bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanics and Composition of Human Subcutaneous Resistance Arteries in Essential Hypertension
Authors: Intengan Hope D. , Deng Li Y. , Li Jin S. , Schiffrin Ernesto L.
Published: June 2012

Abstract
—Mechanical properties of arteries are altered in some rat models of hypertension, and this may influence peripheral resistance and blood pressure as well as some of the complications of hypertension. It has usually been assumed that arterial wall stiffness is increased in hypertension, although recent studies suggest that this may not necessarily be the case in large arteries. We determined whether the mechanics of human resistance arteries are altered in hypertension. Subcutaneous resistance arteries (lumen diameter<300 μm) were isolated from hypertensive and normotensive subjects of similar ages (46±3 and 43±4 years, respectively). Vessels were mounted in a pressurized myograph, deactivated, and exposed to intraluminal pressures ranging from 3 to 140 mm Hg. At each pressure, lumen and media dimensions were measured. Media-to-lumen ratio and media width were greater in hypertensive vessels, reducing wall stress (
P
<0.01), whereas media cross section was similar in vessels from both groups. Isobaric elastic modulus (which is influenced by vessel geometry and by wall component stiffness) was lower in hypertensive vessels (
P
<0.01). Stiffness of wall components (slope of incremental elastic modulus versus stress, which is geometry-independent) was significantly lower in hypertensive vessels (8.2±0.7) versus normotensive vessels (11.0±1.0,
P
<0.05), whereas distensibility was unchanged. Electron microscopic analysis of the media of the small arteries showed a greater collagen to elastin ratio (
P
<0.05) in the media of vessels from hypertensive patients. In conclusion, the stiffness of wall components (slope of elastic modulus versus stress) is not increased but is in fact decreased in subcutaneous resistance arteries from patients with mild essential hypertension. Reduced stiffness of resistance arteries from hypertensive patients does not appear to relate to changes in volume density of extracellular matrix components but may be the result of changes in extracellular matrix architecture or cell-matrix attachment, which remains to be established.
Systemic Blockade of the Endothelin-B Receptor Increases Peripheral Vascular Resistance in Healthy Men
Authors: Strachan Fiona E. , Spratt James C. , Wilkinson Ian B. , Johnston Neil R. , Gray Gillian A. , Webb David J.
Published: June 2012

Abstract
—Endothelin-1 (ET-1) is an important mediator of vascular tone in humans, and a number of endothelin receptor antagonists are currently in clinical development as vasodilator agents. While the vasoconstrictor role of the ET
A
receptor is undisputed, the role of the ET
B
receptor remains unclear. Hemodynamic effects of systemic doses of the ET
B
-selective antagonist BQ-788 were investigated in 5 healthy male volunteers (age range, 33 to 48 years) in a placebo-controlled, four-way crossover study. After a 15-minute infusion of BQ-788 (3, 30, or 300 nmol/min) or placebo, plasma ET-1 and big ET-1, blood pressure, heart rate, cardiac index, and stroke index were measured. Total peripheral vascular resistance was calculated from cardiac index and mean arterial pressure. Hemodynamic data are expressed as maximum, placebo-corrected, percentage change from baseline following BQ-788 (300 nmol/min) and were examined by ANOVA. Plasma ET-1 increased by 3.7±1.2 pg/mL (maximum at 15 minutes,
P
=0.02), whereas there was no significant change in plasma big ET-1. Although BQ-788 had no effect on mean arterial pressure, there was a reduction in heart rate (13±7% at 50 minutes;
P
=0.002), cardiac index (17±5% at 40 minutes;
P
<0.0001), and stroke index (8±4% at 40 minutes;
P
=0.002) and an increase in total peripheral vascular resistance (24±5% at 40 minutes;
P
<0.0001). The selective ET
B
receptor antagonist BQ-788 causes peripheral vasoconstriction in healthy volunteers, suggesting that the overall balance of effects of endogenous ET-1 at the vascular ET
B
receptor favors vasodilatation. Further investigation is now clearly required to address whether selective ET
A
or combined ET
A
/ET
B
receptor blockade will be more effective in the clinical setting.
Hypertension and Arsenic Exposure in Bangladesh
Authors: Rahman Mahfuzar , Tondel Martin , Ahmad S. Akhtar , Chowdhury Ireen Akhter , Faruquee Mohammad Hossain , Axelson Olav
Published: June 2012

Abstract
—A prevalence comparison of hypertension among subjects with and those without arsenic exposure through drinking water was conducted in Bangladesh to confirm or refute an earlier observation of a relation in this respect. Wells with and without present arsenic contamination were identified, and we interviewed and examined 1595 subjects who were depending on drinking water from these wells for living, all ≥30 years of age. The interview was based on a questionnaire, and arsenic exposure was estimated from the history of well-water consumption and current arsenic levels. Of the 1595 subjects studied, 1481 had a history of arsenic-contaminated drinking water, whereas 114 had not. Time-weighted mean arsenic levels (in milligrams per liter) and milligram-years per liter of arsenic exposure were estimated for each subject. Exposure categories were assessed as <0.5 mg/L, 0.5 to 1.0 mg/L, and >1.0 mg/L and alternatively as <1.0 mg-y/L, 1.0 to 5.0 mg-y/L, >5.0 but ≤10.0 mg-y/L, and >10.0 mg-y/L, respectively. Hypertension was defined as a systolic blood pressure of ≥140 mm Hg in combination with a diastolic blood pressure of ≥90 mm Hg. Corresponding to the exposure categories, and using “unexposed” as the reference, the prevalence ratios for hypertension adjusted for age, sex, and body mass index were 1.2, 2.2, 2.5 and 0.8, 1.5, 2.2, 3.0, in relation to arsenic exposure in milligrams per liter and milligram-years per liter, respectively. The indicated dose-response relationships were significant (
P
≪0.001) for both series of risk estimates. These results suggest that arsenic exposure may induce hypertension in humans.
Renal Characteristics and Effect of Angiotensin Suppression in Oral Contraceptive Users
Authors: Ribstein Jean , Halimi Jean-Michel , du Cailar Guilhem , Mimran Albert
Published: June 2012

