bluuebunny/crossref_metadata_2025 huggingface dataset:
Human α-Adducin Gene, Blood Pressure, and Sodium Metabolism
Authors: Kamitani Atsushi , Wong Zilla Y. H. , Fraser Robert , Davies David L. , Connor J. Michael , Foy Chris J. W. , Watt Graham C. M. , Harrap Stephen B.
Published: June 2012

Abstract
—The adducin genes contribute significantly to population variation in rat blood pressure and cell membrane sodium transport. The 460Trp mutation of the human α-adducin gene has been associated with hypertension, in particular hypertension sensitive to sodium restriction. We studied the relationship between the 460Trp mutation and population variation in blood pressure and sodium metabolism. From 603 Scottish families, we selected 151 offspring and 224 parents with blood pressures in either the upper (high) or bottom (low) 30% of the population distribution and measured the 460Trp mutation using allele-specific hybridization. In offspring, we also measured exchangeable sodium, plasma volume, and total body water. Plasma levels of components of the renin-angiotensin system, atrial natriuretic peptide, and cellular sodium and transmembrane sodium efflux were also estimated. The overall frequency of the 460Trp mutation was 27.1%. In offspring and parent groups, we found no difference in the genotype or allele frequencies of the 460Trp mutation between subjects with high or low blood pressure. There was no overall association between the α-adducin genotypes and blood pressure variation. In offspring, the 460Trp mutation was not associated with any significant differences in body fluid volumes or exchangeable sodium; levels of plasma renin, angiotensin II, aldosterone, or atrial natriuretic peptide; intracellular sodium; or ouabain-sensitive transmembrane sodium efflux. These findings suggest that in our Scottish population, the α-adducin 460Trp polymorphism is not related to blood pressure and does not affect whole body or cellular sodium metabolism.
Differences in the Mechanical Properties of the Rat Carotid Artery In Vivo, In Situ, and In Vitro
Authors: Zanchi Anne , Stergiopulos Nikos , Brunner Hans R. , Hayoz Daniel
Published: June 2012

Abstract
—The elastic properties of carotid arteries of spontaneously hypertensive rats (SHR) and normotensive controls (Wistar-Kyoto rats [WKY]) were examined in vivo, in situ, and in vitro. The changes of internal diameter were measured with a high-resolution A-mode echo-tracking device simultaneously with the intra-arterial pressure at the carotid. The internal diameter at mean arterial blood pressure (MBP) was substantially smaller in vitro than in vivo in SHR (−33.8%) and WKY (−48.3%). The arterial distensibility was lower in vitro in all arteries compared with in vivo conditions (SHR, −30.1%; WKY, −60.4%; at MBP) despite a reduced incremental elastic modulus in vitro (SHR, −56.9%; WKY, −45.1%; at MBP). However, the in vitro and in vivo measurements show consistent elastic behavior of the carotid arteries between both strains of rats. Carotid arteries from WKY were also examined in situ. Although no significant reduction in internal diameter could be observed in situ, distensibility was dramatically decreased (−87% at MBP). These results emphasize the importance of considering the original vascular geometry when determining elastic properties of arteries. We conclude that experimental conditions are likely to be a critical determinant for the assessment of the mechanical properties of conduit vessels.
Normalization of Blood Pressure and Renal Vascular Resistance in SHR With a Membrane-Permeable Superoxide Dismutase Mimetic
Authors: Schnackenberg Christine G. , Welch William J. , Wilcox Christopher S.
Published: June 2012

Abstract
—Superoxide radical (O
2
−
) is increased in the vessel wall of spontaneously hypertensive rats (SHR) where its blockade potentiates endothelium-dependent vasodilation. The purpose of this study was to determine the role of O
2
−
in the hypertension and renal vasoconstriction of SHR and its interaction with nitric oxide (NO). Baseline mean arterial pressure (MAP) and renal vascular resistance were markedly elevated in SHR (n=6) compared with Wistar-Kyoto rats (WKY; n=6) (145±4 versus 118±4 mm Hg,
P
<0.05, and 24±3 versus 17±1 mm Hg · mL
−1
· min
−1
, respectively;
P
<0.05). The stable membrane-permeable superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (tempol; 72 μmol/kg IV) normalized MAP (103±9 versus 96±6 mm Hg for SHR and WKY, respectively) and RVR (17±2 versus 15±1 mm Hg · mL
−1
· min
−1
) of SHR. The MAP of SHR was more sensitive and responsive to graded infusions of tempol (0, 1.8, 18, 180, and 1800 μmol · kg
−1
· h
−1
IV) than that of WKY. To determine whether O
2
−
increases MAP by inactivation of NO, its synthesis was blocked in SHR with
N
w
-nitro-
l
-arginine methyl ester (L-NAME, 11 μmol · kg
−1
· min
−1
IV, n=6). Whereas tempol alone significantly reduced MAP by 32% (184±12 to 121±18 mm Hg,
P
<0.05, n=6), L-NAME infusion abolished the MAP response to tempol (187±8 to 186±4 mm Hg, n=5). In contrast, tempol did reduce MAP of SHR (188±7 to 161±7 mm Hg,
P
<0.05) where MAP was elevated by norepinephrine (31 nmol · kg
−1
· min
−1
IV, n=6). Finally, to determine the longer-term effect of O
2
−
, tempol (1.5 mmol · kg
−1
· d
−1
IP) was given for 7 days. Tempol had no effect on MAP in WKY (96±1 to 97±1 mm Hg, n=7) but significantly decreased MAP in SHR (133±2 to 120±3 mm Hg,
P
<0.05, n=7). These data implicate O
2
−
in the hypertension of SHR in vivo. The antihypertensive action of tempol depends on NO synthesis presumably because O
2
−
inactivates NO and thus diminishes its vasodilatory actions.
Structural Analysis and Evaluation of the Aldosterone Synthase Gene in Hypertension
Authors: Brand Eva , Chatelain Nathalie , Mulatero Paolo , Féry Isabelle , Curnow Kathleen , Jeunemaitre Xavier , Corvol Pierre , Pascoe Leigh , Soubrier Florent
Published: June 2012

