bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct and Combined Vascular Effects of ACE Blockade and HMG-CoA Reductase Inhibition in Hypertensive Subjects
Authors: Nazzaro Pietro , Manzari Margherita , Merlo Massimo , Triggiani Rita , Scarano Annamaria , Ciancio Luigi , Pirrelli Anna
Published: June 2012

Abstract
—Hypercholesterolemia and hypertension are frequently associated with elevated sympathetic activity. Both are independent cardiovascular risk factors and both affect endothelium-mediated vasodilation. To identify the effects of cholesterol-lowering and antihypertensive treatments on vascular reactivity and vasodilative capacity, we studied 30 hypercholesterolemic hypertensive subjects. They received placebo for 4 weeks, either enalapril or simvastatin for 14 weeks, and, finally, both medications for an additional 14 weeks. Postischemic forearm blood flow (MFBF) and minimal vascular resistance (mFVR) were used as indices of vasodilative capacity and structural vascular damage, respectively. Total (resting-stress-recovery phases) cardiovascular (blood pressure [BP] and heart rate [HR]) and regional hemodynamic (FBF and FVR) reactivity to stressful stimuli were calculated as area-under-the-curve (auc) (value×time). Compared with baseline levels, simvastatin reduced total (TOT-C) and LDL cholesterol (LDL-C) (1.27 mmol/L,
P
<0.001 and 1.33 mmol/L,
P
<0.001, respectively). Enalapril also reduced TOT-C and LDL-C (0.6 mmol/L,
P
<0.001 and 0.58 mmol/L,
P
<0.05, respectively). MFBF was increased substantially by both treatments (
P
<0.001). Enalapril had a greater effect (−1.7 arbitrary units (AU),
P
<0.001) than simvastatin (−0.6 AU,
P
<0.05) on mFVR. During stress, FBF increased more with enalapril (4.4 FBF×minutes,
P
<0.001) than with simvastatin (1.8 FBF×minutes,
P
<0.01). Conversely, FVR stress response was reduced more with enalapril (9.1 FVR×minutes,
P
<0.001) than with simvastatin (2.9 FVR×minutes,
P
<0.01). During combination treatment, a significant (0.001>
P
<0.05) additive effect on hypercholesterolemia, structural vascular damage, BP, and FVR was shown. The findings suggest that angiotensin-converting enzyme (ACE) inhibition induces a larger reduction than HMG-CoA reductase blockade in vascular reactivity and structural damage in hypercholesterolemic hypertensive subjects.
Hyponatremic-Hypertensive Syndrome With Renal Ischemia
Authors: Agarwal Mamta , Lynn Kelvin L. , Richards A. Mark , Nicholls M. Gary
Published: June 2012

Abstract
—Renal artery stenosis or occlusion causing the hyponatremic-hypertensive syndrome has been rarely reported. Our impression, however, was that the disorder is not uncommon. Case records from patients in one city (population 350 000) presenting between 1980 and 1997 with hypertension, hyponatremia, and evidence of renal ischemia were scrutinized. Thirty-two patients fulfilling inclusion criteria were identified. Admission supine arterial pressures were high (mean 228/124 mm Hg), but there was a vigorous fall in pressure on standing (26/12.7 mm Hg recorded in 27 patients). Mean plasma concentrations of sodium (129.7 mmol/L) and potassium (2.7 mmol/L) were low, and 24-hour urine protein excretion was elevated in 19 of 26 patients. Twenty-two of the 32 patients were female, the majority were asthenic, and all but 5 were smokers. Symptoms precipitating hospitalization were headache, clouding of consciousness, confusion, weakness, weight loss, thirst, and polyuria. Plasma renin levels, measured in 20 patients, were elevated in most cases and correlated inversely (
r
=−0.63,
P
<0.01) with the plasma sodium concentration. The hyponatremic-hypertensive syndrome in patients with renal ischemia is not rare: Rather, it is underreported. It tends to affect elderly asthenic women who smoke heavily. Stimulation of renin release from the ischemic kidney is probably central to the pathophysiology. The syndrome deserves better recognition to ensure appropriate investigations and management.
Local Renin-Angiotensin System Is Involved in K
+
-Induced Aldosterone Secretion from Human Adrenocortical NCI-H295 Cells
Authors: Hilbers Urte , Peters Jörg , Bornstein Stefan R. , Correa Fernando M. A. , Jöhren Olaf , Saavedra Juan M. , Ehrhart-Bornstein Monika
Published: June 2012

Abstract
—NCI-H295, a human adrenocarcinoma cell line, has been proposed as a model system to define the role of the renin-angiotensin system in the regulation of aldosterone production in humans. Because the precise cellular localization of the components of the renin-angiotensin system in human adrenal cortical cells remains unclear, we investigated their localization in this defined cell system. NCI-H295 cells expressed both angiotensinogen and renin as shown by reverse transcriptase polymerase chain reaction and immunohistochemistry. Human angiotensin-converting enzyme (ACE) was not detectable by immunocytochemistry, ACE binding, or reverse transcriptase polymerase chain reaction. However, 3.5 mmol/L K
+
stimulated the formation of both angiotensin I and angiotensin II 1.9- and 2.5-fold, respectively, and increased aldosterone release 3.0-fold. The K
+
-induced stimulation of aldosterone release was decreased by captopril and enalaprilat (24% and 26%, respectively) and by the angiotensin type 1 (AT
1
)-receptor antagonist losartan (28%). Angiotensin II–induced stimulation of aldosterone release was abolished by losartan treatment. Specific [
125
I]Sar1-angiotensin II binding was detected by receptor autoradiography. The binding of [
125
I]Sar
1
-angiotensin II was completely displaced by the AT
1
antagonist losartan but not by the AT
2
receptor ligand PD 123319, confirming the expression of angiotensin II AT
1
receptors in NCI-H295 cells. Our results demonstrate that NCI-H295 cells express most of the components of the renin-angiotensin system. Our failure to detect ACE, however, suggests that the production of angiotensin II in NCI-H295 cells may be ACE independent. NCI-H295 cells are able to produce angiotensin II, and K
+
increases aldosterone secretion in part through an angiotensin-mediated pathway. The production of angiotensin II in NCI-H295 cells demonstrates that this human cell line can be useful to characterize the role of locally produced angiotensin II in the regulation of aldosterone release.
Inhibition of Carbonic Anhydrase Accounts for the Direct Vascular Effects of Hydrochlorothiazide
Authors: Pickkers Peter , Garcha Robinder S. , Schachter Michael , Smits Paul , Hughes Alun D.
Published: June 2012