Abstract
—The determinants of the increase in arterial blood pressure associated with the use of estrogen-progestogen oral contraceptives (OC) remain poorly known. The purpose of this study was to assess the renal characteristics and the role of the renin-angiotensin system in women with OC-associated hypertension. Urinary clearances of technetium-labeled diethylene triaminopentaacetic acid (glomerular filtration rate) and
131
I-ortho iodohippurate (effective renal plasma flow) were estimated before and after acute administration of captopril in 38 women who became hypertensive while taking OC, 38 non-OC users with essential hypertension matched for age, body mass index, and level of blood pressure, and 38 normotensive women (19 with and 19 without OC). Plasma renin activity was higher in OC hypertensives when compared with those with essential hypertension, but captopril-induced changes in blood pressure and renal hemodynamics and function were similar in both groups. In addition, 24-hours urinary albumin excretion was increased in OC users when compared with nonusers with similar arterial blood pressure. In 13 hypertensive women followed up for 6 months after OC withdrawal, a decrease in plasma renin activity, blood pressure, and glomerular filtration rate but no significant change in urinary albumin excretion and captopril-induced changes in blood pressure and renal hemodynamics were observed. These results indicate that the use of OC is associated with an increased albuminuria and no evidence of a prominent role for the renin-angiotensin system in the maintenance of high blood pressure and renal hemodynamics when compared with non-OC users with essential hypertension.
Recent Progress in Angiotensin II Type 2 Receptor Research in the Cardiovascular System
Authors: Horiuchi Masatsugu , Akishita Masahiro , Dzau Victor J.
Published: June 2012

Abstract
—Angiotensin II (Ang II) plays an important role in regulating cardiovascular hemodynamics and structure. Multiple lines of evidence have suggested the existence of Ang II receptor subtypes, and at least 2 distinct receptor subtypes have been defined on the basis of their differential pharmacological and biochemical properties and designated as type 1 (AT
1
) and type 2 (AT
2
) receptors. To date, most of the known effects of Ang II in adult tissues are attributable to the AT
1
receptor. Recent cloning of the AT
2
receptor contributes to reveal its physiological functions, but many functions of the AT
2
receptor are still an enigma. AT
1
and AT
2
receptors belong to the 7-transmembrane, G protein–coupled receptor family. However, accumulating evidence demonstrates that the function and signaling mechanisms of these receptor subtypes are quite different, and these receptors may exert opposite effects in terms of cell growth and blood pressure regulation. We will review the role of the AT
2
receptor in the cardiovascular system and the molecular and cellular mechanisms of AT
2
receptor action.
Role of Nitric Oxide–cGMP Pathway in Adrenomedullin-Induced Vasodilation in the Rat
Authors: Hayakawa Hiroshi , Hirata Yasunobu , Kakoki Masao , Suzuki Yasuko , Nishimatsu Hiroaki , Nagata Daisuke , Suzuki Etsu , Kikuchi Kazuya , Nagano Tetsuo , Kangawa Kenji , Matsuo Hisayuki , Sugimoto Tsuneaki , Omata Masao
Published: June 2012

Abstract
—We previously reported that adrenomedullin (AM), a potent vasodilator peptide discovered in pheochromocytoma cells, stimulates nitric oxide (NO) release in the rat kidney. To further investigate whether the NO-cGMP pathway is involved in the mechanisms of AM-induced vasodilation, we examined the effects of E-4021, a cGMP-specific phosphodiesterase inhibitor, on AM-induced vasorelaxation in aortic rings and perfused kidneys isolated from Wistar rats. We also measured NO release from the kidneys using a chemiluminescence assay. AM (10
−10
to 10
−7
mol/L) relaxed the aorta precontracted with phenylephrine in a dose-dependent manner. Denudation of endothelium (E) attenuated the vasodilatory action of AM (10
−7
mol/L AM: intact (E+) −25.7±5.2% versus denuded (E−) −7.8±0.6%,
P
<0.05). On the other hand, pretreatment with 10
−8
mol/L E-4021 augmented AM-induced vasorelaxation in the intact aorta (−49.0±7.9%,
P
<0.05) but not in the denuded one. E-4021 also enhanced acetylcholine (ACh)-induced vasorelaxation in the rat intact aorta (10
−7
mol/L ACh −36.6±8.4% versus 10
−8
mol/L E-4021+10
−7
mol/L ACh −62.7±3.1%,
P
<0.05). In perfused kidneys, AM-induced vasorelaxation was also augmented by preincubation with E-4021 (10
−9
mol/L AM −15.4±0.6% versus 10
−8
mol/L E-4021+10
−9
mol/L AM −23.6±1.2%,
P
<0.01). AM significantly increased NO release from rat kidneys (ΔNO: +11.3±0.8 fmol · min
–1
· g
–1
kidney at 10
−9
mol/L AM), which was not affected by E-4021. E-4021 enhanced ACh-induced vasorelaxation (10
−9
mol/L ACh −9.7±1.7% versus 10
−8
mol/L E-4021+10
−9
mol/L ACh −18.8±2.9%,
P
<0.01) but did not affect ACh-induced NO release from the kidneys. In the aorta and the kidney, 10
−4
mol/L of
N
G
-nitro-
l
-arginine methyl ester, an NO synthase inhibitor, and 10
−5
mol/L of methylene blue, a guanylate cyclase inhibitor, reduced the vasodilatory effect of AM. These results suggest that the NO-cGMP pathway is involved in the mechanism of AM-induced vasorelaxation, at least in the rat aorta and kidney.
Parental Hyperdynamic Circulation Predicts Insulin Resistance in Offspring
Authors: Palatini Paolo , Vriz Olga , Nesbitt Shawna , Amerena John , Majahalme Silja , Valentini Mariaconsuelo , Julius Stevo
Published: June 2012