Abstract
—Anomalies in either of the tightly linked genes encoding the enzymes CYP11B1 (11β-hydroxylase) or CYP11B2 (aldosterone synthase) can lead to important changes in arterial pressure and are responsible for several monogenically inherited forms of hypertension. Mutations in these genes or their regulatory regions could thus contribute to genetic variation in susceptibility to essential hypertension. To test this hypothesis, we performed 2 complementary studies of the
CYP11B1
/
CYP11B2
locus in essential hypertension. After characterizing a DNA contig containing the
CYP11B1
gene and mapping the gene in the Centre d’Etudes du Polymorphisme Humain reference panel of families, we performed a linkage study with 292 hypertensive sibling pairs and a highly informative microsatellite marker near
CYP11B1
. We also analyzed the association of 2 frequent biallelic polymorphisms of the
CYP11B2
gene, 1 in the promoter at position −344 (−344C/T) and the other, a common gene conversion in intron 2, with hypertension in 380 hypertensive patients and 293 normotensive individuals. Statistical analyses did not show significant linkage of the
CYP11B1
microsatellite marker to hypertension. No positive association with hypertension was found with the gene conversion in intron 2, but a positive association with hypertension was found with the −344T allele. The hypertensive and normotensive samples differed significantly in both genotype (
P
=0.023) and allele frequencies (
P
=0.010). Our data suggest a modest contribution of the
CYP11B2
gene to essential hypertension.
Insulin Resistance and the Effect of Insulin on Blood Pressure in Essential Hypertension
Authors: Heise Tim , Magnusson Kai , Heinemann Lutz , Sawicki Peter T.
Published: June 2012

Abstract
—The aim of this study was to investigate the effect of 2 weeks of insulin administration on blood pressure and to simultaneously measure insulin sensitivity and insulin-induced vasodilatation in obese hypertensive patients. In a prospective, randomized, double-blind, crossover study (study 1), 23 obese, untreated, nondiabetic, hypertensive patients received either neutral protamine Hagedorn (NPH) insulin (0.3 U/kg body wt per day) or placebo subcutaneously for 2 weeks (washout period, 2 weeks). Office and 24-hour blood pressure values were measured at the beginning and end of each treatment period. In an open-label study (study 2), 8 obese hypertensive patients and 10 healthy control subjects underwent a 3-step hyperinsulinemic, euglycemic glucose clamp (step 1, 0.5; step 2, 2.5; step 3, 5.0 mU · kg
−1
· min
−1
[120 minutes each]). Leg blood flow (LBF) was measured by venous occlusion plethysmography. Insulin administration decreased mean±SD office blood pressure from 131±13 to 128±12 mm Hg (placebo, 132±13 and 132±13 mm Hg;
P
<0.05 between final examinations) and mean±SD 24-hour blood pressure by −3.3±6.9 mm Hg (placebo, +0.7±4.6 mm Hg;
P
<0.05). Insulin infusion increased LBF significantly in the healthy controls but not in obese insulin-resistant hypertensive subjects. Obese hypertensive patients are resistant to the effects of insulin with regard to both glucose uptake and vasodilatation. Administration of insulin exerts a small blood pressure–lowering effect in these patients. These data strongly argue against the postulated pressor action of insulin in essential hypertension.
Transvascular and Urinary Leakage of Albumin in Atherosclerotic and Hypertensive Men
Authors: Pedrinelli Roberto , Penno Giuseppe , Dell’Omo Giulia , Bandinelli Simona , Giorgi Davide , Di Bello Vitantonio , Nannipieri Monica , Navalesi Renzo , Mariani Mario
Published: June 2012

Abstract
—Increased urine albumin is associated with atherosclerotic disease and predicts cardiovascular morbidity and mortality in nondiabetic populations. This finding is frequently postulated to reflect the impact of atherosclerotic damage on glomerular and systemic capillary permeability, an interesting but as yet untested hypothesis. The transcapillary escape rate of albumin (TERalb, the 1-hour decline rate of intravenous
125
I-albumin, a measure of capillary macromolecular permeability), albuminuria, lipid levels, echocardiographic wall thickness, and insulin responses to oral glucose were measured in 30 untreated dipstick-negative lean men and clinically stable atherosclerotic peripheral vascular disease; tolerance to oral glucose was a requirement for inclusion in the study. Because hypertension per se might influence TERalb, the sample included either normotensive (n=18, 118±6/72±7 mm Hg) or hypertensive (n=12, 141±7/84±6 mm Hg by 24-hour blood pressure monitoring) arteriopathic patients; 11 normal age- and gender-matched subjects (121±7/76±5 mm Hg) were used as control subjects. TERalb was higher in patients (10.7±3.2 versus 7.4±1.7%/h,
P
<0.013), a difference that persisted after postload glucose, insulin, and lipid levels were accounted for by covariance analysis; atherosclerosis and hypertension together did not further impair vascular permeation to albumin. In contrast with TERalb, albuminuria was elevated only in the hypertensive subgroup; the 2 variables showed no relationship, even when the data were analyzed separately in normotensive and hypertensive subgroups. Urine albumin correlated positively with 24-hour blood pressure and wall thickness. Thus, systemic capillary permeability is altered in nondiabetic atherosclerotic patients independently from blood pressure levels, but this abnormality is not reflected by proportionate changes in albuminuria.
Signal Transduction of Mechanical Stresses in the Vascular Wall
Authors: Lehoux Stéphanie , Tedgui Alain
Published: June 2012

