bluuebunny/crossref_metadata_2025 huggingface dataset:
Importance of the Renin System in Determining Blood Pressure Fall With Salt Restriction in Black and White Hypertensives
Authors: He Feng J. , Markandu Nirmala D. , Sagnella Giuseppe A. , MacGregor Graham A.
Published: June 2012

Abstract
—Seventy-one white and 33 black patients with essential hypertension were studied while on a high sodium intake of 350 mmol/d for 5 days and low sodium intake of 10 mmol/d for 5 days. The fall in blood pressure on changing from the high sodium to the low sodium diet was 17/6 mm Hg in whites and 22/10 mm Hg in blacks. Compared with whites, black patients had a 7-mm Hg greater fall (
P
<0.05) in systolic blood pressure and 4-mm Hg greater fall (
P
=0.068) in diastolic blood pressure (adjusted for age and blood pressure on the normal diet) with similar changes in urinary sodium excretion. With sodium restriction, plasma renin activity rose from 0.65 to 3.03 ng · mL
−1
· h
−1
in whites, whereas in blacks it rose only from 0.3 to 1.28 ng · mL
−1
· h
−1
(
P
<0.001 between blacks and whites). From the high to the low salt diet, plasma angiotensin II increased by 31 pmol/L in whites and by 12 pmol/L in blacks (
P
<0.05 compared with whites), and plasma aldosterone rose by 499 pmol/L in whites and by 256 pmol/L in blacks (
P
<0.01). Significant inverse correlations were obtained for all patients between the fall in systolic blood pressure from the high to low salt diet and the rise in plasma renin activity and angiotensin II, as well as the absolute level on the low salt diet. These results demonstrate that the larger fall in blood pressure with a reduction in salt intake in blacks is due at least in part to a less responsive renin-angiotensin-aldosterone system in blacks.
AT
1
Receptor A/C
1166
Polymorphism Contributes to Cardiac Hypertrophy in Subjects With Hypertrophic Cardiomyopathy
Authors: Osterop Arthur P. R. M. , Kofflard Marcel J. M. , Sandkuijl Lodewijk A. , Cate Folkert J. ten , Krams Rob , Schalekamp Maarten A. D. H. , Danser A. H. Jan
Published: June 2012

Abstract
—The development of left ventricular hypertrophy (LVH) in subjects with hypertrophic cardiomyopathy (HCM) is variable, suggesting a role for modifying factors such as angiotensin II. We investigated whether the angiotensin II type 1 receptor (AT
1
-R) A/C
1166
polymorphism, the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and/or plasma renin influence LVH in HCM. Left ventricular mass index (LVMI) and interventricular septal thickness were determined by 2-dimensional echocardiography in 104 genetically independent subjects with HCM. Extent of hypertrophy was quantified by a point score (Wigle score). Plasma prorenin, renin, and ACE were measured by immunoradiometric or fluorometric assays, and ACE and AT
1
-R genotyping were performed by polymerase chain reactions. The ACE D allele did not affect any of the measured parameters except plasma ACE (
P
<0.04). LVMI was higher (
P
<0.05) in patients carrying the AT
1
-R C allele (190±8.3 g/m
2
) than in AA homozygotes (168±7.2 g/m
2
), and similar patterns were observed for interventricular septal thickness (23.0±0.7 versus 21.6±0.7 mm) and Wigle score (7.0±0.3 versus 6.3±0.3). Plasma renin was higher (
P
=0.05) in carriers of the C allele than in AA homozygotes. Multivariate regression analysis, however, revealed no independent role for renin in the prediction of LVMI. Plasma prorenin and ACE were not affected by the AT
1
-R A/C
1166
polymorphism, nor did the ACE and AT
1
-R polymorphisms interact with regard to any of the measured parameters. We conclude that the AT
1
-R C
1166
allele modulates the phenotypic expression of hypertrophy in HCM, independently of plasma renin and the ACE I/D polymorphism.
Relationship Between Insulin Sensitivity and Maximal Forearm Blood Flow in Young Men
Authors: Fossum Eigil , Høieggen Aud , Moan Andreas , Rostrup Morten , Nordby Gudmund , Kjeldsen Sverre E.
Published: June 2012

Abstract
—Insulin resistance is a part of the metabolic cardiovascular syndrome. We aimed to test the hemodynamic hypothesis of insulin resistance, which suggests that a decreased skeletal muscle blood supply with subsequent reduced nutritional flow causes insulin resistance in skeletal muscle. We assessed determinants of peripheral blood flow such as maximal forearm blood flow (MFBF), minimal forearm vascular resistance (MFVR), and whole blood viscosity (WBV) in 27 young men with borderline elevation of blood pressure. Insulin sensitivity measured as glucose disposal rate (GDR) correlated with MFBF (
r
=0.55,
P
=0.003), MFVR (
r
=−0.58,
P
=0.002), and WBV (
r
=−0.39,
P
=0.046 at shear rate 201 s
−1
). There was no correlation between GDR and myocardial thickness or left ventricular mass. In a stepwise multiple regression analysis, MFVR and WBV explained 54% of the variation in GDR. The relative increase in mean arterial blood pressure during a mental stress test, as a marker of reactivity or an alert reaction, was correlated with MFVR (
r
=0.56,
P
=0.002) and inversely with GDR (
r
=−0.45,
P
=0.018) and MFBF (
r
=−0.49,
P
=0.01) but not with cardiac dimensions. In a stepwise multiple regression analysis, 48% of the increase in blood pressure during a mental stress test was explained by MFVR and WBV. Fasting insulin correlated with MFVR (
r
=0.41,
P
=0.036) and GDR (
r
=−0.62,
P
=0.001). These data show a positive association between the appearance of peripheral structural vascular changes as quantified through a hemodynamic technique and insulin resistance in young men with borderline elevation of blood pressure. The cause-effect relationship of this finding needs further evaluations.
Expression of the Dopamine D
3
Receptor Protein in the Rat Kidney
Authors: O’Connell Damian P. , Vaughan Carl J. , Aherne Anna M. , Botkin Suzanne J. , Wang Zhi-Qin , Felder Robin A. , Carey Robert M.
Published: June 2012