Abstract
—Controversy surrounds the pathogenetic mechanisms of the relationship between hyperdynamic circulation and insulin resistance. Two hundred eight children and young adults (mean age, 17.2±3.0 years; range, 11 to 26 years) from the Tecumseh Offspring Study whose parents had been assessed with Doppler echocardiography at the age of 34 years during the previous Tecumseh Blood Pressure Study were considered for this analysis. Offspring data were stratified according to tertiles of parental cardiac index. Parents in the top cardiac index tertile had increased heart rate (
P
=0.001), stroke volume (
P
=0.0001), left ventricular fractional shortening (
P
=0.02), and plasma epinephrine (
P
=0.02) compared with parents in the other tertiles. Body mass index (BMI) and blood pressure were similar in all groups. Offspring of parents with a high cardiac index had greater BMI (
P
=0.001), skinfold thickness (
P
=0.008), and waist/hip ratio (
P
=0.02), higher diastolic blood pressure (
P
=0.02) and plasma insulin level (
P
=0.001), and higher heart rate during Stroop’s color test (
P
=0.02) than offspring of parents with a lower cardiac index. In a multivariate regression analysis, offspring BMI was predicted by parental BMI and cardiac index (
P
=0.0001 and 0.003, respectively). The mother-child relationship explained most of the cardiac index–BMI association. In summary, parental hyperdynamic circulation was an important predictor of overweight, abnormal fat distribution, increased blood pressure, and hyperinsulinemia in offspring. Our results illustrate the complexity of interaction between a genetic tendency and its phenotypic expression. We speculate that the degree of β-adrenergic responsiveness may be a major determinant of the phenotypic differences between the parents and offspring found in this study.
Stroke Volume/Pulse Pressure Ratio and Cardiovascular Risk in Arterial Hypertension
Authors: de Simone Giovanni , Roman Mary J. , Koren Michael J. , Mensah George A. , Ganau Antonello , Devereux Richard B.
Published: June 2012

Abstract
—Ratio of stroke volume (SV, M-mode echocardiography) to pulse pressure (PP) has been proposed as an estimate of total arterial compliance and has been shown to be related to body size, age, and heart rate in normal adults. SV/PP was estimated in 294 hypertensive patients (98 women) as a raw value by use of SV/body surface area (SVi) and by the ratio of SV/PP to the value predicted by a previously developed equation (%SV/PP). At baseline, the 50 patients who had cardiovascular events over the following 10 years exhibited higher PP and lower SV/PP, SVi/PP, and %SV/PP (all
P
<0.008) than patients without events. Crude risk of follow-up total and fatal cardiovascular events increased with increasing level of PP and decreasing SV/PP, SVi/PP, and %SV/PP (all
P
<0.002). In multivariate logistic regression models with continuous covariates, the risk of total cardiovascular events was independently related to increasing age (
P
<0.0001) and left ventricular (LV) mass index (
P
<0.003) and decreasing values of %SV/PP (
P
<0.006) but not to increasing systolic, pulse, or mean blood pressure or gender. Similar although less strong results were obtained with the use of SVi/PP (
P
<0.02), whereas SV/PP did not enter the model as an independent predictor. Risk of cardiovascular death was only predicted by age and LV mass index. The %SV/PP was also an independent predictor of total cardiovascular events in Cox proportional hazards analysis (exp[b]: 2.49,
P
<0.001) independent of age (exp[b]: 1.05,
P
<0.003) and LV mass index (exp[b]: 1.02,
P
<0.0003), whereas no effect was detected for height. Thus, in patients with arterial hypertension, a reduced ratio of M-mode echocardiographic SV/PP as a percentage of the value predicted by demographic variables is a predictor of cardiovascular morbid events independent of age and LV mass index.
Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension
Authors: Hocher Berthold , George Ines , Rebstock Johannes , Bauch Alexandra , Schwarz Anja , Neumayer Hans-H. , Bauer Christian
Published: June 2012

Abstract
—The aim of the present study was to analyze whether the cardiac endothelin system contributes to cardiac remodeling in rats with 2-kidney, 1 clip (2K1C) renovascular hypertension. The endothelin system seems to be a promising candidate for cardiac remodeling because endothelin (ET)-1 promotes growth of cardiomyocytes in vitro and induces cardiac collagen synthesis. The activity of the cardiac endothelin system was analyzed by measuring cardiac tissue big ET-1 and ET-1 concentrations as well as by estimating the cardiac expression of the ETA and ETB receptors 10 days, 4 weeks, and 12 weeks after the renal artery was clipped. The effects of long-term treatment with ETA, ETB, and combined ETA/ETB receptor antagonists on cardiac hypertrophy, media/lumen ratio of intracardiac arteries, and left ventricular fibrosis were also analyzed. This study demonstrated that the overall left ventricular cardiac endothelin system has a similar activity in the early, middle, and late stages of 2K1C renovascular hypertension compared with sham-operated controls. Fibrosis of the left ventricle and hypertrophy of intracardiac arteries, however, were markedly altered after long-term treatment with endothelin receptor antagonists in a blood pressure–independent manner. These 2 effects are mediated by different subtypes of endothelin receptors. ETA receptor blockade completely normalized the hypertrophy of intracardiac arteries (
P
<0.01 compared with 2K1C without treatment) in renovascular hypertension, whereas the ETB antagonist reduced cardiac fibrosis of the left ventricle (
P
<0.001 compared with 2K1C without treatment) to baseline values. This study demonstrates that the cardiac endothelin system plays an important role in the development of cardiac fibrosis as well as in hypertrophy of intracardiac arteries in 2K1C renovascular hypertensive rats.
Kinin B
1
Receptor Antagonists Containing α-Methyl-
l
-Phenylalanine: In Vitro and In Vivo Antagonistic Activities
Authors: Gobeil Fernand , Charland Stéphanie , Filteau Catherine , Perron Stéphan I. , Neugebauer Witold , Regoli Domenico
Published: June 2012