Abstract
—Hydrochlorothiazide has been shown to exert direct vasodilator effects by activation of calcium-activated potassium (K
Ca
) channels in human and guinea pig isolated resistance arteries. Since hydrochlorothiazide binds to and inhibits the enzyme carbonic anhydrase and because K
Ca
channel activation is pH sensitive, we investigated the role of intracellular and extracellular carbonic anhydrase in the vascular effects of thiazide diuretics. Small arteries were isolated from guinea pig mesentery and studied by use of a microvascular myograph technique. In some experiments, tone and intracellular pH (pH
i
) were measured simultaneously with 2′,7′-bis(2-carboxyethyl)-5(6)′-carboxyfluorescein (BCECF-
am)
. Bendroflumethiazide, a thiazide diuretic with minimal inhibitory effects on carbonic anhydrase, had little effect on noradrenaline-induced tone (16±8% relaxation) compared with hydrochlorothiazide (74±12% relaxation). In contrast to hydrochlorothiazide, the action of bendroflumethiazide was unaffected by 100 nmol/L charybdotoxin, a selective blocker of K
Ca
channels. All inhibitors of carbonic anhydrase relaxed noradrenaline-induced tone in a concentration-dependent manner, and this effect was blocked by charybdotoxin. Hydrochlorothiazide and the inhibitors of carbonic anhydrase failed to relax tone induced by a depolarizing potassium solution. Acetazolamide and hydrochlorothiazide increased pH
i
by 0.27±0.07 and 0.21±0.04, respectively, whereas bendroflumethiazide had a much smaller effect: 0.06±0.03. The rise in pH
i
induced by any agent was not inhibited by charybdotoxin. The vasorelaxant effect of hydrochlorothiazide is shared by other inhibitors of carbonic anhydrase. Inhibitors of carbonic anhydrase, but not bendroflumethiazide, cause intracellular alkalinization, which is associated with K
Ca
channel opening. These data suggest that the vasodilator effect of thiazide diuretics results primarily from inhibition of vascular smooth muscle cell carbonic anhydrase, which results in a rise in pH
I
, leading to K
Ca
channel activation and vasorelaxation.
G-Protein β3 Subunit C825T Variant and Ambulatory Blood Pressure in Essential Hypertension
Authors: Beige Joachim , Hohenbleicher Henriette , Distler Armin , Sharma Arya M.
Published: June 2012

Abstract
—Recent studies have identified a novel polymorphism (C825T) of the gene encoding the β3 subunit of heterotrimeric G proteins (
Gβ3
) associated with enhanced activation of G proteins, which appears to be more common in hypertensive patients. In the present study we examine the relationship between this genetic variant and hypertension in 479 white patients with established essential hypertension recruited from the hypertension clinic of the Universitätsklinikum Benjamin Franklin in Berlin, Germany, and 1000 normotensive gender- and age-matched controls. All patients were screened for the presence of secondary hypertension and were further characterized by ambulatory blood pressure measurements performed in 295 treated and 184 untreated patients. Genotype distribution for the
Gβ3
-C825T genotype in patients (
CC
=204,
CT
=224,
TT
=51) was significantly different from that in controls (
CC
=514,
CT
=412,
TT
=74; χ
2
=11.5,
P
<0.01), and the T allele was associated with an odds ratio of 1.5 (95% CI, 1.1 to 2.2) versus non-T carriers for the presence of hypertension. However, in both the whole group and the untreated subgroup, blood pressure levels between the genotypic groups were virtually identical. Furthermore, age of onset of hypertension and number of antihypertensive medications (in treated patients) were similar between the genotypic groups. Thus, while our data confirm the association between the
Gβ3
-C825T variant and essential hypertension, they do not support the hypothesis that this marker is associated with more severe blood pressure in patients with already established hypertension.
Angiotensin AT
1
Receptor Subtype as a Cardiac Target of Aldosterone
Authors: Robert Valérie , Heymes Christophe , Silvestre Jean-Sébastien , Sabri Abdelkarim , Swynghedauw Bernard , Delcayre Claude
Published: June 2012

Abstract
—This study tests the hypothesis that aldosterone induces cardiac fibrosis through an increase of cardiac angiotensin II (Ang II) AT
1
receptor levels, thereby potentiating the fibrotic effect of Ang II by determining the effects of spironolactone and losartan on cardiac fibrosis, AT
1
density, and gene expression in aldosterone-salt–treated rats. Fibrosis was quantified by slot blots of collagen I and III mRNA levels and videomorphometry of Sirius red–stained collagen. AT
1
receptor density was determined by (
125
I-Sar
1
-Ile
8
)–Ang II competition binding, and AT
1
mRNA levels were analyzed by quantitative reverse transcriptase polymerase chain reaction. One month of aldosterone-salt treatment induced a decrease in plasma Ang II and an increase in blood pressure, left ventricular hypertrophy, and ventricular fibrosis. Spironolactone (20 mg/kg per day) and losartan spironolactone (10 mg/kg per day) had no effect on the first 3 parameters. Losartan was as effective as spironolactone in preventing ventricular collagen mRNA increase and fibrosis. Ventricular density of AT
1
receptors increased 2-fold and was accompanied by a 3-fold increase in the corresponding mRNA in aldosterone-salt compared with sham-operated rats. Both spironolactone and losartan prevented the elevation of ventricular AT
1
density and that of right ventricular AT
1
mRNA levels. These results demonstrate that the mechanism by which aldosterone-salt induces cardiac fibrosis involves Ang II acting through AT
1
receptors. They also suggest that the cardiac AT
1
receptor is a target for aldosterone.
Effect of Magnesium Deficiency on Blood Pressure and Mechanical Properties of Rat Carotid Artery
Authors: Laurant Pascal , Hayoz Daniel , Brunner Hans R. , Berthelot Alain
Published: June 2012