Abstract
—The dopamine D
3
receptor subtype was identified in rat kidney using both light microscopic immunohistochemistry and electron microscopic immunocytochemistry. Antipeptide polyclonal antisera were directed to both extracellular and intracellular regions of the native D
3
receptor. Selectivity of the antipeptide antisera was validated by their ability to recognize native receptor protein expressed in permanently transfected mouse LTK
−
cells or
Spodoptera fragiperda
(Sf9) cell membranes. Light microscopic immunohistochemical staining for the D
3
receptor was observed only in the cortex. Specific staining was present in proximal and distal tubules, cortical collecting ducts, glomeruli, and renal vasculature. Immunostaining was observed predominantly in the apical portion of both the proximal and distal tubules. Renal arterial staining was prominent in the medial and adventitial layers. Electron microscopic immunocytochemistry revealed immunogold particles in arteriolar smooth muscle cells of the renal vasculature. In proximal and distal tubules and cortical collecting duct, immunogold staining was localized to apical portions of tubule cells. D
3
receptor immunogold staining in the glomeruli was clearly present in podocytes. Western blot analysis demonstrated a single D
3
receptor band in infected Sf9 cell membranes, in transfected LTK
−
cells, and in kidney and brain but not in noninfected Sf9 cell membranes or in D
2
or D
3
receptor transfected or nontransfected LTK
−
cells. The use of receptor subtype–selective antibodies allows for the tissue localization of specific dopamine receptors that are not distinguished by current pharmacological or ligand-binding technology. The rat kidney expresses the D
3
receptor at sites previously deemed to have D
2
-like receptors.
Increased Kidney Xanthine Oxidoreductase Activity in Salt-Induced Experimental Hypertension
Authors: Laakso Juha , Mervaala Eero , Himberg Jaakko-Juhani , Teräväinen Terttu-Liisa , Karppanen Heikki , Vapaatalo Heikki , Lapatto Risto
Published: June 2012

Abstract
—Clinical and experimental studies have established an association between high sodium intake and arterial hypertension. The renal mechanisms resulting in impaired sodium excretion in hypertension-prone subjects are not clear. In hypertension-prone rats, high blood pressure results in increased renal mass and hemodynamic changes, both of which may alter renal oxygen distribution. Xanthine oxidoreductase (XOR) oxidizes ATP metabolites hypoxanthine and xanthine to urate. Because XOR is induced by hypoxia, we assessed kidney XOR activity in 2 models of salt-sensitive hypertension, spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (Dahl S) rats. Increasing sodium intake from basal (0.08%) to high (2.56% wt/dry wt in the diet) increased renal XOR activity dose-dependently from 68±8 to 143±21 μU/mg protein in the Dahl S (
P
<0.05) but not in Dahl salt-resistant (Dahl R) rats. On basal and high sodium diets, SHR had higher renal XOR activity (101±10 and 134±26 μU/mg protein, respectively) than normotensive Wistar-Kyoto rats (55±2 and 58±6 μU/mg protein,
P
<0.05). Sodium restriction (0.02% wt/wt) downregulated kidney XOR activity in both Dahl S and R rats by nearly 40%. In SHR, allopurinol treatment totally inhibited renal XOR activity, but neither systolic blood pressure nor renal mass changed. The results suggest that renal XOR induction is a consequence of increased salt intake or the resulting hypertension. However, further studies on renal XOR activity during the development of hypertension are needed to assess the importance of XOR in the pathophysiology of arterial hypertension.
Baroreflex Control of Sympathetic Nerve Activity and Heart Rate in Obstructive Sleep Apnea
Authors: Narkiewicz Krzysztof , Pesek Catherine A. , Kato Masahiko , Phillips Bradley G. , Davison Diane E. , Somers Virend K.
Published: June 2012

Abstract
—Patients with obstructive sleep apnea are at increased risk for hypertension. The mechanisms underlying this increased risk are not known. We tested the hypothesis that obstructive sleep apnea, independent of factors such as hypertension, obesity, and age, is characterized by impairment of baroreflex sensitivity. We measured muscle sympathetic nerve activity (MSNA) and heart rate responses to activation and deactivation of baroreceptors in newly diagnosed, never treated, normotensive patients with obstructive sleep apnea. These responses were compared with those obtained in healthy control subjects closely matched for age, body mass index, and blood pressure. Heart rate and MSNA changes during infusion of phenylephrine (baroreceptor activation) were similar in the control subjects and patients with sleep apnea. Infusion of nitroprusside (baroreceptor deactivation) elicited similar decreases in mean arterial pressure (MAP) but lesser MSNA increases in patients with sleep apnea than in control subjects. Calculation of ΔMSNA/ΔMAP ratio revealed that baroreflex regulation of sympathetic activity for similar blood pressure changes was diminished in patients with sleep apnea in comparison to normal control subjects (
P
=0.01). However, increases in heart rate during nitroprusside infusion were comparable in both groups. Sympathetic, blood pressure and heart rate responses to the cold pressor test were also similar in the 2 groups. Our results indicate that normotensive patients with sleep apnea have a selective impairment of the sympathetic response to baroreceptor deactivation but not to baroreceptor activation or to the cold pressor test. The impairment of baroreflex sympathetic modulation in patients with sleep apnea is not accompanied by any impairment of baroreflex control of heart rate.
Bromocriptine Regulates Angiotensin II Response on Sodium Pump in Proximal Tubules
Authors: Hussain Tahir , Abdul-Wahab Renee , Kotak Dharmi K. , Lokhandwala Mustafa F.
Published: June 2012