Abstract
—To protect from metabolism and to improve potency of the AcLys-[
d
-βNal
7
,Ile
8
]desArg
9
-bradykinin (BK) (R 715), we prepared and tested 3 analogues containing α-methyl-
l
-Phe ([
α
Me]Phe) in position 5: these are the AcLys-[(
α
Me)Phe
5
,
d
-βNal
7
,Ile
8
]desArg
9
BK (R 892), Lys-Lys-[(
α
Me)Phe
5
,
d
-βNal
7
,Ile
8
]desArg
9
BK (R 913), and AcLys-Lys-[(
α
Me)Phe
5
,
d
-βNal
7
,Ile
8
]desArg
9
BK (R 914). The new compounds were tested against the contractile effect induced by desArg
9
BK on 2 B
1
receptor bioassays, the human umbilical vein, and the rabbit aorta. Their antagonistic activities were compared with those of the early prototypes (Lys-[Leu
8
]desArg
9
BK and [Leu
8
]desArg
9
BK) and with other recently described peptide antagonists. The 3 (
α
Me)Phe analogues showed high antagonistic potencies (pA
2
) at both the human (8.8, 7.7, and 8.7, respectively) and rabbit (8.6, 7.8, and 8.6, respectively) B
1
receptors. No antagonistic effects (pA
2
<5) were observed on the B
2
receptors that mediate the contractile effects of BK on the human umbilical vein, the rabbit jugular vein, and the guinea pig ileum. Moreover, these new B
1
antagonists were found to be resistant to in vitro degradation by purified angiotensin-converting enzyme from rabbit lung. The N
α
-acetylated forms, R 892 and R 914, were resistant to aminopeptidases from human plasma. In vivo antagonistic potencies (ID
50
) of B
1
receptor antagonists were evaluated in anesthetized lipopolysaccharide-treated (for B
1
receptor) and nontreated (for B
2
receptor) rabbits against the hypotensive effects of exogenous desArg
9
BK and BK. R 892 efficiently inhibited (ID
50
2.8 nmol/kg IV) hypotension induced by desArg
9
BK without affecting that evoked by BK (ID
50
>600 nmol/kg IV). Conversely, the peptide antagonists Lys-Lys-[Hyp
3
,Igl
5
,
d
-Igl
7
,Oic
8
]desArg
9
BK (B 9858) and
d
Arg-[Hyp
3
,Thi
5
,
d
-Tic
7
,Oic
8
] desArg
9
BK (S 0765) showed dual B
1
/B
2
receptor antagonism in vitro and in vivo. It is concluded that R 892 and congeners provide selective, highly potent, and metabolically stable B
1
kinin receptor antagonists that can be useful for the assessment of the physiological and pathological roles of kinin B
1
receptors.
Angiotensin II Receptor Blockade in Normotensive Subjects
Authors: Mazzolai Lucia , Maillard Marc , Rossat Julien , Nussberger Jürg , Brunner Hans R. , Burnier Michel
Published: June 2012

Abstract
—Use of angiotensin (Ang) II AT
1
receptor antagonists for treatment of hypertension is rapidly increasing, yet direct comparisons of the relative efficacy of antagonists to block the renin-angiotensin system in humans are lacking. In this study, the Ang II receptor blockade induced by the recommended starting dose of 3 antagonists was evaluated in normotensive subjects in a double-blind, placebo-controlled, randomized, 4-way crossover study. At 1-week intervals, 12 subjects received a single dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), or placebo. Blockade of the renin-angiotensin system was assessed before and 4, 24, and 30 hours after drug intake by 3 independent methods: inhibition of the blood pressure response to exogenous Ang II, in vitro Ang II receptor assay, and reactive changes in plasma Ang II levels. At 4 hours, losartan blocked 43% of the Ang II–induced systolic blood pressure increase; valsartan, 51%; and irbesartan, 88% (
P
<0.01 between drugs). The effect of each drug declined with time. At 24 hours, a residual effect was found with all 3 drugs, but at 30 hours, only irbesartan induced a marked, significant blockade versus placebo. Similar results were obtained when Ang II receptor blockade was assessed with an in vitro receptor assay and by the reactive rise in plasma Ang II levels. This study thus demonstrates that the first administration of the recommended starting dose of irbesartan induces a greater and longer lasting Ang II receptor blockade than that of valsartan and losartan in normotensive subjects.
Hypertension in Diet Versus Pharmacologically Treated Diabetics
Authors: Tenenbaum Alexander , Fisman Enrique Z. , Boyko Valentina , Goldbourt Uri , Graff Eran , Shemesh Joseph , Shotan Avraham , Reicher-Reiss Henrietta , Behar Solomon , Motro Michael
Published: June 2012