Abstract
—The purpose of this study was to determine the effect of dietary Mg deficiency (80 mg/kg versus control diet: 960 mg/kg) on blood pressure and mechanical properties of the rat common carotid artery. The internal diameter and intra-arterial pressure of carotid artery were measured continuously with an echo-tracking device. At 19 weeks, systolic, diastolic, and mean blood pressures were higher in Mg-deficient rats. Histological examination showed an increase in cross-sectional area, intima-media thickness, and media-to-lumen ratio in carotid artery of Mg-deficient rats. Mg deficiency did not modify the arterial distensibility–blood pressure curve. At mean blood pressure, arterial distensibility was significantly less in 19-week-old rats than in 5-week-old rats of both control and Mg-deficient groups. A significant interaction between age and Mg-deficient diet on arterial distensibility (
P
<0.04) indicates an accelerated age-dependent decreased arterial distensibility with Mg deficiency. At 19 weeks, the artery was stiffer in hypertensive Mg-deficient rats, as illustrated by a shift to higher levels of the incremental elastic modulus–stress curve. In conclusion, the increased blood pressure and the vascular morphological alterations observed in Mg-deficient rats may contribute to an accelerated alteration of the wall material, which in turn leads to a stiffening of the carotid artery.
Diabetes and Cardiovascular Events in Hypertensive Patients
Authors: Alderman Michael H. , Cohen Hillel , Madhavan Shantha
Published: June 2012

Abstract
—To determine the relation of self-reported history of diabetes as well as baseline and in-treatment blood sugar to subsequent cardiovascular disease (CVD) in treated hypertensive patients, we assessed the experience of 6886 participants in a systematic treatment program. The presence or absence of a history of diabetes was known for all patients, who were then stratified into 3 groups according to blood sugar at baseline and in treatment (<6.11, 6.11 to 7.74, and ≥7.75 mmol/L). Some 7.4% of all patients reported history of diabetes, and the overall prevalence of blood sugar ≥7.75 mmol/L was 7.7% and 10.4% at baseline and in treatment, respectively. Patients with a history of diabetes were 10 or 8 times as likely to have blood sugar ≥7.75 mmol/L at baseline (47.2% versus 4.5%) or in treatment (55.0% versus 6.8%), as were patients without history. During an average 6.3 years of follow-up, patients with history of diabetes had a cardiovascular event incidence 2-fold higher than those without history (20.8 versus 8.6/1000 person-years). Age-gender–adjusted CVD incidence rate but not non-CVD was twice as high in the highest compared with the lowest blood sugar stratum (baseline 16.6 versus 8.4/1000 person-years; in treatment 15.2 versus 8.2). Three separate models of Cox multivariate analysis revealed that history of diabetes (with no history as reference) had a greater association with CVD events (hazard ratio 2.37, 95% confidence interval 1.80 to 3.11) than did baseline (1.75, 1.31 to 2.33) or in-treatment blood sugar (1.55, 1.19 to 2.02). Furthermore, in the presence of history of diabetes (2.15, 1.58 to 2.92), neither baseline nor in-treatment blood sugar was independently associated with CVD risk. In the elevated (≥7.75 mmol/L) in-treatment blood sugar group, the age-gender–adjusted rate of CVD events in frequent diuretic users (30.79/1000 person-years) was significantly higher than in moderate (13.34,
P
=0.004) and rare users (13.25,
P
=0.008). These data affirm that the coincidence of diabetes and hypertension is common, that evidence of diabetes substantially increases CVD risk, that self-reported history is a more powerful predictor of CVD events than any measure of blood sugar, and that CVD increases in hypertensive diuretic users who develop hyperglycemia even when blood pressure is well controlled.
11β-Hydroxysteroid Dehydrogenase in Cultured Human Vascular Cells
Authors: Hatakeyama Haruhiko , Inaba Satoru , Miyamori Isamu
Published: June 2012

Abstract
—11β-Hydroxysteroid dehydrogenases (11β-HSD) interconvert cortisol, the physiological glucocorticoid, and its inactive metabolite cortisone in humans. The diminished dehydrogenase activity (cortisol to cortisone) has been demonstrated in patients with essential hypertension and in resistance vessels of genetically hypertensive rats. 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) catalyzes only 11β-dehydrogenation. However, a functional relationship between diminished vascular 11β-HSD2 activity and elevated blood pressure has been unclear. In this study we showed the expression and enzyme activity of 11β-HSD2 and 11β-HSD type 1 (which is mainly oxoreductase, converting cortisone to cortisol) in human vascular smooth muscle cells. Glucocorticoids and mineralocorticoids increase vascular tone by upregulating the receptors of pressor hormones such as angiotensin II. We found that physiological concentrations of cortisol-induced increase in angiotensin II binding were significantly enhanced by the inhibition of 11β-HSD2 activity with an antisense DNA complementary to 11β-HSD2 mRNA, and the enhancement was partially but significantly abolished by a selective aldosterone receptor antagonist. This may indicate that impaired 11β-HSD2 activity in vascular wall results in increased vascular tone by the contribution of cortisol, which acts as a mineralocorticoid. In congenital 11β-HSD deficiency and after administration of 11β-HSD inhibitors, suppression of 11β-HSD2 activity in the kidney has been believed to cause renal mineralocorticoid excess, resulting in sodium retention and hypertension. In the present study we provide evidence for a mechanism that could link impaired vascular 11β-HSD2 activity, increased vascular tone, and elevated blood pressure without invoking renal sodium retention.
Estradiol With or Without Progesterone and Ambulatory Blood Pressure in Postmenopausal Women
Authors: Seely Ellen W. , Walsh Brian W. , Gerhard Marie D. , Williams Gordon H.
Published: June 2012