Abstract
—Dopamine and angiotensin II (Ang II) receptors have been reported to exhibit an interaction in renal proximal tubules. The present study was designed to investigate the regulation by a D
2
-like dopamine receptor of Ang II–mediated stimulation of Na,K-ATPase activity in the renal proximal tubules. Ang II (10
−13
to 10
−9
mol
/L
) stimulated Na,K-ATPase activity in the proximal tubules that was completely abolished when the tubules were pretreated with the D
2
-like receptor agonist bromocriptine (1 μmol/L) for 30 minutes. The effect of bromocriptine on Ang II response was prevented by domperidone (1 μmol/L), a D
2
-like dopamine receptor antagonist. Similarly, the inhibition of forskolin (1 μmol/L)–induced cAMP accumulation caused by Ang II (10 pmol/L) was also abolished in bromocriptine-pretreated tubules. Basal and forskolin-stimulated cAMP was not significantly different in bromocriptine-treated tubules compared with the control. [
3
H]-Ang II binding sites (angiotensin type 1 [AT
1
] receptors) were reduced by ≈65% in bromocriptine-treated proximal tubules, a result that was further substantiated by Western blot analysis revealing a 50% decrease in AT
1
receptors in bromocriptine-treated tubules compared with the control. Western blot analysis of G proteins revealed a 2-fold increase in G
sα
and a 20% decrease in G
iα1
and G
iα2
in the bromocriptine-treated proximal tubules. Bromocriptine (1 μmol/L) alone stimulated Na,K-ATPase activity during the first 30 minutes of incubation, and thereafter the stimulation fell to the basal level. Similarly, bromocriptine-mediated inhibition of cAMP lasted only up to 20 minutes. The data suggest that preactivation of D
2
-like dopamine receptors abolishes Ang II–mediated stimulation of Na,K-ATPase activity and inhibition of cAMP accumulation. This phenomenon may be a consequence of a decrease in AT
1
receptors and alterations in G protein levels in the proximal tubules. We propose that such a regulation of Ang II response by bromocriptine is the result of heterologous desensitization of the D
2
-like receptor system.
Glucocorticoids Inhibit Superoxide Anion Production and p22 Phox mRNA Expression in Human Aortic Smooth Muscle Cells
Authors: Marumo Takeshi , Schini-Kerth Valérie B. , Brandes Ralf P. , Busse Rudi
Published: June 2012

Abstract
—Recent reports suggest that the increased production of reactive oxygen species (ROS) in the vascular wall may contribute to the functional and structural changes associated with hypertension and atherosclerosis. Although glucocorticoid therapy can promote atherosclerosis, protective effects of these compounds on vascular lesion formation have been reported. In the present study, we investigated whether ROS production in cultured human aortic smooth muscle cells (HSMCs) can be modulated by glucocorticoids. Pretreatment of HSMCs with dexamethasone for 24 hours attenuated the basal and platelet-derived growth factor (PDGF)-AB– and angiotensin II–induced superoxide anion (O
2
· −
) production. PDGF-AB–stimulated O
2
· −
production was also inhibited by prednisolone and hydrocortisone but not by other steroids, such as testosterone and norgestrel. Incubation of HSMCs with glucocorticoids for 24 hours decreased 2′,7′-dichlorodihydrofluorescein (DCHF) oxidation, an indicator of intracellular ROS levels. Dexamethasone decreased the mRNA expression of p22 phox, one of the components of NADPH oxidase, but had no effect on the activity of superoxide dismutase. The effects of dexamethasone on DCHF oxidation, and p22 phox mRNA expression and PDGF-AB–stimulated O
2
· −
production were inhibited by the glucocorticoid receptor antagonist RU486. These results indicate that glucocorticoids decrease O
2
· −
production by HSMCs via a receptor-dependent pathway. This effect is likely to be mediated by a decrease in the generating system, such as downregulation of p22 phox mRNA, rather than an increased inactivation of O
2
· −
. The inhibition of ROS production might contribute to the local protective effects that glucocorticoids have on vascular lesion formation.
G-Protein β3 Subunit Gene (
GNB3
) Variant in Causation of Essential Hypertension
Authors: Benjafield Adam V. , Jeyasingam Cheryl L. , Nyholt Dale R. , Griffiths Lyn R. , Morris Brian J.
Published: June 2012

Abstract
—Essential hypertensives display enhanced signal transduction through pertussis toxin–sensitive G proteins. The
T
allele of a C825T variant in exon 10 of the G protein β3 subunit gene (
GNB3
) induces formation of a splice variant (Gβ3-s) with enhanced activity. The
T
allele of
GNB3
was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with
Bse
DI, which either cut (
C
allele) or did not cut (
T
allele) the 268-bp polymerase chain reaction product.
T
allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group (χ
2
=22;
P
=0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The
T
allele tracked with higher pretreatment blood pressure: diastolic=105±7, 109±16, and 128±28 mm Hg (mean±SD) for
CC
,
CT
, and
TT
, respectively (
P
=0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a
T
allele (
P
=0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein β3 subunit gene in the causation of essential hypertension.
Ambulatory Pulse Pressure
Authors: Verdecchia Paolo , Schillaci Giuseppe , Borgioni Claudia , Ciucci Antonella , Pede Sergio , Porcellati Carlo
Published: June 2012