Abstract
—The vascular wall is constantly subjected to a variety of mechanical forces in the form of stretch (tensile stress), due to blood pressure, and shear stress, due to blood flow. Alterations in either of these stresses are known to result in vascular remodeling, an adaptation characterized by modified morphology and function of the blood vessels, allowing the vessels to cope with physiological or pathological conditions. The processes involved in vascular remodeling include cellular hypertrophy and hyperplasia, as well as enhanced protein synthesis or extracellular matrix protein reorganization. In vitro studies using vascular cells have attempted to identify the mechanisms behind structural alterations. Possible pathways include ion channels, integrin interaction between cells and the extracellular matrix, activation of various tyrosine kinases (such as c-Src, focal adhesion kinase, and mitogen-activated protein kinases), and autocrine production and release of growth factors. These pathways lie upstream of de novo synthesis of immediate response genes and total protein synthesis, both of which are likely to be involved in the process of vascular remodeling.
Smooth Muscle Relaxation
Authors: Bank Alan J. , Kaiser Daniel R.
Published: June 2012

Abstract
—Compliance, distensibility, incremental elastic modulus (E
inc
), and pulse wave velocity are all terms used to describe the mechanical properties of arteries. Previous studies assessing the effects of smooth muscle relaxation on each of these parameters have produced conflicting results. Our laboratory has previously demonstrated that intrabrachial infusion of nitroglycerin in normal human subjects results in a large increase in brachial artery compliance without changing arterial wall stiffness as measured by E
inc
. In the present study, the relationships among compliance, distensibility, E
inc
, and pulse wave velocity under different levels of vascular tone are shown using data acquired by intravascular ultrasound as well as theoretical curves. We demonstrate that the effects of smooth muscle relaxation can be depicted as 2 separate steps: (1) a rightward shift to a new theoretical curve describing the relationship between 2 of the above elastic parameters that is solely due to changes in vessel geometry and (2) a shift along the new curve that is dependent on changes in wall stiffness.
Calcium Channel Blockade and Cardiovascular Prognosis in the European Trial on Isolated Systolic Hypertension
Authors: Staessen Jan A. , Thijs Lutgarde , Fagard Robert H. , Birkenhäger Willem H. , Arabidze Guramy , Babeanu Speranta , Gil-Extremera Blas , Bulpitt Christopher J. , Davidson Christopher , de Leeuw Peter W. , Efstratopoulos Aris D. , Fletcher Astrid E. , Fogari Roberto , Jääskivi Matti , Kawecka-Jaszcz Kalina , Nachev Choudomir , Petrie James C. , Seux Marie-Laure , Tuomilehto Jaakko , Webster John , Yodfat Yair
Published: June 2012

Abstract
—In the double-blind Systolic Hypertension in Europe (Syst-Eur) Trial, active treatment was initiated with nitrendipine (10 to 40 mg/d) with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d) titrated or combined to reduce sitting systolic blood pressure by at least 20 mm Hg to <150 mm Hg. In the control group, matching placebos were used similarly. In view of persistent concerns about the use of calcium channel blockers as first-line antihypertensive drugs, this report explored to what extent nitrendipine, administered alone, prevented cardiovascular complications. Age at randomization averaged 70.2 years and systolic/diastolic blood pressure 173.8/85.5 mm Hg. Of 2398 actively treated patients, 1327 took only nitrendipine (average dose, 23.4 mg/d), and 1042 progressed to other treatments including nitrendipine (n=757; 35.7 mg/d), enalapril (n=783; 13.4 mg/d), and/or hydrochlorothiazide (n=294; 21.0 mg/d). Compared with the whole placebo group (n=2297), patients receiving monotherapy with nitrendipine had 25% (
P
=0.05) fewer cardiovascular end points, and those progressing to other active treatments showed decreases (
P
≤0.01) in total mortality (40%), stroke (59%), and all cardiovascular end points (39%). Among the control patients, 863 used only the first-line placebo. Compared with this subgroup, patients receiving monotherapy with nitrendipine showed a nearly 50% (
P
≤0.004) reduction of all types of end points, including total and cardiovascular mortality. The full relative benefit from nitrendipine was seen as early as 6 months after randomization. To ascertain that the benefit conferred by the dihydropyridine was not due to selection bias, the 1327 patients remaining on monotherapy with nitrendipine were matched by gender, age, previous cardiovascular complications, and systolic blood pressure at entry with an equal number of placebo patients. In this analysis, nitrendipine reduced (
P
≤0.05) cardiovascular mortality by 41%, all cardiovascular end points by 33%, and fatal and nonfatal cardiac end points by 33%. Despite the limitations inherent in post hoc analyses, the present findings suggest that the calcium channel blocker nitrendipine, given as a single antihypertensive medication, prevents cardiovascular complications in older patients with isolated systolic hypertension.
Pressure Mediates Angiotensin II–Induced Arterial Hypertrophy and PDGF-A Expression
Authors: Parker Sheri B. , Wade Suzanne S. , Prewitt Russell L.
Published: June 2012