Abstract
—The purpose of this study was to determine whether transdermal estradiol and intravaginal progesterone given in doses to mimic the premenopausal state would lower blood pressure (BP) in postmenopausal women. Fifteen healthy postmenopausal women were studied in each of 3 conditions: on placebo, after 8 weeks of transdermal estradiol 0.2 mg twice per week, and again 2 weeks after addition of intravaginal progesterone 300 mg/d. Women were studied at each point after 2 days of 100 mmol/d sodium intake. Twenty-four–hour ambulatory BP monitoring was performed, and blood was assayed for estradiol, progesterone, and hormones of the renin-angiotensin-aldosterone system (RAAS). ANOVA with pairwise comparisons was used for analysis. Urinary sodium excretion was similar at each time point. Levels of estrogen and progesterone similar to those in premenopausal women were achieved. On estradiol, nocturnal systolic BP (110±3 mm Hg), diastolic BP (63±2 mm Hg), and mean BP (77±2 mm Hg) fell significantly (
P
<0.02) compared with placebo systolic BP (116±2 mm Hg), diastolic BP (68±2 mm Hg), and mean BP (82±2 mm Hg). Daytime BP followed the same trend but was significantly lower only for mean BP. There was no activation of the RAAS. The addition of progesterone resulted in no further fall in BP but a significant activation of the RAAS. Thus, contrary to what is often assumed, administration of estradiol with or without progesterone not only did not raise BP but rather substantially lowered BP. This BP-lowering effect may be responsible for the lower incidence of hypertension in premenopausal than in postmenopausal women.
Seven Lessons From Two Candidate Genes in Human Essential Hypertension
Authors: Corvol Pierre , Persu Alexandre , Gimenez-Roqueplo Anne-Paule , Jeunemaitre Xavier
Published: June 2012

Abstract
—The candidate gene approach to understanding the genetics of human essential hypertension is discussed by analyzing the contribution of 2 genes, angiotensinogen (AGT) and epithelial amiloride-sensitive sodium channel (ENaC). From a large series of studies conducted in humans and animals, it appears that the AGT gene plays a significant but modest role in human blood pressure variance. Mutations of the β- and γ-ENaC subunits are responsible for Liddle’s syndrome, but the implication of the 3 ENaC subunits in essential hypertension is still questionable. Several lessons can be learned from these studies and applied to other candidate genes in essential hypertension: (1) Many linkage or association studies have a limited statistical power; (2) The genetic findings may vary greatly according to the populations studied; (3) There is a need for better phenotyping of the hypertensive population; (4) The causal relationship between molecular variants and hypertension is and will be difficult to establish firmly; (5) The contribution of genetic studied in rodents to the molecular genetics of human hypertension must be re-examined; (6) Most molecular variants lead to a low attributable risk in the population or a low individual effect at the individual level; and (7) It is too early to propose dietary recommendations and specific drug treatment according to patients’ genotypes.
Factor V Leiden and Thermolabile Methylenetetrahydrofolate Reductase Gene Variants in an East Anglian Preeclampsia Cohort
Authors: O’Shaughnessy Kevin M. , Fu Beiyuan , Ferraro Franco , Lewis Ian , Downing Sarah , Morris Nick H.
Published: June 2012

Abstract
—Preeclampsia is a heritable condition that develops as a result of widespread vascular endothelial dysfunction. The thrombotic tendency in this condition has suggested a number of candidate genes, and there have been recent reports of positive association with the Leiden variant of factor V and the thermolabile variant of methylenetetrahydrofolate reductase. We attempted to reproduce these results in a large cohort of well-characterized women with preeclampsia, recruited prospectively within the East Anglian region of the United Kingdom. Women in the preeclampsia cohort (n=283) were genotyped for both the Leiden variant (G1691A) of factor V and the thermolabile variant (C677T) of methylenetetrahydrofolate reductase. Genotype and allele frequencies were compared with those of 2 control groups, one consisting of women recruited prospectively (n=100) from the same maternity hospital as the subjects and another consisting of normotensive women (n=100) from East Anglia. No significant differences were detected. Specifically, the carrier rate for the Leiden variant was 5.3% in the preeclampsia group and 5.5% in the combined control group. T677 homozygotes for methylenetetrahydrofolate reductase were 11% and 11.5% in the 2 groups, respectively. We conclude that there is no evidence of association of preeclampsia with either of these 2 polymorphisms in our study population.
Variable Renal Atrial Natriuretic Factor Gene Expression in Hypertension
Authors: Ogawa Tsuneo , Linz Wolfgang , Schölkens Bernward A. , de Bold Adolfo J.
Published: June 2012