Abstract
—A wide pulse pressure (PP) is a marker of increased artery stiffness and high cardiovascular (CV) risk. To investigate the prognostic value of ambulatory PP, which is currently unknown, we studied 2010 initially untreated subjects with uncomplicated essential hypertension (mean age, 51.7 years; 52% men). All subjects underwent baseline procedures including 24-hour noninvasive ambulatory blood pressure (BP) monitoring. The mean duration of follow-up was 3.8 years (range, 0 to 11 years), and CV morbidity and mortality were the outcome measures. There were 200 major CV events (2.61 per 100 person-years), 36 of which were fatal (0.47 per 100 person-years). In the 3 tertiles of the distribution of office PP, the rate of total CV events (per 100 persons per year) was 1.38, 2.12, and 4.34, respectively, and that of fatal events was 0.12, 0.30, and 1.07 (log-rank test, both
P
<0.01). In the 3 tertiles of the distribution of average 24-hour PP, the rate of total CV events was 1.19, 1.81, and 4.92, and that of fatal events was 0.11, 0.17, and 1.23 (log-rank test, both
P
<0.01). After controlling for several independent risk markers including white coat hypertension and nondipper status, we found that ambulatory PP was associated with the biggest reduction in the –2 log likelihood statistics for CV morbidity (
P
<0.05 versus office PP). In each of the 3 tertiles of office PP, CV morbidity and mortality increased from the first to the third tertile of average 24-hour ambulatory PP (log-rank test, all
P
<0.01). Age, left ventricular hypertrophy, and nondipper status were independent predictors of CV mortality, and the further predictive effect of ambulatory PP (
P
<0.001) was marginally but not significantly superior to that of office PP and average 24-hour systolic BP. We conclude that ambulatory PP is a potent risk marker in essential hypertension. CV morbidity is more closely predicted by ambulatory than by office PP even after control for multiple risk factors.
Role of C/A Polymorphism at −20 on the Expression of Human Angiotensinogen Gene
Authors: Zhao Yan Yan , Zhou Jie , Narayanan Chittampalli S. , Cui Yanning , Kumar Ashok
Published: June 2012

Abstract
—Angiotensinogen is the glycoprotein precursor of 1 of the most potent vasoactive hormones, angiotensin II. Human angiotensinogen gene contains a C/A polymorphism at −20 located between the TATA box and transcriptional initiation site. We show here that when nucleoside A is present at −20, this sequence binds to the estrogen receptor. We also show that transcriptional activity of reporter constructs containing human angiotensinogen gene promoter with nucleoside A at −20 is increased on cotransfection of an expression vector containing human estrogen receptor-α coding sequence in human hepatoma cells (HepG2) followed by estrogen treatment. On the other hand, adenoviral major late transcription factor binds preferentially to this region of the promoter when nucleoside C is present at −20. We also show that reporter constructs containing human angiotensinogen gene promoter with nucleoside C at −20 have increased basal promoter activity on transient transfection in HepG2 cells as compared with reporter constructs with nucleoside A at −20. Our data suggest that C/A polymorphism at −20 may modulate the expression of human angiotensinogen gene in a sex-specific manner.
Interferon Regulatory Factors Regulate Interleukin-1β–Converting Enzyme Expression and Apoptosis in Vascular Smooth Muscle Cells
Authors: Horiuchi Masatsugu , Yamada Hiroyuki , Akishita Masahiro , Ito Masaaki , Tamura Kouichi , Dzau Victor J.
Published: June 2012

Abstract
—Apoptosis has been reported to play a pivotal role in vascular remodeling. However, cellular mechanisms of apoptosis in vascular smooth muscle cells (VSMCs) have not been well defined. In this study, we focused on interleukin-1β–converting enzyme (ICE), a key protease in the induction of apoptosis in lymphocytes and fibroblasts. We observed an increase in ICE mRNA expression in rat aortic VSMCs after serum depletion, with a peak at 12 hours and then a gradual decline. This was associated with DNA fragmentation, a hallmark of apoptosis and morphological changes of apoptosis. Treatment of these VSMCs with the ICE inhibitor
N
-(
N
-acetyl-tyrosinyl-valinyl-alaninyl)-3-amino-4-oxobutanoic acid (YVAD-CHO) attenuated DNA fragmentation. The increased ICE mRNA expression was preceded by an increase in the mRNA expression of interferon regulatory factor (IRF)-1, peaking at 6 hours after serum removal, and a rapid but transient decrease in IRF-2 mRNA expression, reaching a nadir at 3 hours after serum depletion. To demonstrate that these reciprocal changes in IRF-1 and IRF-2 regulated ICE expression and induced apoptosis, we transfected antisense oligonucleotides for IRF-1 and IRF-2 into VSMCs and examined ICE mRNA expression and apoptotic changes. IRF-1 antisense pretreatment attenuated the increase in ICE expression and reduced apoptotic changes, whereas IRF-2 antisense treatment increased ICE mRNA expression and enhanced apoptotic changes. Taken together, our results suggest that serum growth factor depletion in VSMCs upregulates IRF-1 and downregulates IRF-2, thereby increasing ICE expression and inducing apoptosis.
Normotensive Salt Sensitivity
Authors: Morris R. Curtis , Sebastian Anthony , Forman Alex , Tanaka Masae , Schmidlin Olga
Published: June 2012