Abstract
—The natural history of non–insulin-dependent diabetes mellitus (NIDDM) differs markedly between patients with diet treated and pharmacologically treated disease. However, the interrelationship between hypertension and these common diabetes types has not been specifically addressed in previous studies. This study was designed to evaluate the prognostic significance and prevalence of hypertension in coronary patients with diet versus pharmacologically treated NIDDM over a 5-year follow-up period. The study sample comprised 11 515 patients aged 45 to 74 years with a previous myocardial infarction and/or anginal syndrome who had been screened but were not included in the Bezafibrate Infarction Prevention study. Among them, 9033 were nondiabetics and 2482, diabetics (987 diet treated and 1495 pharmacologically treated). The prevalence of hypertension among nondiabetics, diet-treated diabetics, and pharmacologically treated diabetics was 31%, 42%, and 43%, respectively. Crude all-cause mortality (CM) was lower in the nondiabetic patients (11.2% versus 22.0%;
P
<0.001). Among diabetics, 548 patients died: 81 diet treated normotensives (CM 14%); 100 diet-treated hypertensives (CM 24.4%); 205 pharmacologically treated normotensives (CM 24.2%); and 162 pharmacologically treated hypertensive patients (CM 25.0%). Age-adjusted mortality was lowest for the normotensive patients in the diet-treated group and highest for the hypertensive pharmacologically treated patients. Multivariate analysis shows that hypertension is a strong and independent predictor of increased CM in diet-treated but not in pharmacologically treated NIDDM: hazard ratio (HR) was 1.68 (95% confidence interval [CI] 1.24 to 2.29) for the diet-treated versus 1.01 (95% CI 0.82 to 1.26) for the pharmacologically treated diabetics. The contribution of hypertension to stroke mortality was substantial for both diet treated and pharmacologically treated NIDDM: hazard ratios were 3.17 (95% CI 1.12 to 8.98) and 2.21 (95% CI 0.72 to 6.77), respectively. The increased risk of mortality associated with hypertension in relatively mild diet-treated NIDDM strongly supports the clinical benefit of early blood pressure control among diabetic patients with ischemic heart disease.
Alexithymia
Authors: Jula Antti , Salminen Jouko K. , Saarijärvi Simo
Published: June 2012

Abstract
—Two hundred thirty-seven newly diagnosed yet untreated hypertensive men and women, 35 to 54 years of age, were compared with an age- and gender-stratified random population sample of 146 normotensive men and women to find out whether psychological distress symptoms, anger expression, and alexithymia are associated with elevated blood pressure and whether the possible associations are independent of sodium and alcohol intake, body mass index, and physical fitness. The independent attributes of mean arterial pressure were studied by multivariate regression analyses after combining the subjects in the hypertensive and control groups. Three questionnaires were used: the Brief Symptom Inventory (BSI-37), a 31-item version of the Spielberger State-Trait Anger Expression Inventory (STAXI), and the Toronto Alexithymia Scale (TAS-26). Total scores of the TAS-26 were higher (
P
<0.001) in hypertensive men and women than in their normotensive control subjects (75.6±7.8 vs 64.1±9.8 in men and 72.9±7.1 vs 57.5±11.5 in women). There were no differences between the study and control groups in psychological distress symptoms, including anxiety, depression, and hostility, or in anger expression. In multivariate regression analyses, higher age, male gender, higher sodium intake, lower physical fitness, and alexithymia were independently and highly significantly (
P
<0.01 for male gender,
P
<0.0001 for other variables) associated with increased blood pressure, explaining altogether 39.5% of the cross-sectional variation in mean arterial pressure. We conclude that alexithymia, that is, poor ability to experience and express emotions, is associated with elevated blood pressure independent of sodium and alcohol intake, body mass index, and physical fitness.
Troglitazone Upregulates Nitric Oxide Synthesis in Vascular Smooth Muscle Cells
Authors: Hattori Yoshiyuki , Hattori Sachiko , Kasai Kikuo
Published: June 2012

Abstract
—We investigated the effects of troglitazone on cytokine-stimulated nitric oxide (NO) production in cultured rat vascular smooth muscle cells (VSMC). The increase in NO formation caused by interleukin-1α (IL-1) was enhanced by troglitazone in a concentration-dependent manner. Bacterial lipopolysaccharide–stimulated NO synthesis was also increased by troglitazone. The combinations of IL-1, tumor necrosis factor-α, or lipopolysaccharide with interferon-γ (IFN) were strong stimuli for induction of NO synthesis in VSMC, which were further potentiated by the presence of troglitazone. When troglitazone was added at increasing intervals after the stimulation of VSMC with IL-1, the enhancement in NO production decreased as the interval lengthened, suggesting that troglitazone alters NO synthase (NOS) expression by VSMC rather than having a direct affect on VSMC NOS activity. Troglitazone had no effect on IL-1–elicited or IL-1/IFN–elicited nuclear factor-κB activity in VSMC. Troglitazone inhibited the degradation of cytokine-induced NOS mRNA. Thus troglitazone appears to enhance IL-1–induced NOS mRNA levels by prolonging its half-life rather than activating its transcription, which is nuclear factor -κB–dependent. No expression of peroxisome proliferator–activated receptor-γ (PPARγ) was detected in VSMC, and 15-deoxy-D
12,14
prostaglandin J
2
, the natural ligand for the PPARγ, did not resemble the effect of troglitazone on IL-1–induced NO synthesis. These results indicate that troglitazone upregulates cytokine-stimulated NO synthesis in VSMC through PPARγ-independent mechanisms. Considering its inhibitory effects on the action of numerous growth factors on VSMC, the direct vascular effects of troglitazone shown in this study may have important implications for prevention of restenosis and possibly atherosclerosis.
Aortic Pulse Wave Velocity as a Marker of Cardiovascular Risk in Hypertensive Patients
Authors: Blacher Jacques , Asmar Roland , Djane Saliha , London Gérard M. , Safar Michel E.
Published: June 2012