Abstract
—We have previously established the existence of atrial natriuretic factor (ANF) gene expression within the renal parenchyma. Neither the role nor the regulation of this extracardiac source of ANF is clearly defined. To determine whether renal ANF gene expression, similar to cardiac expression, is linked to the activity of the renin-angiotensin system (RAS), we compared renal ANF gene expression in rats after suprarenal aortic banding, a hypertension model associated with activation of RAS, and in the deoxycorticosterone acetate (DOCA)–salt model, which is characterized by depression of RAS. Renal ANF mRNA was measured with a quantitative competitive reverse transcription polymerase chain reaction method. DOCA-salt hypertension significantly reduced the expression of renal ANF. In contrast, aortic banding significantly increased renal ANF expression. In both cases, ANF gene expression in the heart increased. Ramipril treatment at 10 μg/kg of aortic-banded rats, a treatment that specifically affects local RAS but maintains hypertension, normalized renal ANF mRNA levels. Altogether, these results suggest that renal ANF gene expression is modulated by local RAS and is independent of circulating RAS and hypertension per se. The marked decrease of renal ANF mRNA in DOCA-salt hypertension suggests a pathogenic role for renal ANF gene downregulation by decreasing the sodium excretory mechanism mediated by the local expression of ANF acting on receptors found in the inner medullary collecting ducts. In aortic banding, renal ANF gene expression upregulation suggests a local compensatory function consistent with the consensus role of natriuretic peptides in the modulation of RAS, thus ameliorating the sodium-retaining effects of renal underperfusion.
Age-Related Abnormalities in Arterial Compliance Identified by Pressure Pulse Contour Analysis
Authors: McVeigh Gary E. , Bratteli Christopher W. , Morgan Dennis J. , Alinder Cheryl M. , Glasser Stephen P. , Finkelstein Stanley M. , Cohn Jay N.
Published: June 2012

Abstract
—The objective of this study was to evaluate age-related changes in pulsatile arterial function. Aging alters arterial pulsatile function and produces consistent changes in the pressure pulse contour. A reduced systemic arterial compliance that can be derived from analysis of the pulse contour is regarded as the best clinical index of impaired pulsatile arterial function and may mark the presence of early vascular damage. We analyzed intra-arterial brachial artery waveforms in 115 healthy normotensive volunteers (83 men, 32 women) and radial artery waveforms obtained with the use of a calibrated tonometer device in 212 healthy volunteers (147 women, 65 men). A computer-based assessment of the diastolic pressure decay and a modified Windkessel model of the circulation were used to quantify changes in arterial waveform morphology in terms of large artery or capacitive compliance, oscillatory or reflective compliance in the small arteries, inertance, and systemic vascular resistance. Large artery compliance and oscillatory compliance correlated negatively with age for both invasive and noninvasive groups (
r
=−0.50 and
r
=−0.55;
r
=−0.37 and
r
=−0.66;
P
<0.001 for all). The slopes of the regression lines for the decline in oscillatory compliance with age were significantly steeper than those recorded for large artery compliance estimates. The change in blood pressure with age independently contributed to the decrease in large artery compliance but not oscillatory compliance in both groups. Consistent age-related changes were found in the pressure pulse contour by analysis of waveforms obtained invasively or noninvasively from the upper limb. The change in the oscillatory or reflective compliance estimate was independent of blood pressure change and may represent a better marker than large artery or capacitive compliance of the degenerative aging process in altering pulsatile arterial function.
Bradykinin Stimulates Tissue Plasminogen Activator Release in Human Vasculature
Authors: Brown Nancy J. , Gainer James V. , Stein C. Michael , Vaughan Douglas E.
Published: June 2012

Abstract
—Bradykinin stimulates tissue plasminogen activator (tPA) release in isolated perfused animal tissues. The present study tests the hypothesis that bradykinin increases tPA release in humans through local effects on the vasculature. Graded doses of sodium nitroprusside (0.8 to 3.2 μg/min), acetylcholine (ACh) (7.5 to 60 μg/min), and bradykinin (100 to 400 ng/min) were administered intra-arterially in random order in 10 salt-depleted (10 mmol/d of Na) normotensive volunteers. None of the drugs altered mean arterial pressure or heart rate. Forearm blood flow (FBF) was measured by strain-gauge plethysmography. All 3 drugs caused a dose-dependent increase in FBF, although ACh was less potent than either nitroprusside or bradykinin (maximum FBF 7.5±2.4 versus 10.0±1.5 and 11.9±2.1 mL · 100 mL
−1
· min
−1
, respectively). Bradykinin caused a significant, dose-dependent increase in venous (effect of dose F=9.9,
P
=0.028 by ANOVA), but not arterial (F=0.154,
P
=0.92) tPA antigen in the infused arm. Thus, net tPA release increased significantly in response to bradykinin (50.6±13.3 at the highest dose versus 0.9±0.4 ng · 100 mL
−1
· min
−1
at baseline,
P
=0.014). In contrast, bradykinin did not affect plasminogen activator inhibitor antigen. Neither nitroprusside nor ACh altered plasma levels of tPA or plasminogen activator inhibitor antigen. Bradykinin increased tPA release across the forearm in the absence of systemic effects. This effect could not be attributed to changes in blood flow because doses of equivalent potency of the vasodilator nitroprusside did not increase tPA. These data demonstrate that bradykinin stimulates tPA release in the human vasculature.
Brain Renin-Angiotensin System and Ouabain-Induced Sympathetic Hyperactivity and Hypertension in Wistar Rats
Authors: Huang Bing S. , Leenen Frans H. H.
Published: June 2012