Abstract
—Normotensive salt sensitivity, a putative precursor of hypertension, might be quite frequent in African Americans (blacks) and less frequent in Caucasian Americans (whites), but only when dietary potassium is deficient and not when maintained well within the normal range. We tested this hypothesis in 41 metabolically controlled studies of 38 healthy normotensive men (24 blacks, 14 whites) who ate a basal diet low in sodium (15 mmol/d) and marginally deficient in potassium (30 mmol/d) for 6 weeks. Throughout the last 4 weeks, NaCl was loaded (250 mmol/d); throughout the last 3, potassium was supplemented (as potassium bicarbonate) to either mid- or high-normal levels, 70 and 120 mmol/d. Salt sensitivity, defined as an increase in mean arterial blood pressure ≥3 mm Hg with salt loading, was deemed “moderate” if increasing ≤10 mm Hg and “severe” if increasing more. When dietary potassium was 30 mmol/d, salt loading induced a mean increase in blood pressure only in blacks (
P
<0.001), and salt sensitivity occurred in most blacks but not whites (79% vs 36% (
P
<0.02). Supplementing potassium only to 70 mmol/d attenuated moderate salt sensitivity similarly in blacks and whites; 120 mmol/d abolished it, attenuated severe salt sensitivity, which occurred in a quarter of affected blacks, and suppressed the frequency and severity of salt sensitivity in blacks to levels similar to those observed in whites. These observations demonstrate that in most normotensive black men but not white men, salt sensitivity occurs when dietary potassium is even marginally deficient but is dose-dependently suppressed when dietary potassium is increased within its normal range. Such suppression might prevent or delay the occurrence of hypertension, particularly in the many blacks, in whom dietary potassium is deficient.
TGF-β
1
DNA Polymorphisms, Protein Levels, and Blood Pressure
Authors: Li Baogui , Khanna Ashwani , Sharma Vijay , Singh Tejinder , Suthanthiran Manikkam , August Phyllis
Published: June 2012

Abstract
—Transforming growth factor-β
1
(TGF-β
1
), a multifunctional cytokine with fibrogenic properties, has been implicated in the pathogenesis of the vascular and target organ complications of hypertension. TGF-β
1
may also regulate blood pressure via stimulation of endothelin-1 and/or renin secretion. Herein we explored the hypothesis that circulating levels of TGF-β
1
protein (quantified using a TGF-β
1
–specific sandwich ELISA) are correlates of blood pressure levels. This hypothesis was tested in 98 stable end-stage renal disease (ESRD) patients. (The use of ESRD patients as the study cohort eliminates renal function–dependent alterations in circulating levels of TGF-β
1
protein.) In addition, in view of the previously reported correlation among TGF-β
1
DNA polymorphisms and systolic blood pressure, TGF-β
1
codon 25 genotype and alleles were identified in 71 hypertensive subjects and 57 normotensives using amplification refractory mutation system polymerase chain reaction. Our studies demonstrate for the first time that TGF-β
1
levels (209±13 ng/mL, mean±SEM) are positive correlates (Pearson correlation analysis) of mean arterial pressure (
P
=0.008), systolic pressure (
P
=0.02), and diastolic pressure (
P
=0.01). We also report that a higher percentage of hypertensives (92%) compared with normotensives (86%) are homozygous for the arginine allele at codon 25. Our observations support the idea that genetically determined TGF-β
1
protein concentrations may play a role in blood pressure regulation in humans.
Interleukin-1β Regulation of Inducible Nitric Oxide Synthase and Cyclooxygenase-2 Involves the p42/44 and p38 MAPK Signaling Pathways in Cardiac Myocytes
Authors: LaPointe Margot C. , Isenović Esma
Published: June 2012

Abstract
—The genes encoding inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2, also known as prostaglandin-endoperoxide synthase-2) are induced in many types of cells in response to proinflammatory cytokines. We have previously shown that interleukin-1β (IL) stimulates iNOS and COX-2 mRNA in cardiac myocytes. Because IL has been shown to activate mitogen-activated protein kinase (MAPK) signaling pathways in many different cells, we tested whether the p42/44 and p38 MAPK pathways were involved in IL stimulation of iNOS and COX-2, using a specific inhibitor of p42/44 activation, PD98059 (PD), and the p38 inhibitor SB205380 (SB). Nitrites were measured using the Griess reagent, prostaglandin PGE
2
by an enzyme immunoassay, iNOS and COX-2 protein by Western blot analysis, and iNOS mRNA by Northern blot analysis. Tested separately, the p38 kinase and MAPK inhibitors partially reduced IL stimulation of nitrite, iNOS protein, and iNOS mRNA; used together, they completely abolished the effect of IL. SB and PD inhibited IL-stimulated COX-2 protein by 60% and 80%, respectively, and IL-stimulated COX-2 protein was totally prevented by the combination of inhibitors. PGE
2
production was inhibited more than 99% by either drug alone, suggesting a posttranslational effect on enzyme activity. To test whether this posttranslational effect involved the cytosolic phospholipase A
2
(cPLA
2
) isoform, Western blots were probed for cPLA
2
protein. Results indicated that IL stimulated cPLA
2
activity and synthesis, which was inhibited by SB but not PD. These data indicate that (1) IL induction of iNOS synthesis depends on both the p42/44 and p38 signaling pathways, acting primarily at the level of transcriptional regulation; and (2) IL regulation of COX-2 synthesis involves the p42/44 and p38 signaling pathways, with an additional level of regulation occurring posttranslationally, perhaps at the level of activation of the cPLA
2
isoform, which may be involved in intracellular signaling, as well as regulation of arachidonic acid release for COX-2 activity.
Angiotensin II Signaling in Vascular Smooth Muscle Cells Under High Glucose Conditions
Authors: Natarajan Rama , Scott Stephen , Bai Wei , Yerneni Kiran Kumar V. , Nadler Jerry
Published: June 2012