Abstract
—Large artery damage is a major contributory factor to cardiovascular morbidity and mortality of patients with hypertension. Pulse wave velocity (PWV), a classic evaluation of arterial distensibility, has never been ascertained as a cardiovascular risk marker. To determine the factors influencing aortic PWV and the potential predictor role of this measurement, we studied a cohort of 710 patients with essential hypertension. Atherosclerosis alterations (AA) were defined on the basis of clinical events. Calculation of cardiovascular risks, by use of Framingham equations, was performed in subjects without AA. PWV was higher in the presence of AA (14.9±4.0 versus 12.4±2.6 m/s,
P
<0.0001), even after adjustments on confounding factors and was the first determinant (
P
<0.0001) of the extent of atherosclerosis assessed as the sum of the atherosclerotic sites. In patients without AA, all cardiovascular risks increased constantly with PWV. Furthermore, at a given age, aortic PWV was the best predictor of cardiovascular mortality. The odds ratio of being in a high cardiovascular mortality risk group (>5% for 10 years) for patients in the upper quartile of PWV was 7.1 (95% confidence intervals 4.5 to 11.3). The presence of a PWV >13 m/s, taken alone, appeared as a strong predictor of cardiovascular mortality with high performance values. This study shows that aortic PWV is strongly associated with the presence and extent of atherosclerosis and constitutes a forceful marker and predictor of cardiovascular risk in hypertensive patients.
Relation Between Body Fat–Corrected ECG Voltage and Ambulatory Blood Pressure in Patients With Essential Hypertension
Authors: Tochikubo Osamu , Miyajima Eiji , Shigemasa Tomohiko , Ishii Masao
Published: June 2012

Abstract
—Because adipose tissue has high electric resistance, the amount of body fat influences ECG voltage. In this study, body fat weight of patients with essential hypertension was measured by means of the impedance method and was used to correct mean ECG voltage. Then the relation between body fat–corrected mean ECG voltage (V
fm
) and ambulatory blood pressure (BP) was investigated. The subjects were 172 patients with essential hypertension (88 men, 84 women, none receiving medication) between the ages of 30 and 75 years. Ambulatory BP was measured by a multi-biomedical recorder. Minimum sleep-time BP (base BP) was calculated to correspond with minimum sleep-time heart rate. The tetrapolar bioelectric impedance method was used to measure body fat (kg). Left ventricular mass (LVM) was obtained by echocardiography. Then comparisons were made with standard 12-lead ECG, and the statistical mean ECG voltage (V
m
) and V
fm
were derived by multivariate statistical analysis. The following formula was devised to obtain V
fm
resulting from the multivariate analysis that demonstrated a high correlation with LVM (
r
=0.85): V
fm
=0.175(Body Fat)
1/3
×V
m
+0.5 (mV). The coefficient of correlation (
r
) between V
fm
and ambulatory BP was not smaller than that between LVM and ambulatory BP. Base systolic BP demonstrated a significantly higher
r
value (
r
=0.83) with V
fm
/BSA
1/2
(where BSA is body surface area) than mean daytime SBP (
r
=0.65). In many subjects with white-coat hypertension, V
fm
/BSA
1/2
was <1.33 mV/m (34 of 38 cases; sensitivity, 89%; specificity, 89%). These results indicate that V
fm
is a better indicator of hypertensive left ventricular hypertrophy and that it may be useful in estimating minimum sleep-time systolic BP and in diagnosing white-coat hypertension in the outpatient clinic.
Long-Term Effects of Angiotensin-Converting Enzyme Inhibition on Renal Medullary Neutral Lipid in Spontaneously Hypertensive Rats
Authors: O’Sullivan Joseph B. , Harrap Stephen B.
Published: June 2012

Abstract
—Short-term treatment of young spontaneously hypertensive rats (SHR) with angiotensin-converting enzyme (ACE) inhibitors reduces systolic blood pressure. Renal medullary neutral lipids (RMNLs) have vasodilator properties that may explain the effects of ACE inhibition. We measured RMNL levels of SHR treated between 6 and 10 weeks of age with (1) vehicle, (2) ramipril 1 mg · kg
−1
· d
−1
, (3) the bradykinin B
2
receptor antagonist icatibant 0.5 mg · kg
−1
· d
−1
, or (4) icatibant 0.5 mg · kg
−1
· d
−1
plus ramipril 1 mg · kg
−1
· d
−1
. RMNLs were quantified by oil red O fluorescence at 10 and 20 weeks of age. Systolic blood pressure (BP) was measured by tail-cuff plethysmography. Ramipril reduced BP at 10 weeks of age and increased RMNLs compared with controls (0.99±0.07% versus 0.56±0.06%,
P
<0.01). Icatibant alone had no significant effect on RMNLs (0.55±0.04%) but attenuated the increase in RMNLs by ramipril (0.81±0.05%). In control SHR, the increase in BP between 10 and 20 weeks of age was associated with a significant increase in RMNLs (0.79±0.09%). SHR that had received ramipril had significantly lower BP than controls at 20 weeks of age, but RMNL was not significantly different (0.92±0.10%). Therefore, in young SHR, ACE inhibition increases RMNLs and reduces blood pressure, an effect that appears to depend on bradykinin. The changes in RMNLs at the age of 10 weeks paralleled long-term BP effects and may be involved in setting the BP track in SHR.
Mechanistic Differences of Various AT
1
-Receptor Blockers in Isolated Vessels of Different Origin
Authors: Morsing Peter , Adler Gunnel , Brandt-Eliasson Ulla , Karp Linda , Ohlson Kristina , Renberg Lars , Sjöquist Per-Ove , Abrahamsson Tommy
Published: June 2012