Abstract
—In Dahl salt-sensitive rats on a high salt diet or normotensive rats with chronic central infusion of sodium, increased brain “ouabain” results in sympathetic hyperactivity and hypertension, possibly by activating the brain renin-angiotensin system. In the present study, we tested whether the hypertension caused by exogenous ouabain also depends on activation of brain renin-angiotensin system. In Wistar rats, ouabain (50 μg/d) was infused subcutaneously for 14 days with the use of osmotic minipumps. Concomitantly, in one group, the angiotensin II type 1 receptor blocker losartan (1 mg/kg per day) was infused intracerebroventricularly. On day 15, mean arterial pressure, heart rate, central venous pressure, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, intracerebroventricular injection of the α
2
-agonist guanabenz (25 and 75 μg) or angiotensin II (30 ng), acute volume expansion, and ramp changes of blood pressure by ±50 mm Hg with phenylephrine and nitroprusside. Compared with control rats, in rats treated with ouabain, resting mean arterial pressure was significantly increased (111±4 versus 93±3 mm Hg;
P
<0.05), and increases or decreases in mean arterial pressure, heart rate, and renal sympathetic nerve activity in response to air stress or guanabenz were enhanced significantly. These effects of ouabain were prevented when losartan was given concomitantly. Maximal slopes of arterial baroreflex control of renal sympathetic nerve activity and heart rate tended to be decreased in ouabain-treated versus control rats and were significantly increased in ouabain-treated rats with versus without losartan. No differences in cardiopulmonary baroreflex function were detected. It seems that by day 14 to 15, the central effect of ouabain on baroreflex control prevails over its peripheral sensitizing effect on baroreceptors, leading to a tendency of desensitization. These results indicate that chronic administration of ouabain activates the brain renin-angiotensin system, resulting in decreased sympathoinhibition and increased sympathoexcitation, impairment of baroreflex function, and hypertension.
Endothelium-Derived Contracting Factor in Carotid Artery of Hypertensive Dahl Rats
Authors: Zhou Ming-Sheng , Nishida Yasuhiro , Chen Qing-Hui , Kosaka Hiroaki
Published: June 2012

Abstract
—The present study is designed to investigate whether acetylcholine (ACh) elicits an endothelium-derived contracting factor (EDCF) and whether it contributes to decreased relaxant response induced by ACh in Dahl rats. Dahl salt-sensitive (DS) and -resistant (DR) rats were fed a 0.4% NaCl or an 8% NaCl diet for 4 weeks. High sodium intake significantly increased blood pressure in DS rats but not in DR rats. The carotid rings were suspended for isometric tension recording. ACh caused an endothelium-dependent contraction in carotid rings from hypertensive DS rats but not from normotensive Dahl rats. Atropine, indomethacin, SQ29548, or ONO-3708 (prostaglandin H
2
[PGH
2
]/thromboxane A
2
[TXA
2
] receptor antagonist) abolished ACh-induced contraction, and OKY-046 (inhibitor of TXA
2
synthetase) partially attenuated the contraction. High sodium intake significantly enhanced contraction evoked by U46619, a PGH
2
/TXA
2
receptor agonist, in both DS and DR rats. In contrast, ACh-induced relaxation was significantly depressed in the rings from hypertensive DS rats, and ONO-3708 partially improved the depressed relaxation. Administration of ONO-8809 (an orally active PGH
2
/TXA
2
receptor antagonist; 30 μg per body per day) for 4 weeks neither reduced blood pressure nor improved the depressed ACh-induced relaxation in hypertensive DS rats. These results suggest that ACh causes release of EDCF in carotid rings of hypertensive DS rats, which is likely to be PGH
2
and TXA
2
. The EDCF contributed in part to the depressed ACh-induced relaxation.
Effects of Glutathione on Red Blood Cell Intracellular Magnesium
Authors: Barbagallo Mario , Dominguez Ligia J. , Tagliamonte Maria Rosaria , Resnick Lawrence M. , Paolisso Giuseppe
Published: June 2012

Abstract
—Recent evidence suggests that the endogenous antioxidant glutathione may play a protective role in cardiovascular disease. To directly investigate the role of glutathione in the regulation of glucose metabolism in hypertension, we studied the acute effects of in vivo infusions of this antioxidant (alone or in combination with insulin) on whole body glucose disposal (WBGD) using euglycemic glucose clamp and the effects on total red blood cell intracellular magnesium (RBC-Mg) in hypertensive (n=20) and normotensive (n=30) subjects. The relationships among WBGD, circulating reduced/oxidized glutathione (GSH/GSSG) levels, and RBC-Mg in both groups were evaluated. The in vitro effects of glutathione (100 μmol/L) on RBC free cytosolic magnesium (Mg
i
) were also studied. In vivo infusions of glutathione (15 mg/min×120 minutes) increased RBC-Mg in both normotensives and hypertensives (1.99±0.02 to 2.13±0.03 mmol/L,
P
<0.01, and 1.69±0.03 to 1.81±0.03 mmol/L,
P
<0.01, respectively). In vitro GSH but not GSSG increased Mg
i
(179±3 to 214±5 μmol/L,
P
<0.01). In basal conditions, RBC-Mg values were related to GSH/GSSG ratios (
r
=0.84,
P
<0.0001), and WBGD was directly, significantly, and independently related to both GSH/GSSG ratios (
r
=0.79,
P
<0.0001) and RBC-Mg (
r
=0.89,
P
<0.0001). This was also true when hypertensive and control groups were analyzed separately. On multivariate analysis, basal RBC-Mg (
t
=6.81,
P
<0.001), GSH/GSSG (
t
=3.67,
P
<0.02), and blood pressure (
t
=2.89,
P
<0.05) were each independent determinants of WBGD, with RBC-Mg explaining 31% of the variability of WBGD. These data demonstrate a direct action of glutathione both in vivo and in vitro to enhance intracellular magnesium and a clinical linkage between cellular magnesium, GSH/GSSG ratios, and tissue glucose metabolism.
Association of the G
s
α Gene With Essential Hypertension and Response to β-Blockade
Authors: Jia Haiyan , Hingorani Aroon D. , Sharma Pankaj , Hopper Ruth , Dickerson Claire , Trutwein Debra , Lloyd Deborah D. , Brown Morris J.
Published: June 2012