Abstract
—The mechanisms responsible for the accelerated cardiovascular disease in diabetes, as well as the increased hypertrophic effects of angiotensin II (Ang II) under hyperglycemic conditions, are not very clear. We examined whether the culture of vascular smooth muscle cells (VSMC) under hyperglycemic conditions to simulate the diabetic state can lead to increased activation of key growth- and stress-related kinases, such as the mitogen-activated protein kinases (MAPKs), in the basal state and in response to Ang II. Treatment of porcine VSMC for short time periods (0.5 to 3 hours) with high glucose (HG; 25 mmol/L) markedly increased the activation of the extracellular signal–regulated kinase (ERK1/2) and c-Jun/
N
-terminal kinase (JNK) relative to cells cultured in normal glucose (NG; 5.5 mmol/L). p38 MAPK also was activated by HG, and this effect remained sustained for several hours. Ang II treatment increased the activity of all 3 families of MAPKs. Ang II–induced ERK activation was potentiated nearly 2-fold in cells treated with HG for 0.5 hour. However, Ang II–induced JNK was not altered. In VSMC cultured for 24 hours with HG, Ang II and HG displayed an additive response on p38 MAPK activity. MAPKs can lead to activation of transcription factors such as activator protein-1 (AP-1). HG alone significantly increased AP-1 DNA-binding activity. Furthermore, Ang II and HG combined had additive effects on AP-1 activity. These results suggest that increased activation of specific MAPKs and downstream transcription factors, such as AP-1, may be key mechanisms for the increased VSMC growth potential of HG alone and of Ang II under HG conditions.
Role of Tyrosine Kinase and PKC in the Vasoconstrictor Response to 20-HETE in Renal Arterioles
Authors: Sun Cheng-Wen , Falck John R. , Harder David R. , Roman Richard J.
Published: June 2012

Abstract
—The present study examined the hypothesis that activation of protein kinase C (PKC), components of the mitogen-activated protein (MAP) kinase pathway, or both contributes to the inhibitory effects of 20-hydroxyeicosatetraenoic acid (20-HETE) on K
+
-channel activity and its vasoconstrictor response in renal arterioles. 20-HETE (0.1 to 50 μmol/L) dose-dependently produced a 30% increase in PKC activity and a fivefold rise in the expression of active extracellular signal-regulated kinase 1 (ERK1) and ERK2 proteins in renal microvessels. 20-HETE (0.01 to 1 μmol/L) reduced the diameter of isolated perfused renal interlobular arterioles by 33±2%. Blockade of PKC activity with an N-myristoylated PKC pseudosubstrate inhibitor (Myr-PKCi, 100 μmol/L) or calphostin C (0.5 μmol/L) had no significant effect on the vasoconstrictor response to 20-HETE. In contrast, the tyrosine kinase inhibitors genistein (30 μmol/L) and tyrphostin 25 (10 μmol/L) reduced the response to 20-HETE by 76.5±2.1% and 67.5±1.8%, respectively. A specific inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK), PD98059, had no effect on the vasoconstrictor response to 20-HETE. In cell-attached patches on renal vascular smooth muscle cells, 20-HETE reduced the open state probability of a large-conductance K
+
channel (from 0.0026±0.0004 to 0.0006±0.0001). The Myr-PKCi (100 μmol/L) did not alter the inhibitory effects of 20-HETE on this channel. In contrast, the tyrosine kinase inhibitor genistein (30 μmol/L) blocked the inhibitory effects of 20-HETE on the large-conductance K
+
channel. These data suggest that 20-HETE activates the MAP kinase system in renal arterioles and that the activation of a tyrosine kinase, which is proximal to MEK in this cascade, contributes to the inhibitory effects of 20-HETE on K
+
-channel activity and its vasoconstrictor effects in the renal arterioles.
Renal Mechanoreceptor Dysfunction
Authors: DiBona Gerald F. , Jones Susan Y. , Kopp Ulla C.
Published: June 2012

Abstract
—This study tested the hypothesis that decreased responsiveness of renal mechanosensitive neurons constitutes an intermediate phenotype in spontaneously hypertensive rats (SHR). Decreased responsiveness of these sensory neurons would contribute to increased renal sympathetic nerve activity and sodium retention, characteristic findings in hypertension. A backcross population, developed by mating borderline hypertensive rats with Wistar-Kyoto rats (WKY) (the F
1
of a cross between an SHR and a normotensive WKY), was fed 8% NaCl food for 12 weeks from age 4 to 16 weeks. Responses to increases in ureteral pressure to 20 and 40 mm Hg in 80 backcross rats instrumented for measurement of mean arterial pressure and afferent renal nerve activity were determined. Mean arterial pressure ranged from 110 to 212 mm Hg and was inversely correlated with the magnitude of the increase in afferent renal nerve activity during increased ureteral pressure. Thus, decreased responsiveness of renal mechanosensitive neurons cosegregated with hypertension in this backcross population. This aspect of the complex quantitative trait of altered renal sympathetic neural control of renal function, ie, decreased renal mechanoreceptor responsiveness, is part of an intermediate phenotype in SHR.
Autoantibodies to OxLDL Are Decreased in Individuals With Borderline Hypertension
Authors: Wu Ruihua , de Faire Ulf , Lemne Carola , Witztum Joseph L. , Frostegård Johan
Published: June 2012

Abstract
—Elevated antibody levels to oxidized low-density lipoprotein (aOxLDL) have been shown to correlate with the degree of atherosclerosis in some studies. On the other hand, immunization of experimental animals with OxLDL, leading to enhanced aOxLDL levels, inhibits the development of the disease. The role of antibodies to OxLDL during different stages of disease development is thus not clear. The objective of this study was to determine the level of aOxLDL in early cardiovascular disease, such as borderline hypertension (BHT). Seventy-three men with BHT were matched with 75 age-matched normotensive (NT) men (diastolic blood pressures, 85 to 94 and <80 mm Hg, respectively). Antibody levels to epitopes of OxLDL were determined by use of conventional and chemiluminescence ELISA techniques. Presence of carotid atherosclerosis was determined by B-mode ultrasonography; atherosclerotic plaques were detected in 29 individuals. BHT men had significantly lower aOxLDL levels of IgG class (
P
=0.001) and IgM class (
P
=0.001) than NT controls, as determined using chemiluminescence ELISA. Similar results were obtained using conventional ELISA, with which aOxLDL of IgG (
P
=0.0002) and IgM (
P
=0.026) classes and antibody levels to malondialdehyde–LDL were significantly lower in BHT individuals. There was no difference in antibody levels between individuals with or without carotid atherosclerosis. It is not clear whether the decreased aOxLDL levels in BHT are due to a decreased immune reaction to OxLDL or to an increased consumption of aOxLDL due to binding to early atherosclerotic lesions. The possible implications of these findings are discussed.
Clonidine Prevents Insulin Resistance and Hypertension in Obese Dogs
Authors: Rocchini Albert P. , Mao Hui Z. , Babu Keshava , Marker Paul , Rocchini Albert J.
Published: June 2012