Abstract
—The functional inhibitory characteristics of the angiotensin II type 1 receptor blockers (ARB) candesartan; irbesartan; and losartan and its active metabolite EXP 3174 (EXP) were studied in rabbit aortic strips and rat portal vein preparations in vitro. Moreover, plasma-protein binding was determined, and the binding was high (>98.5%) for all ARBs. These values were needed to relate the concentrations of the ARBs used in vitro to the nonprotein bound concentrations in clinical use. In both vascular preparations, candesartan caused a marked decrease in the maximal contractile response of the angiotensin II (Ang II) concentration-response curve. Losartan, EXP, and irbesartan caused a rightward parallel shift without any major effects on the maximal response to Ang II. The inhibitory effect of candesartan developed slowly (maximal effect after >30 minutes) and lasted >2 hours despite repeated washing of the vessels. The effect of losartan, irbesartan, and EXP had a faster onset, and most of the inhibitory effect disappeared after washing. The duration of the inhibitory effects of the ARBs were not related to lipophilicity of the compounds. Cooling of the rat portal vein preparations to 4°C before administration of candesartan prevented the persistent inhibition of Ang II response seen at 37°C. For the other ARBs studied, the magnitude of inhibition and the speed of recovery of the Ang II response were independent of the incubation temperature before washing. In addition, when candesartan was given to conscious rats, the inhibitory effect on Ang II–induced blood pressure responses persisted during the 24-hour period despite nondetectable plasma concentrations of candesartan at 24 hours. It is concluded that functional inhibitory characteristics of candesartan differ from those of the other ARBs tested. At clinically relevant concentrations, candesartan is an insurmountable and long-lasting antagonist of the vascular contractile responses to Ang II.
AT
2
Receptor and Vascular Smooth Muscle Cell Differentiation in Vascular Development
Authors: Yamada Hiroyuki , Akishita Masahiro , Ito Masaaki , Tamura Kouichi , Daviet Laurent , Lehtonen Jukka Y. A. , Dzau Victor J. , Horiuchi Masatsugu
Published: June 2012

Abstract
—The angiotensin II type 2 (AT
2
) receptor is transiently expressed at late gestation in the fetal vasculature, but its expression rapidly declines after birth. We have previously demonstrated that the expression of this receptor mediates decline in vascular DNA synthesis that occurs at this stage of vascular development. To examine further the role of the AT
2
receptor in vasculogenesis, we have focused on the effect of the AT
2
receptor on vascular smooth muscle cell (VSMC) differentiation. In this study, we examined the time-dependent expression of differentiation markers for VSMCs in the aorta of wild-type and AT
2
receptor–null mice. α-Smooth muscle actin was expressed at the early stage of differentiation and exhibited unchanged expression before and after the peak of AT
2
receptor expression, which was observed at embryonic day 20, neonatal day 1, and thereafter. No difference in α-smooth muscle actin expression was observed between the wild-type and AT
2
receptor–null mice. In contrast, the mRNA levels for calponin, expressed in the late stage of VSMC differentiation, were significantly higher in the wild-type mouse aorta as compared with the AT
2
receptor–null mice, which correlates with expression of the AT
2
receptor. Moreover, the protein levels of calponin and high-molecular-weight caldesmon (h-caldesmon) showed lower expression in the aorta of AT
2
receptor knockout mice at 2 and 4 weeks after birth. Taken together, our results suggest that the AT
2
receptor promotes vascular differentiation and contributes to vasculogenesis.
Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs
Authors: Berthold Heike , Münter Klaus , Just Armin , Kirchheim Hartmut R. , Ehmke Heimo
Published: June 2012

Abstract
—Previous studies in dogs have shown additive or even synergistic effects of combined angiotensin-converting enzyme inhibition and either nonselective endothelin subtype A/B (ET
A/B
) or selective endothelin subtype A (ET
A
) receptor blockade on renal vascular resistance and mean arterial blood pressure. A possible mechanism underlying this interaction may be a stimulation of the renin-angiotensin system during endothelin (ET) receptor blockade. We therefore investigated whether plasma renin activity and renin release are regulated by the ET
A
receptor. Experiments were made in conscious, chronically instrumented dogs receiving either saline or the selective ET
A
receptor antagonist LU 135252 (10 mg/kg IV). Eighty to 100 minutes after the administration of LU 135252 (n=5), heart rate (99±7 versus 81±6 bpm;
P
<0.05) and renal blood flow (327±40 versus 278±36 mL/min;
P
<0.05) were increased significantly, whereas mean arterial blood pressure tended to be lower (93±5 versus 105±7 mm Hg). These changes were associated with a 2-fold increase in plasma renin activity (0.74±0.12 versus 0.37±0.10 ng angiotensin I per milliliter per hour;
P
<0.05). Measurements of renin release at various renal perfusion pressures (n=5) with the use of a vascular occluder implanted around the left renal artery revealed that ET
A
receptor blockade did not alter renin release at resting renal perfusion pressure (78±25 versus 71±39 U/min) but strongly enhanced the sensitivity of pressure-dependent renin release <80 mm Hg ≈2.2-fold. In conclusion, selective ET
A
receptor blockade is associated with a stimulation of the circulating renin-angiotensin system, which results from both a sensitization of pressure-dependent renin release and a larger proportion of blood pressure values falling into the low pressure range, where renin release is stimulated. These find-ings strengthen the view that ET and the renin-angiotensin system closely interact to regulate vascular resistance and provide a physiological basis for synergistic hypotensive effects of a combined blockade of both pressor systems.
β-2 Adrenergic Receptor Variants Affect Resting Blood Pressure and Agonist-Induced Vasodilation in Young Adult Caucasians
Authors: Gratze Gerfried , Fortin Jürgen , Labugger Ralf , Binder Alexander , Kotanko Peter , Timmermann Bernd , Luft Friedrich C , Hoehe Margret R , Skrabal Falko
Published: June 2012