Abstract
—Angiotensin II (Ang II) may induce arterial hypertrophy either directly or through an increase in arterial pressure. To separate these 2 mechanisms, rats were implanted with osmopumps delivering either Ang II (100 ng · kg
−1
· min
−1
) or saline. 5-Bromo-2′-deoxyuridine (BrdU) was delivered to both groups by osmopump (2.5 μg · kg
−1
· min
−1
). Half of the rats in each group were given minoxidil (9 mg · kg
−1
· d
−1
) in their drinking water. After 14 days, systolic blood pressure was 117±2, 124±3, and 115±2 mm Hg in the control, Ang II–minoxidil, and minoxidil groups, respectively, and 181±6 mm Hg in the Ang II group (
P
<0.05). After perfusion-fixation, the thoracic aorta, carotid artery, small mesenteric artery, external spermatic artery, and kidneys were harvested, paraffin-embedded, and used for morphological measurements, immunohistochemistry for BrdU, and in situ hybridization with a
35
S-labeled riboprobe for platelet-derived growth factor–A chain (PDGF-A) mRNA. The walls of the aorta and carotid arteries hypertrophied in the Ang II group only. There were no significant morphological differences in the small arteries. BrdU was negative in all arteries but positive in the renal tubules. Expression of PDGF-A was elevated 8-fold in the thoracic aorta of the Ang II group (
P
<0.05). These results show that (1) arterial hypertrophy from Ang II infusion occurs in response to elevated arterial pressure, (2) hypertrophy was not associated with hyperplasia or polyploidy of vascular smooth muscle cells, and (3) PDGF-A expression correlated with elevated pressure and arterial wall hypertrophy.
Angiotensin II Type 1 Receptor
Authors: Ishizaka Nobukazu , Griendling Kathy K. , Lassègue Bernard , Alexander R. Wayne
Published: June 2012

Abstract
—Caveolae are membrane domains that have been implicated in signal transduction, and caveolins are major structural components of these domains. We found that all reported caveolin isoforms (caveolin-1, -2, and -3) were expressed in vascular smooth muscle cells (VSMCs); however, only caveolin-1 mRNA was regulated by angiotensin II (Ang II). Ang II (100 nmol/L) increased caveolin-1 mRNA, with a peak at 2 hours (193±6% of control,
P
<0.01, n=4). In contrast, Ang II significantly decreased caveolin-1 protein, with a nadir at 4 hours (64±5% of control,
P
<0.01, n=6). [
35
S]Methionine labeling showed that Ang II increased caveolin biosynthesis (226±33% of control labeling at 4 hours), suggesting that the transient decrease in caveolin protein levels is due to increased degradation. When cells were fractionated with sucrose, on agonist stimulation, AT
1
receptors appeared in fraction 5 where caveolin was fractionated. This migration was blocked by low temperature and treatment with phenylarsine oxide, interventions that interfere with agonist-induced Ang II type 1 (AT
1
) receptor sequestration and tonic phase signaling. In addition, caveolin-1 coimmunoprecipitates with AT
1
receptor only on agonist stimulation. These data support the concept that the caveola is a specialized signaling domain in VSMCs that can be dynamically accessed by the AT
1
receptor. Because of the signaling and coupling proteins that are localized in caveolae and because of evidence that these proteins may interact directly with caveolin, caveola–AT
1
receptor interaction likely represents an important focus for dynamic control of receptor signaling in VSMCs.
Role of NADH/NADPH Oxidase–Derived H
2
O
2
in Angiotensin II–Induced Vascular Hypertrophy
Authors: Zafari A. Maziar , Ushio-Fukai Masuko , Akers Marjorie , Yin Qiqin , Shah Aalok , Harrison David G. , Taylor W. Robert , Griendling Kathy K.
Published: June 2012

Abstract
—Recent evidence suggests that oxidative mechanisms may be involved in vascular smooth muscle cell (VSMC) hypertrophy. We previously showed that angiotensin II (Ang II) increases superoxide production by activating an NADH/NADPH oxidase, which contributes to hypertrophy. In this study, we determined whether Ang II stimulation of this oxidase results in H
2
O
2
production by studying the effects of Ang II on intracellular H
2
O
2
generation, intracellular superoxide dismutase and catalase activity, and hypertrophy. Ang II (100 nmol/L) significantly increased intracellular H
2
O
2
levels at 4 hours. Neither superoxide dismutase activity nor catalase activity was affected by Ang II; the SOD present in VSMCs is sufficient to metabolize Ang II–stimulated superoxide to H
2
O
2
, which accumulates more rapidly than it is degraded by catalase. This increase in H
2
O
2
was inhibited by extracellular catalase, diphenylene iodonium, an inhibitor of the NADH/NADPH oxidase, and the AT
1
receptor blocker losartan. In VSMCs stably transfected with antisense p22phox, a critical component of the NADH/NADPH oxidase in which oxidase activity was markedly reduced, Ang II–induced production of H
2
O
2
was almost completely inhibited, confirming that the source of Ang II–induced H
2
O
2
was the NADH/NADPH oxidase. Using a novel cell line that stably overexpresses catalase, we showed that this increased H
2
O
2
is a critical step in VSMC hypertrophy, a hallmark of many vascular diseases. Inhibition of intracellular superoxide dismutase by diethylthiocarbamate (1 mmol/L) also resulted in attenuation of Ang II–induced hypertrophy (62±2% inhibition). These data indicate that AT
1
receptor–mediated production of superoxide generated by the NADH/NADPH oxidase is followed by an increase in intracellular H
2
O
2
, suggesting a specific role for these oxygen species and scavenging systems in modifying the intracellular redox state in vascular growth.
Converting Enzyme Determines Plasma Clearance of Angiotensin-(1–7)
Authors: Yamada Kazuo , Iyer Shridhar N. , Chappell Mark C. , Ganten Detlev , Ferrario Carlos M.
Published: June 2012