Abstract
—The role that the central sympathetic nervous system plays in the development of obesity hypertension and insulin was evaluated by feeding dogs a high fat diet with or without clonidine treatment. Thirteen adult mongrel dogs were chronically instrumented and randomly assigned to receive either a high fat diet and no clonidine (n=6) or a high fat diet plus clonidine (n=7), 0.3 mg BID. Blood pressure, heart rate, plasma insulin, and electrolytes were measured daily. Insulin resistance was assessed with a multiple-dose euglycemic clamp (1, 2, and 30 mU · kg
−1
· min
−1
) before and after 1, 3, and 6 weeks of the high fat diet. Clonidine prevented the hypertension, tachycardia, and insulin resistance associated with feeding dogs the high fat diet but did not affect weight gain. The present study suggests that the central sympathetic nervous system plays a critical role in the development of both insulin resistance and hypertension associated with feeding dogs a high fat diet.
Postprandial Hypotension Is Associated With Asymptomatic Cerebrovascular Damage in Essential Hypertensive Patients
Authors: Kohara Katsuhiko , Jiang Yinong , Igase Michiya , Takata Yasunori , Fukuoka Tomikazu , Okura Takafumi , Kitami Yutaka , Hiwada Kunio
Published: June 2012

Abstract
—To elucidate the relationship between postprandial hypotension (PPH) and asymptomatic cerebrovascular damage, we evaluated changes in blood pressure after a meal by 24-hour blood pressure monitoring in 70 hospitalized essential hypertensive patients aged ≥50 years. They received a diet containing standard nutritional ingredients with 120 mmol (7 g) NaCl and were free from medication for at least 1 week. PPH was defined as the mean reduction of systolic blood pressure during 2 hours after a meal. Patients were divided into three groups according to mean values of PPH after 3 meals: PPH-1 (n=16, 5 mm Hg≤PPH<10 mm Hg), PPH-2 (n=18, PPH≥10 mm Hg), and normal (n=36, PPH<5 mm Hg). As asymptomatic cerebrovascular damage, lacunae and leukoaraiosis were evaluated by magnetic resonance imaging. PPH did not correlate with daytime or nighttime blood pressure or the nondipper phenomenon; however, PPH was significantly related to asymptomatic cerebrovascular damage. The prevalence of lacunae in the normal, PPH-1, and PPH-2 groups was 44%, 69%, and 83%, respectively (χ
2
=8.22,
P
<0.05). The number of lacunae in the normal, PPH-1, and PPH-2 groups was 1.0±1.3, 1.3±1.2, and 1.9±1.4, respectively (F[2,67]=3.2,
P
<0.05). The prevalence of advanced leukoaraiosis in the normal, PPH-1, and PPH-2 groups was 44%, 50%, and 83%, respectively (χ
2
=7.63,
P
<0.05). Severity score of leukoaraiosis in the normal, PPH-1, and PPH-2 groups was 1.5±0.7, 1.7±0.8, and 2.1±0.7, respectively (F[2,67]=4.3,
P
<0.05). These findings indicate that elderly hypertensive patients with marked PPH should be considered to have advanced cerebrovascular damage even in the absence of abnormal neurological findings.
NaCl-Induced Renal Vasoconstriction in Salt-Sensitive African Americans
Authors: Schmidlin Olga , Forman Alex , Tanaka Masae , Sebastian Anthony , Morris R. Curtis
Published: June 2012

Abstract
—In 16 African Americans (blacks, 14 men, 2 women) with average admission mean arterial pressure (MAP, mm Hg) 99.9±3.5 (mean±SEM), we investigated whether NaCl-induced renal vasoconstriction attends salt sensitivity and, if so, whether supplemental KHCO
3
ameliorates both conditions. Throughout a 3-week period under controlled metabolic conditions, all subjects ate diets containing 15 mmol NaCl and 30 mmol potassium (K
+
) (per 70 kg body wt [BW] per day). Throughout weeks 2 and 3, NaCl was loaded to 250 mmol/d; throughout week 3, dietary K
+
was supplemented to 170 mmol/d (KHCO
3
). On the last day of each study week, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) using renal clearances of PAH and inulin. Ten subjects were salt sensitive (SS) (ΔMAP >+5%) and 6 salt resistant (SR). In NaCl-loaded SS but not SR subjects, RBF (mL/min/1.73 m
2
) decreased from 920±75 to 828±46 (
P
<0.05); filtration fraction (FF, %) increased from 19.4± to 21.4 (
P
<0.001); and renal vascular resistance (RVR) (10
3
×mm Hg/[mL/min]) increased from 101±8 to 131±10 (
P
<0.001). In all subjects combined, ΔMAP varied inversely with ΔRBF (
r
=−0.57,
P
=0.02) and directly with ΔRVR (
r
= 0.65,
P
=0.006) and ΔFF (
r
= 0.59,
P
=0.03), but not with MAP before NaCl loading. When supplemental KHCO
3
abolished the pressor effect of NaCl in SS subjects, RBF was unaffected but GFR and FF decreased. The results show that in marginally K
+
-deficient blacks (1) NaCl-induced renal vasoconstrictive dysfunction attends salt sensitivity; (2) the dysfunction varies in extent directly with the NaCl-induced increase in blood pressure (BP); and (3) is complexly affected by supplemented KHCO
3
, GFR and FF decreasing but RBF not changing. In blacks, NaCl-induced renal vasoconstriction may be a pathogenetic event in salt sensitivity.
Effects of Amlodipine on Sympathetic Nerve Traffic and Baroreflex Control of Circulation in Heart Failure
Authors: Grassi Guido , Spaziani Domenico , Seravalle Gino , Bertinieri Giovanni , Dell’Oro Raffaella , Cuspidi Cesare , Mancia Giuseppe
Published: June 2012