Abstract
—Recent evidence suggests that the prodownregulatory Gly16 allele of the β-2 adrenergic receptor (β-2 AR) is associated with essential hypertension in African Caribbeans. To further investigate the effect of the glycine (Gly)16 and arginine (Arg)16 β-2 AR variants on hemodynamics, we investigated the agonist-mediated in vivo vasodilation in normotensive Austrian Caucasians and analyzed the results with respect to the Gly16/Arg16 polymorphism. Fifty-seven normotensive men, 20 to 32 years of age with body mass index of 18.7 to 29.9 kg/m
2
, were genotyped for the Arg16/Gly16 β-2 AR alleles. All 15 Gly16/Gly16 subjects, all 12 Arg16/Arg/16 subjects, and 27 of 30 heterozygous subjects underwent hemodynamic measurements while supine after an overnight fast. The observers were unaware of the subjects’ genotypes. The subjects received a graded infusion of the selective β-2 AR agonist salbutamol (0.07, 0.14, and 0.21 μg/kg per minute, respectively), each dose over 8 minutes. Stroke volume and blood pressure were determined continuously by means of impedance cardiography and oscillometry, respectively. The last 4 minutes of each infusion were evaluated statistically. Basal mean blood pressure was higher in the Gly16/Gly16 subjects compared with Arg16/Arg16 subjects (mean±SD: 81.6±6.14 versus 75.2±4.93 mm Hg,
P
<0.01). Homozygous Gly16 subjects showed a significantly decreased vasodilation during the first dose of salbutamol infusion compared with Arg16/Arg16 subjects (Δtotal peripheral resistance index −17.9±14.4 versus −30.6±8.3%,
P
<0.01) despite increased sympathetic counterregulation in the Arg16/Arg16 group (Δheart rate +16.9±7.0% versus +8.6±7.0%,
P
<0.01; Δcardiac index +39.5±18.5% versus 21.4±18.8%,
P
<0.05). Our results provide additional evidence that the Gly16/Arg16 alleles of the β-2 AR are intimately related to blood pressure regulation and deserve further studies in the pathogenesis of essential hypertension.
An Enhanced Effect of Arginine Vasopressin in Bradykinin B
2
Receptor Null Mutant Mice
Authors: Alfie Marcos E. , Alim Shainda , Mehta Dharmesh , Shesely Edward G. , Carretero Oscar A.
Published: June 2012

Abstract
—Under water restriction, arginine vasopressin (AVP) is released and promotes water reabsorption in the distal nephron, mainly through AVP V
2
-receptors. It has been proposed that renal kinins counteract the hydro-osmotic effect of AVP. We hypothesized that kinins acting through B
2
receptors antagonize the urinary concentrating effect of AVP. To test this, bradykinin B
2
receptor knockout mice (B
2
-KO) and 129/SvEv mice (controls) were placed in metabolic cages and urine collected for 24 hours (water ad libitum). After that, urine was again collected from the same mice during 24 hours of water restriction. Urinary volume (UV), urinary osmolarity (UOsm), and urinary Na
+
(U
Na
V) and K
+
(U
K
V) excretion were determined. On water restriction, UV in controls decreased by ≈25%, whereas in B
2
-KO mice there was almost a 60% drop in urinary output (
P
=0.001 versus controls). In the controls, water restriction increased UOsm by 347 mOsm/kg H
2
O, ≈14% above baseline (NS), whereas in knockout mice the increase was 3 times that seen in the controls: >1000 mOsm/kg H
2
O (
P
=0.001 versus controls). Compared with normohydration, U
Na
V and U
K
V in the water-restricted state increased more in controls than in B
2
-KO mice. This difference in electrolyte excretion could be explained by greater dehydration in the controls (dehydration natriuresis). In a second protocol, we tried to mimic the effect of endogenous AVP by exogenous administration of an AVP V
2
-receptor agonist, desmopressin (DDAVP). To suppress endogenous AVP levels before DDAVP administration, mice were volume-overloaded with dextrose and alcohol. UOsm was 685±125 and 561±58 mOsm/kg H
2
O in water-loaded controls and B
2
-KO mice, respectively. After DDAVP was injected subcutaneously at a dose of 1 μg/kg, UOsm increased to 1175±86 mOsm/kg H
2
O (
Δ
+490 mOsm) in the controls and 2347±518 mOsm/kg H
2
O (
Δ
+1786 mOsm) in B
2
-KO mice (
P
<0.05 versus controls). We concluded that water restriction or exogenous administration of an AVP V
2
-receptor agonist has a greater urinary concentrating effect in B
2
-KO mice than in controls, suggesting that endogenous kinins acting through B
2
receptors oppose the antidiuretic effect of AVP in vivo.
Effects of Amlodipine and Cilnidipine on Cardiac Sympathetic Nervous System and Neurohormonal Status in Essential Hypertension
Authors: Sakata Kazuyuki , Shirotani Manabu , Yoshida Hiroshi , Nawada Ryuzou , Obayashi Kazuhiko , Togi Kiyonori , Miho Narimasa
Published: June 2012

Abstract
—N-Type calcium channel antagonists may suppress sympathetic activity. The purpose of this study was to assess the effects of amlodipine and cilnidipine on the cardiac sympathetic nervous system and the neurohormonal status of essential hypertension.
123
I-metaiodobenzylguanidine (MIBG) cardiac imaging was performed and blood samples were taken to determine plasma renin activity and plasma norepinephrine concentration before and 3 months after drug administration in 47 patients with mild essential hypertension. Twenty-four of the patients were treated with 5 to 10 mg/d of amlodipine; the other 23 were treated with 10 to 20 mg/d of cilnidipine. For comparison, 12 normotensive subjects were also studied. No significant differences were found in the basal characteristics between the 2 hypertensive groups. In both hypertensive groups, both the systolic and diastolic blood pressures were significantly reduced to similar levels 3 months after drug treatment. Before the drug treatment, the 2 hypertensive groups had a significantly higher washout rate and lower heart-to-mediastinum (H/M) ratio compared with the normotensive subjects. The H/M ratio significantly increased (
P
<0.05) in combination with a decreased washout rate (
P
<0.02) after drug treatment in the cilnidipine group. In the amlodipine group, a significant decrease in washout rate (
P
<0.04) was noted, without an increase in the H/M ratio. However, no significant changes were found in plasma renin activity and plasma norepinephrine concentration in either group. Thus, in patients with essential hypertension, cilnidipine suppressed cardiac sympathetic overactivity and amlodipine had a little suppressive effect. Cilnidipine may provide a new strategy for treatment of cardiovascular diseases with sympathetic overactivity.