Abstract
—We determined the mechanism accounting for the removal and metabolism of angiotensin-(1–7) [Ang-(1–7)] in 21 anesthetized spontaneously hypertensive (SHR), 18 age-matched normotensive Sprague-Dawley (SD), and 36
mRen-2
transgenic (TG
+
) rats. Animals of all 3 strains were provided with tap water or tap water containing losartan, lisinopril, or a combination of lisinopril and losartan for 2 weeks. On the day of the experiment, Ang-(1–7) was infused for a period of 15 minutes at a rate of 278 nmol · kg
−1
· min
−1
. After this time, samples of arterial blood were collected rapidly at regular intervals for the assay of plasma Ang-(1–7) levels by radioimmunoassay. Infusion of Ang-(1–7) had a minimal effect on vehicle-treated SD rats but elicited a biphasic pressor/depressor response in vehicle-treated SHR and TG
+
rats. In lisinopril-treated rats, Ang-(1–7) infusion increased blood pressure, whereas losartan treatment abolished the pressor component of the response without altering the secondary fall in arterial pressure. Combined treatment with lisinopril and losartan abolished the cardiovascular response to Ang-(1–7) in all 3 strains. In vehicle-treated SD, SHR and TG
+
the half-life (t
1/2
) of Ang-(1–7) averaged 10±1, 10±1, and 9±1 seconds, respectively. Lisinopril alone or in combination with losartan produced a statistically significant rise in the half-life of Ang-(1–7) in all 3 strains of rats. Plasma clearance of Ang-(1–7) was significantly greater in the untreated SD rats compared with either the SHR or TG
+
rat. Lisinopril treatment was associated with reduced clearance of Ang-(1–7) in all 3 strains. Concurrent experiments in pulmonary membranes from SD and SHR showed a statistically significant inhibition of
125
I-Ang-(1–7) metabolism in the presence of lisinopril. These studies showed for the first time that the very short half-life of Ang-(1–7) in the circulation is primarily accounted for peptide metabolism by ACE. These findings suggest a novel role of ACE in the regulation of the production and metabolism of the two primary active hormones of the renin angiotensin system.
Structural Vascular Changes in Hypertension
Authors: Simon Geza , Illyes Gyorgy , Csiky Botond
Published: June 2012

Abstract
—The dose and time dependence of angiotensin II (Ang II)–induced hypertension and structural vascular changes and the effect of dietary sodium supplementation on these relationships were investigated. Male Sprague-Dawley rats were treated with 50, 100, or 200 ng · kg
−1
· min
−1
Ang II subcutaneously for 4 or 12 weeks on normal sodium diet (0.7% NaCl) or with 50 ng · kg
−1
· min
−1
Ang II SC for 12 weeks on high sodium diet (2% NaCl). Additional rats were sham-operated and fed normal sodium (control rats) or high sodium diet. Plasma Ang II level of rats receiving 100 ng · kg
−1
· min
−1
Ang II for 4 weeks was 26±5 pg/mL (mean±SEM, n=7) compared with 11±2 pg/mL (n=15) in control rats (
P
<0.03). Lumen and external diameters of small (50 to 100 μm OD) and intermediate-size (100 to 150 μm OD) resistance arteries were measured in maximally dilated, pump-perfused (55 to 60 mm Hg), in situ fixed mesenteric vascular beds of rats, and wall-to-lumen ratios (W/L) were calculated. Large mesenteric arteries of rats treated with 100 ng · kg
−1
· min
−1
Ang II for 12 weeks were examined to distinguish hypertrophy from hyperplasia of vascular muscle. Tail systolic blood pressure (BP) and W/L of resistance arteries of Ang II–treated rats increased in a dose-dependent manner. Treatment with 50 ng · kg
−1
· min
−1
Ang II for 12 weeks had no significant effect on BP but produced the same increase in W/L (+10%, n=8,
P
<0.06) as 100 ng · kg
−1
· min
−1
Ang II for 4 weeks (+9%, n=18,
P
<0.05) (time dependence). A 2% NaCl diet for 12 weeks had no significant effect on either BP or W/L, but in combination with 50 ng · kg
−1
· min
−1
Ang II, it increased systolic BP by 31 mm Hg (
P
<0.01) and W/L of small resistance arteries by 28% (
P
<0.01) (synergism). In rats treated with 100 ng · kg
−1
· min
−1
Ang II for 12 weeks, arterial smooth muscle cell thickness was increased without a change in the number of cell layers (hypertrophy). There was a dissociation between the average BP load (the area under the weekly systolic BP curve) of Ang II–treated rats and the W/L of their mesenteric resistance arteries. Ang II–induced hypertension and structural vascular changes are dose- and time-dependent and synergistically enhanced by dietary sodium supplementation. Dissociation between BP and vascular structure in Ang II–treated rats suggests that a direct trophic effect of Ang II may contribute to the development of structural vascular changes.
Nitric Oxide–Dependent Vasodilation in Young Spontaneously Hypertensive Rats
Authors: Radaelli Alberto , Mircoli Luca , Mori Ileana , Mancia Giuseppe , Ferrari Alberto U.
Published: June 2012