Abstract
—Short-acting calcium antagonists exert a sympathoexcitation that in heart failure further enhances an already elevated sympathetic activity. Whether this is also the case for long-acting formulations is not yet established, despite the prognostic importance of sympathetic activation in heart failure. It is also undetermined whether in this condition long-acting calcium antagonists favorably affect a mechanism potentially responsible for the sympathetic activation, ie, the baroreflex impairment. In 28 heart failure patients (NYHA functional class II) under conventional treatment we measured plasma norepinephrine and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during arterial baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were performed at baseline and after 8 weeks of daily oral amlodipine administration (10 mg/d, 14 patients) or before and after an 8-week period without calcium antagonist administration (14 patients). Amlodipine caused a small and insignificant blood pressure reduction. Heart rate, left ventricular ejection fraction, and plasma renin and aldosterone concentrations were not affected. This was the case also for plasma norepinephrine (from 2.43±0.41 to 2.50±0.34 nmol/L, mean±SEM), muscle sympathetic nerve activity (from 54.4±5.9 to 51.0±4.3 bursts/min), and arterial baroreflex responses. No change in the above-mentioned variables was seen in the control group. Thus, in mild heart failure amlodipine treatment does not adversely affect sympathetic activity and baroreflex control of the heart and sympathetic tone. This implies that in this condition long-acting calcium antagonists can be administered without untoward neurohumoral effects anytime conventional treatment needs to be complemented by drugs causing additional vasodilatation.
Angiotensinogen Gene Polymorphisms M235T/T174M
Authors: Niu Tianhua , Yang Jianhua , Wang Binyan , Chen Wei , Wang Zhaoxi , Laird Nan , Wei Eric , Fang Zhian , Lindpaintner Klaus , Rogus John J. , Xu Xiping
Published: June 2012

Abstract
—The gene encoding angiotensinogen (
AGT
) has been widely studied as a candidate gene for hypertension. Most studies to date have relied on case-control analysis to test for an excess of
AGT
variants among hypertensive cases compared with normotensive controls. However, with this design, nothing guarantees that a positive finding is due to actual allelic association as opposed to an inappropriate control population. To avoid this difficulty in our study of essential hypertension in Anqing, China, we tested
AGT
variants using the transmission/disequilibrium test, a procedure that bypasses the need for a control sample by testing for excessive transmission of a genetic variant from parents heterozygous for that variant. We analyzed two
AGT
polymorphisms, M235T and T174M, which have been associated with essential hypertension in whites and Japanese, using data on 335 hypertensive subjects from 315 nuclear families and their parents. Except in the group of subjects younger than 25 years, M235 and T174 were the more frequently transmitted alleles. We found that 194 parents heterozygous for M235T transmitted M235 106 times (
P
=0.22) and that 102 parents heterozygous for T174M transmitted T174 60 times (
P
=0.09). Stratifying offspring by gender, M235 and T174 were transmitted 60 of 106 times (
P
=0.21) and 44 of 75 times (
P
=0.17), respectively, in men, and 46 of 88 times (
P
=0.75) and 16 of 27 times (
P
=0.44), respectively, in women. Our results were also negative in all age groups and for the affected offspring with blood pressure values ≥160/95 mm Hg. Thus, this study provides no evidence that either allele of M235T or T174M contributes to hypertension in this Chinese population.
Aldosterone Excretion Rate and Blood Pressure in Essential Hypertension Are Related to Polymorphic Differences in the Aldosterone Synthase Gene
CYP11B2
Authors: Davies Eleanor , Holloway Christine D. , Ingram Mary C. , Inglis Gordon C. , Friel Elaine C. , Morrison Caroline , Anderson Niall H. , Fraser Robert , Connell John M. C.
Published: June 2012

Abstract
—Significant correlation of body sodium and potassium with blood pressure (BP) may suggest a role for aldosterone in essential hypertension. In patients with this disease, the ratio of plasma renin to plasma aldosterone may be lower than in control subjects and plasma aldosterone levels may be more sensitive to angiotensin II (Ang II) infusion. Because essential hypertension is partly genetic, it is possible that altered control of aldosterone synthase gene expression or translation may be responsible. We compared the frequency of 2 linked polymorphisms, one in the steroidogenic factor-1 (SF-1) binding site and the other an intronic conversion (IC), in groups of hypertensive and normotensive subjects. In a larger population, the relationship of aldosterone excretion rate to these polymorphisms was also evaluated. In 138 hypertensive subjects, there was a highly significant excess of TT homozygosity (SF-1) over CC homozygosity compared with a group of individually matched normotensive control subjects. The T allele was significantly more frequent than the C allele in the hypertensive group compared with the control group. Similarly, there was a highly significant relative excess of the conversion allele over the “wild-type” allele and of conversion homozygosity over wild-type homozygosity in the hypertensive group compared with the control group. In 486 subjects sampled from the North Glasgow Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) population, SF-1 and IC genotypes were compared with tetrahydroaldosterone excretion rate. Subjects with the SF-1 genotypes TT or TC had significantly higher excretion rates than those with the CC genotype. The T allele was associated with higher excretion rates than the C allele. However, no significant differences were found in excretion rate between subjects of different IC genotype. Urinary aldosterone excretion rate may be a useful intermediate phenotype linking these genotypes to raised BP. However, no causal relationship has yet been established, and it is possible that the polymorphisms may be in linkage with other causative mutations.