Abstract
—We examined whether the GNAS1 locus, encoding the G
s
protein α-subunit (G
s
α), is implicated in the genetic causes of essential hypertension. A common silent polymorphism (ATT→ATC, Ile
131
) was identified in exon 5 of the G
s
α gene by single-strand conformation polymorphism analysis and DNA sequencing. This polymorphism consists of the presence (+) or absence (−) of a restriction site for
Fok
I. Only 1 other rare allele was found in the coding region; the high GC content of the 5′ noncoding sequence prevented mutation scanning of the promoter region of the gene. There was a significant difference in frequency of the
Fok
I alleles between 268 white hypertensives (
Fok
I+:
Fok
I−, 51%:49%) and a matched group of 231 control subjects (
Fok
I+:
Fok
I−, 58%:42%) (
P
=0.02). Multiple regression analysis showed that the
Fok
I genotype was independently related to the level of untreated systolic blood pressure in 294 well-characterized white hypertensives (
P
=0.01) but not in normotensives. The influence of the
Fok
I allele on blood pressure (BP) response to β-blockade was examined in 114 of the patients randomly assigned to this class of drug. Significant differences in frequency of the
Fok
I allele were observed in the good responders (
Fok
I+:
Fok
I−, 62.5%:37.5%, n=36) versus the poor responders (
Fok
I+:
Fok
I−, 41.7%:58.3%, n=30) after β-blocker therapy (
P
=0.02). In a multiple regression analysis, the G
s
α genotype was the only independent predictor of BP response. These results suggest that the
GNAS
1 locus might carry a functional variant that influences BP variation and response to β-blockade in essential hypertension.
Effect of Magnesium Deficiency on Autonomic Circulatory Regulation in Conscious Rats
Authors: Murasato Yoshinobu , Harada Yuji , Ikeda Masaharu , Nakashima Yasuhide , Hayashida Yoshiaki
Published: June 2012

Abstract
—A close relationship between magnesium and cardiovascular function has been reported; however, the effect of magnesium deficiency on autonomic cardiovascular regulation has not been clarified. We investigated the effect of magnesium deficiency on the autonomic regulation of oscillations of the R-R interval, arterial blood pressure (BP), and renal sympathetic nerve activity (RSNA) by using the maximum entropy method in conscious rats. Its effect on baroreflex control of RSNA and heart rate were also investigated with a logistic function curve. Mean BP in magnesium-deficient rats was higher than that in control rats (mean±SE, 114.0±4.3 versus 101.6±3.4 mm Hg;
P
<0.05), and urinary excretion of catecholamine was increased by 2.4-fold. The fraction of low-frequency oscillation of RSNA was reduced (31.7±0.9% versus 36.2±1.5%,
P
<0.05) and the correlation between low-frequency oscillations of BP and RSNA was weakened in magnesium-deficient rats. There was no difference in high-frequency oscillation of the R-R interval, which is related to vagal tone, whereas sympathetic tone became dominant (square root of low-frequency/high-frequency ratio of R-R interval, 1.00±0.05 versus 0.67±0.05,
P
<0.0001) in magnesium-deficient rats. The maximal gain in the BP-RSNA relation tended to be reduced in magnesium-deficient rats (−7.7±1.1% versus −12.2±1.9%/mm Hg,
P
=0.07); however, that in the BP–heart rate relation was increased (−8.1±0.7 versus −4.5±0.5 bpm/mm Hg,
P
<0.01). These results suggest that magnesium deficiency induces sympathetic excitation, which results in hypertension but attenuates the baroreflex-related response of sympathetic nerves, whereas magnesium deficiency enhances the sensitivity of the sinus node to autonomic regulation.
Docosahexaenoic Acid but Not Eicosapentaenoic Acid Lowers Ambulatory Blood Pressure and Heart Rate in Humans
Authors: Mori Trevor A. , Bao Danny Q. , Burke Valerie , Puddey Ian B. , Beilin Lawrence J.
Published: June 2012

Abstract
—Animal studies suggest that the 2 major ω3 fatty acids found in fish, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have differential effects on blood pressure (BP) and heart rate (HR). The aim of this study was to determine whether there were significant differences in the effects of purified EPA or DHA on ambulatory BP and HR in humans. In a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to 4 g/d of purified EPA, DHA, or olive oil (placebo) capsules and continued their usual diets for 6 weeks. Fifty-six subjects completed the study. Only DHA reduced 24-hour and daytime (awake) ambulatory BP (
P
<0.05). Relative to the placebo group, 24-hour BP fell 5.8/3.3 (systolic/diastolic) mm Hg and daytime BP fell 3.5/2.0 mm Hg with DHA. DHA also significantly reduced 24-hour, daytime, and nighttime (asleep) ambulatory HRs (
P
=0.001). Relative to the placebo group, DHA reduced 24-hour HR by 3.5±0.8 bpm, daytime HR by 3.7±1.2 bpm, and nighttime HR by 2.8±1.2. EPA had no significant effect on ambulatory BP or HR. Supplementation with EPA increased plasma phospholipid EPA from 1.66±0.07% to 9.83±0.06% (
P
<0.0001) but did not change DHA levels. Purified DHA capsules increased plasma phospholipid DHA levels from 4.00±0.27% to 10.93±0.62% (
P
<0.0001) and led to a small, nonsignificant increase in EPA (1.52±0.12% to 2.26±0.16%). Purified DHA but not EPA reduced ambulatory BP and HR in mildly hyperlipidemic men. The results of this study suggest that DHA is the principal ω3 fatty acid in fish and fish oils that is responsible for their BP- and HR-lowering effects in humans. These results have important implications for human nutrition and the food industry.
Comparative Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Antagonism on Plasma Fibrinolytic Balance in Humans
Authors: Brown Nancy J. , Agirbasli Mehmet , Vaughan Douglas E.
Published: June 2012