Abstract
—Conflicting evidence exists on the possible impairment of tonic nitric oxide (NO)–mediated vasodilation as a causative factor in the genesis of human as well as experimental hypertension. We evaluated the tonic NO-dependent vasodilation from the pressor response to NO synthesis inhibition by
N
G
-monomethyl-
l
-arginine (L-NMMA) in 9 conscious, chronically instrumented spontaneously hypertensive rats (SHR) at 12 weeks of age, ie, during the early established hypertensive stage. Nine age-matched Wistar-Kyoto rats (WKY) were used as controls. The pressor responses to L-NMMA (100 mg · kg
−1
IV bolus plus 1.5 mg · kg
−1
· min
−1
infusion for 60 minutes) as well as to non–NO-dependent pressor stimuli, namely, vasopressin (2, 4, and 8 ng · kg
−1
) and phenylephrine (0.5, 1, and 2 μg · kg
−1
) given as IV boluses, were assessed both under control conditions and during suppression of autonomic reflexes by hexamethonium (30 mg · kg
−1
IV bolus+1.5 mg · kg
−1
· min
−1
infusion). Rather than being reduced, the pressor responses to L-NMMA were 39% and 71% larger in the control and areflexic conditions, respectively, than those observed in WKY (both
P
<0.01). A similar pattern was observed for the pressor responses to vasopressin (+37% and +68% in the control and areflexic conditions, respectively; both
P
<0.01) and phenylephrine, (+20% and +52%; both
P
<0.05). Additional groups of 6-week-old prehypertensive SHR (n=11) and age-matched WKY (n=11) were subjected to an identical protocol: in these animals, the pressor responses to L-NMMA were similar in each strain, as were the pressor responses to vasopressin and phenylephrine in both control and areflexic conditions. In conclusion, our observations indicate that during the developmental phase of hypertension in the SHR model, namely, during the prehypertensive as well as the early established hypertensive stage, NO-dependent vasodilation is preserved (if not enhanced) so that a putative impairment of this function provides no significant pathogenic contribution to the onset of hypertension in this experimental model.
Chamber-Specific Alterations of Norepinephrine Uptake Sites in Cardiac Hypertrophy
Authors: Böhm Michael , Castellano Maurizio , Flesch Markus , Maack Christoph , Moll Marianne , Paul Martin , Schiffer Frank , Zolk Oliver
Published: June 2012

Abstract
—The present study investigated local differences of sympathetic activation and sympathetic neuroeffector defects in nonhypertrophied right and hypertrophied left ventricles in a rat model with renin-induced pressure overload [TG(m
REN
2)27]. As judged from the depletion of myocardial norepinephrine stores, sympathetic activation was more pronounced in the left than in the right ventricles. In addition, norepinephrine uptake
1
carrier sites were reduced in left but unchanged in right ventricles. Gene expression of the carrier was unchanged in stellate ganglia. An increase of G
iα
expression and a heterologous adenylyl cyclase desensitization occurred only in the left but not in the right ventricles, whereas a reduction of β-adrenergic receptors was observed in both chambers. We concluded that general sympathetic activation can lead to β-adrenoceptor downregulation but that pressure overload further increases sympathetic activation involving norepinephrine uptake mechanisms in the left ventricles, resulting in heterologous β-adrenergic desensitization.
Clustering of Endothelial Markers of Vascular Damage in Human Salt-Sensitive Hypertension
Authors: Ferri Claudio , Bellini Cesare , Desideri Giovambattista , Giuliani Elisabetta , De Siati Luca , Cicogna Sabrina , Santucci Anna
Published: June 2012

Abstract
—The contributing role of vascular endothelium in the development of hypertension-related vascular damage is well accepted. Salt-sensitive hypertension is characterized by a cluster of renal, hormonal, and metabolic derangements that might favor the development of cardiovascular and renal damage. To evaluate endothelial involvement in salt-sensitive essential hypertension, plasma levels of several markers of endothelial damage such as endothelin-1 (ET-1), von Willebrand factor (vWf), and soluble (S-) adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and 24-hour urinary albumin excretion (UAE) were measured in 39 nondiabetic, nonobese, never-treated essential hypertensive patients after intermediate (120 mmol/d), high (220 mmol/d), and low (20 mmol/d) NaCl diets. Patients were classified as salt sensitive (n=18) or salt resistant (n=21) according to their blood pressure responses to changes in dietary NaCl intake. Salt-sensitive hypertensives showed higher plasma ET-1 (
P
<0.05), vWf (
P
<0.005), and S-E-selectin levels (
P
<0.04) and increased UAE (
P
<0.05) than salt-resistant hypertensives. By contrast, circulating S-ICAM-1 and S-VCAM-1 concentrations were not significantly higher in salt-sensitive (596.56±177.05 ng/mL and 541.06±157.84 ng/mL, respectively) than salt-resistant patients (516.86±147.99 ng/mL and 449.48±158.91 ng/mL, respectively). During the intermediate NaCl diet, plasma ET-1 responses to oral glucose load were greater in salt-sensitive (
P
<0.05) than in salt-resistant patients. A marked (
P
<0.05) hyperinsulinemic response to oral glucose load was evident in salt-sensitive but not salt-resistant patients after each diet. This study shows increased plasma levels of the endothelium-derived substances E-selectin, vWf, and ET-1 in salt-sensitive hypertensives. Our findings support the hypothesis that salt sensitivity is correlated with an increased risk for developing hypertension-related cardiovascular damage.
Autocrine Role for the Endothelin-B Receptor in the Secretion of Adrenomedullin
Authors: Jougasaki Michihisa , Schirger John A. , Simari Robert D. , Burnett John C.
Published: June 2012

Abstract
—Adrenomedullin, originally discovered in human pheochromocytoma, is a vasodilating and natriuretic peptide of vascular endothelial and smooth muscle cell origin. Although endothelin-1 (ET-1) has been implicated as a vasoconstricting and growth-promoting peptide of endothelial origin, it may more importantly function as an autocrine factor and release vasodilatory substances such as nitric oxide by mechanisms linked to the endothelin-B (ET
B
) receptor subtype. The present study was designed to establish that the ET
B
receptor stimulates the secretion of adrenomedullin from cultured canine aortic endothelial cells. We first sought to determine the presence and production of adrenomedullin in canine aortic endothelial cells using immunohistochemistry and Northern blot analysis, which revealed that adrenomedullin immunoreactivity and adrenomedullin mRNA were present in canine aortic endothelial cells. Second, adrenomedullin was time-dependently secreted from canine aortic endothelial cells, with a secretion rate of 15.7±1.5 pg/10
5
cells per 24 hours. Furthermore, immunohistochemistry revealed the presence of the ET
B
receptor in canine aortic endothelial cells, and ET
B
receptor stimulation by sarafotoxin S6c increased adrenomedullin production and secretion from canine aortic endothelial cells. Such actions were blocked with the ET
B
receptor antagonist IRL-2500 but not with ET
A
receptor antagonist FR-139317. These studies are the first to report an additional autocrine role of the ET
B
receptor in the release of vasodilating and natriuretic peptide adrenomedullin, and they suggest another important vasoactive system regulated by the ET receptor subtype.
G Protein β3 Subunit Variant and Essential Hypertension in Japanese
Authors: Kato Norihiro , Sugiyama Takao , Morita Hiroyuki , Kurihara Hiroki , Yamori Yukio , Yazaki Yoshio
Published: June 2012

