furosemide-insensitive) sodium efflux were similar in hypertensives and in normotensives. The cause of the reduced rate constant for ouabain-sensitive sodium efflux is not clear. However, as suggested for other types of altered erythrocyte transport mechanisms described recently, it might be determined genetically.
Acute hypertension in a nonhuman primate: humoral and hemodynamic mechanisms.
Authors: Cody R J , Rodger R F , Hartley L H , Burton J , Herd J A
Published: June 2012

The present study assessed the contribution of the renin-angiotensin system (RAS), dietary sodium, and cardiac output (CO) to the genesis of primate hypertensin in a one-kidney model which was developed to test species-specific renin inhibitors. Reduction of renal perfusion pressure increased mean arterial pressure (MAP) from 105 +/- 4 to 127 +/- 3 mm Hg (p less than 0.0005), associated with increased plasma renin activity (PRA) from 4.9 +/- 0.7 to 13.8 +/- 1.1 ng. ml-1.hr-1 (p less than 0.0005). Correlation of MAP with PRA yielded an r value of 0.662 (p less than 0.0005). Significant blood pressure elevation was obtained with both regular (R) and low sodium (LS) diet (p less than 0.0005), although the MAP change was greater with LS. With both R and LS diet, hypertension was associated with increased PRA (p less than 0.0005), and normotensive pressures were achieved with converting enzyme inhibitor (teprotide). The hemodynamic change with hypertension was an increase of systemic vascular resistance (SVR) from 0.89 +/- 0.12 to 1.17 +/- 0.09 units (p less than 0.05); cardiac output (CO) and central blood volume did not change significantly. Thus, acute hypertension, mediated by the RAS, was developed in a one-kidney primate model. The hemodynamic correlate of hypertension was increased SVR; CO and volume redistribution were not initiating factors.