Abstract
—Angiotensin-converting enzyme (ACE) inhibition significantly decreases plasminogen activator inhibitor-1 (PAI-1) without altering tissue plasminogen activator (tPA) during activation of the renin-angiotensin-aldosterone system in humans. Because ACE inhibitors and angiotensin II type 1 (AT
1
) receptor antagonists differ in their effects on angiotensin II formation and bradykinin degradation, the present study compared the effect of equivalent hypotensive doses of an ACE inhibitor and AT
1
antagonist on fibrinolytic balance. Plasma PAI-1 antigen, tPA antigen, plasma renin activity, and aldosterone were measured in 25 normotensive subjects (19 white, 6 black; 14 men, 11 women; mean age 38.5±1.8 years; mean body mass index 25.3±0.7 kg/m
2
) during low salt intake alone (10 mmol Na/d), low salt intake + quinapril (40 mg PO bid), and low salt intake + losartan (50 mg PO bid). Compared with low salt alone (systolic blood pressure [BP] 118.8±2.2 mm Hg), both quinapril (106.3±2.5 mm Hg,
P
<0.001) and losartan (105.4±2.8 mm Hg,
P
<0.001) reduced BP. No statistical difference was found between quinapril and losartan in their BP lowering effect. Losartan (
P
=0.009), but not quinapril, lowered heart rate. Both drugs significantly lowered aldosterone (
P
<0.001 versus low salt alone for each); however, this effect was significantly greater for quinapril than for losartan (
P
<0.001 for quinapril versus losartan). Treatment with quinapril, but not with losartan, was associated with a decrease in both PAI-1 antigen (
P
=0.03) and activity (
P
=0.018). PAI-1 activity was lower during treatment with quinapril than with losartan (
P
=0.015). The average PAI-1 antigen concentration was 13.0±2.0 ng/mL during low salt alone, 10.5±1.6 ng/mL during quinapril treatment, and 12.3±2.1 ng/mL during losartan treatment. In contrast, plasma tPA antigen concentrations were reduced during treatment with losartan (
P
=0.03) but not with quinapril. This study provides the first evidence that ACE inhibitors and AT
1
antagonists differ in their effects on fibrinolytic balance under conditions of activation of the renin-angiotensin-aldosterone system. Further studies are needed to address the mechanism for the contrasting effects of these 2 classes of drugs on fibrinolysis and to define the clinical significance of these differences.
Isolated Systolic Hypertension
Authors: Domanski Michael J. , Davis Barry R. , Pfeffer Marc A. , Kastantin Mark , Mitchell Gary F.
Published: June 2012

Abstract
—Increased arterial stiffness results in increased characteristic impedance of the aorta and increased pulse wave velocity, which increases systolic and pulse pressures. An association between increased pulse pressure and adverse cardiovascular events has been found in normotensive and hypertensive patient populations. Increased pulse pressure has also been associated with thickening of the carotid intima and media. However, the relationship between pulse pressure and stroke has not previously been evaluated. In this study, we examined the hypothesis that pulse pressure is an independent predictor of stroke in elderly patients with systolic hypertension entered in the Systolic Hypertension in the Elderly Program. Differences in baseline characteristics were examined by tertiles of pulse pressure. The independent prognostic value of pulse pressure and mean arterial pressure for predicting either stroke or total mortality was assessed with Cox proportional hazards models that included pulse pressure, mean arterial pressure, and other variables that were significant on univariate analysis. This analysis demonstrated an 11% increase in stroke risk and a 16% increase in risk of all-cause mortality for each 10-mm Hg increase in pulse pressure. Each 10-mm Hg increase in mean arterial pressure was independently associated with a 20% increase in the risk of stroke and a 14% increase in the risk of all-cause mortality. These data provide strong evidence of an association of increased conduit vessel stiffness, as indicated by increased pulse pressure, with stroke and total mortality, independent of the effects of mean arterial pressure, in elderly patients with isolated systolic hypertension.
Differential Impact of Systolic and Diastolic Blood Pressure Level on JNC-VI Staging
Authors: Lloyd-Jones Donald M. , Evans Jane C. , Larson Martin G. , O’Donnell Christopher J. , Levy Daniel
Published: June 2012

Abstract
—The sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure classifies blood pressure into stages on the basis of both systolic (SBP) and diastolic (DBP) blood pressure levels. When a disparity exists between SBP and DBP stages, patients are classified into the higher stage (“up-staged”). We evaluated the effect of disparate levels of SBP and DBP on blood pressure staging and eligibility for therapy. We examined 4962 Framingham Heart Study subjects between 1990 and 1995 and determined blood pressure stages on the basis of SBP alone, DBP alone, or both. After the exclusion of subjects on antihypertensive therapy (n=1306), 3656 subjects (mean age 58±13 years; 55% women) were eligible. In this sample, 64.6% of subjects had congruent stages of SBP and DBP, 31.6% were up-staged on the basis of SBP, and 3.8% on the basis of DBP; thus, SBP alone correctly classified JNC-VI stage in ≈96% (64.6%+31.6%) of the subjects. Among subjects >60 years of age, SBP alone correctly classified 99% of subjects; in those ≤60 years old, SBP alone correctly classified 95%. Of 1488 subjects with high-normal blood pressure or hypertension, who were potentially eligible for drug therapy, 13.0% had congruent elevations of SBP and DBP, 77.7% were up-staged on the basis of SBP, and 9.3% were up-staged on the basis of DBP; SBP alone correctly classified 91%, whereas DBP alone correctly classified only 22%. SBP elevation out of proportion to DBP is common in middle-aged and older persons. SBP appears to play a greater role in the determination of JNC-VI blood pressure stage and eligibility for therapy. Given these results, combined with evidence from hypertension treatment trials, future guidelines might consider a greater role for SBP than for DBP in determining the presence of hypertension, risk of cardiovascular events, eligibility for therapy, and benefits of treatment.