Abstract
—Enhanced G protein activation has been implicated to underlie the increased sodium-proton transport in blood cells, an impaired characteristic observed in 30% to 50% of patients with essential hypertension. Recently, significant association between a C825T polymorphism of the gene encoding the G protein β3 subunit and hypertension was demonstrated in a white population, together with the finding that the T825 variant might be related to alternative splicing through unidentified mechanisms. We therefore investigated the disease relevance of this candidate gene by conducting an association study in a relatively large Japanese population. Participants comprised 718 hypertensive case subjects (without diabetes mellitus), 515 normotensive control subjects, and 191 hypertensive subjects with borderline or established diabetes mellitus; all individuals were recruited at a single institution. Genotype distribution of the C825T polymorphism was compared between hypertensive subjects, with or without diabetes, and the control group with χ
2
statistics. No significant association was observed in the present study. Results were still not significant when the case group was subdivided according to more stringent classification criteria. Allele frequencies of T825 proved to be almost concordant among the 3 study groups and higher in Japanese (49.0% to 49.6%) compared with a reported prevalence of 25% to 31% in whites. Our data suggest that the T825 variant of the G protein β3 subunit gene is unlikely to constitute major susceptibility for essential hypertension in the Japanese population studied. However, further investigation is required to answer the question of whether the lack of association reflects ethnic differences in the nature of genetic susceptibility loci.
Chloride Regulates Afferent Arteriolar Contraction in Response to Depolarization
Authors: Hansen Pernille Bjørg , Jensen Boye L. , Skøtt Ole
Published: June 2012

Abstract
—Renal vascular reactivity is influenced by the level of dietary salt intake. Recent in vitro data suggest that afferent arteriolar contractility is modulated by extracellular chloride. In the present study, we assessed the influence of chloride on K
+
-induced contraction in isolated perfused rabbit afferent arterioles. In 70% of vessels examined, K
+
-induced contraction was abolished by acute substitution of bath chloride. Consecutive addition of Cl
−
(30, 60, 80, 100, 110, and 117 mmol/L) restored the sensitivity to K
+
, and half-maximal response was observed at 82 mmol/L chloride. The calcium channel antagonist diltiazem (10
−6
mol/L) abolished K
+
-induced contractions. Bicarbonate did not modify the sensitivity to chloride. Norepinephrine (10
−6
mol/L) induced full contraction in depolarized vessels even in the absence of chloride. Iodide and nitrate were substituted for chloride with no inhibitory effect on K
+
-induced contraction. Approximately 30% of the vessels constricted in response to K
+
in the absence of chloride. This response was reversibly blocked by the α
1
-blocker phentolamine (PA) (10
−5
mol/L) and, with PA present, the dependence on chloride was similar to the above series. The results show that K
+
-induced contraction of smooth muscle cells in the afferent arteriole is highly sensitive to chloride, whereas neurotransmitter release and ensuing contraction is not dependent on chloride. Thus, there are different activation pathways for depolarizing vasoconstrictors and for the sympathetic nervous system in renal afferent arterioles. This could be of physiological relevance for the resetting of afferent arteriolar sensitivity during changes in salt intake.
Renal 11β-Hydroxysteroid Dehydrogenase in Genetically Salt-Sensitive Hypertensive Rats
Authors: Takeda Yoshiyu , Inaba Satoru , Furukawa Kenji , Miyamori Isamu
Published: June 2012

Abstract
—Renal 11β-hydroxysteroid dehydrogenase II (11β-HSDII) converts glucocorticoids into inactive metabolites and plays an important role in controlling blood pressure and sodium retention. To examine whether this enzyme may be involved in the pathophysiology of salt-sensitive hypertension, we determined 11β-HSDII activity and mRNA levels in the blood vessel and kidney of Dahl Iwai salt-sensitive (DS) rats and Dahl Iwai salt-resistant (DR) rats. Urinary free corticosterone:free 11-dehydrocorticosterone ratio was measured to estimate renal 11β-HSD activity. Vascular 11β-HSDII activity was expressed as percent conversion of [
3
H]corticosterone to [
3
H]11-dehydrocorticosterone in homogenized mesenteric arteries. 11β-HSDII mRNA was estimated with the use of competitive polymerase chain reaction (PCR). Renal 11β-HSDII activity and mRNA levels were significantly decreased in 8- and 12-week-old high salt DS rats compared with DR, Sprague-Dawley (SD), or low salt DS rats of the same age. Decreased 11β-HSDII activity and mRNA levels in mesenteric arteries were observed in 8- and 12-week-old high salt DS rats. Urinary excretion of 11β-HSDII inhibitory factors was measured by inhibition of enzyme activity in microsomes from human kidney. The urinary inhibitors were significantly increased in 8- and 12-week-old high salt DS rats compared with DR, SD, or low salt DS rats of the same age. There were no significant differences in 11β-HSDII activity and mRNA levels in mesenteric arteries and kidney or in urinary inhibitors between 4-week-old DS, DR, and SD rats. These results indicate that 11β-HSDII may play a role in salt sensitivity and development of hypertension in the DS rat.
Inverse Relationship Between Fenfluramine-Induced Prolactin Release and Blood Pressure in Humans
Authors: Muldoon Matthew F. , Sved Alan F. , Flory Janine D. , Perel James M. , Matthews Karen A. , Manuck Stephen B.
Published: June 2012

Abstract
—Although substantial evidence from experimental animals suggests that augmentation and reduction in serotonergic neurotransmission both affect arterial blood pressure (BP), it is unknown whether “tonic” central serotonergic activity is related to resting BP variability in humans. We tested this hypothesis in a community sample by evaluating the relationship between resting BP and a neuropharmacologic index of brain serotonergic activity (the fenfluramine challenge test). Subjects were 270 generally healthy men and women aged 25 to 60 years who were not receiving prescribed antihypertensive or psychotropic medications. The sample included 216 non-Hispanic whites and 47 blacks. Resting systolic BP ranged from 85 to 161 mm Hg and diastolic from 58 to 98 mm Hg. Each subject received 0.55 to 0.65 mg/kg
d,l
-fenfluramine hydrochloride, and the plasma prolactin concentration was measured over 3.5 hours. Analyses revealed a linear, inverse relationship between the maximum fenfluramine-induced prolactin rise and systolic and diastolic BP in whites:
r
=−0.36 and
r
=−0.29, respectively (
P
<0.001 for both). These relationships were not observed in the black participants. In whites, the prolactin response to fenfluramine remained a significant predictor of systolic and diastolic BPs in multivariate models including age, gender, body mass index, physical activity, smoking, and alcohol consumption (
P
≤0.001). When compared with subjects in the highest quartile of prolactin response, individuals whose prolactin responses to fenfluramine comprised the lowest quartile were 2.6 times more likely to have a resting systolic/diastolic BP of >135/85 mm Hg. These data reveal that in white but not black adults, fenfluramine-induced prolactin release correlates inversely with BP and may indicate a role of central serotonergic activity in the pathogenesis of hypertension.
Proximal Tubular Angiotensin II Levels and Renal Functional Responses to AT
1
Receptor Blockade in Nonclipped Kidneys of Goldblatt Hypertensive Rats
Authors: Cervenka Ludek , Wang Chi-Tarng , Mitchell Kenneth D. , Navar L. Gabriel
Published: June 2012

Abstract
—Previous studies have shown that whereas the nonclipped kidney in two-kidney, one clip (2K1C) rats undergoes marked depletion of renin content and renin mRNA, intrarenal angiotensin II (Ang II) levels are not suppressed; however, the distribution and functional consequences of intrarenal Ang II remain unclear. The present study was performed to assess the plasma, kidney, and proximal tubular fluid levels of Ang II and the renal responses to intrarenal Ang II blockade in the nonclipped kidneys of rats clipped for 3 weeks. The Ang II concentrations in proximal tubular fluid averaged 9.19±1.06 pmol/mL, whereas plasma Ang II levels averaged 483±55 fmol/mL and kidney Ang II content averaged 650±66 fmol/g. Thus, as found in kidneys from normal rats with normal renin levels, proximal tubular fluid concentrations of Ang II are in the nanomolar range. To avoid the confounding effects of decreases in mean arterial pressure (MAP), we administered the nonsurmountable AT
1
receptor antagonist candesartan directly into the renal artery of nonclipped kidneys (n=10). The dose of candesartan (0.5 μg) did not significantly decrease MAP in 2K1C rats (152±3 versus 148±3 mm Hg), but effectively prevented the renal vasoconstriction elicited by an intra-arterial bolus of Ang II (2 ng). Candesartan elicited significant increases in glomerular filtration rate (GFR) (0.65±0.06 to 0.83±0.11 mL · min
−1
· g
−1
) and renal blood flow (6.3±0.7 to 7.3±0.9 mL · min
−1
· g
−1
), and proportionately greater increases in absolute sodium excretion (0.23±0.07 to 1.13±0.34 μmol · min
−1
· g
−1
) and fractional sodium excretion (0.38±0.1% to 1.22±0.35%) in 2K1C hypertensive rats. These results show that proximal tubular fluid concentrations of Ang II are in the nanomolar range and are much higher than can be explained on the basis of plasma levels. Further, the data show that the intratubular levels of Ang II in the nonclipped kidneys of 2K1C rats remain at levels found in kidneys with normal renin content and could be exerting effects to suppress renal hemodynamic and glomerular function and to enhance tubular reabsorption rate.
C-Type Natriuretic Peptide Attenuates Evoked Dopamine Efflux by Influencing G
o
α
Authors: Takida Satoshi , Elmquist Barbara J. , Trachte George J.
Published: June 2012

Abstract
—Natriuretic peptides suppress adrenergic neurotransmission by a mechanism sensitive to pertussis toxin, suggesting that GTP-binding proteins are involved in the response. The major GTP-binding proteins present in the pheochromocytoma (PC12) cells used in this report are G
o
α and G
i
α
2
. We tested the hypothesis that the more abundant GTP-binding protein, G
o
α, mediates natriuretic peptide effects in PC12 cells by selectively ablating G
o
α from the cells with antisense oligodeoxynucleotides. The results indicate that a selective ablation of G
o
α with this technique eliminated C-type natriuretic peptide (CNP) effects and suppressed dopamine efflux evoked by a depolarizing stimulus. However, the activation of guanylyl cyclase (GC) by CNP was sustained after the G
o
α ablation. Further,
N
ω
-nitro-
l
-arginine methyl ester suppressed evoked dopamine efflux equally in the presence and absence of G
o
α. These results suggest that CNP attenuates evoked catecholamine efflux from PC12 cells by a mechanism requiring G
o
α but independent of GC activation.