bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevention of Hypertension by Irbesartan in Dahl S Rats Relates to Central Angiotensin II Type 1 Receptor Blockade
Authors: Leenen Frans H. H. , Yuan Baoxue
Published: June 2012

Hypertension in Dahl S rats on high-salt intake is in general considered a model of “low-renin hypertension,” unresponsive to treatment with blockers of the renin-angiotensin system. However, direct central administration of an angiotensin II type 1 (AT
1
) receptor blocker prevents both the sympathoexcitation and hypertension caused by high-salt intake in Dahl S rats. In the present study, we tested the hypothesis that chronic peripheral administration of an AT
1
receptor blocker inhibits the salt-induced hypertension relative to the extent of central AT
1
receptor blockade that is induced. Dahl S rats received a high-salt (1370 μmol Na
+
/g) or regular (101 μmol Na
+
/g) diet from 4 to 8 weeks of age. In 3 different sets of experiments, Dahl S on high salt were randomized to intracerebroventricular (ICV) treatment with control infusion versus irbesartan at 50 or 250 μg · kg
−1
· d
−1
, oral treatment with control versus irbesartan at 125 or 500 mg · kg
−1
· d
−1
once daily by gavage, or subcutaneous treatment with control versus irbesartan at 50 or 150 mg · kg
−1
· d
−1
by once daily injection. At 8 weeks of age, MAP was measured in conscious rats at rest and in response to angiotensin II ICV or IV. On high-salt intake, Dahl S developed the anticipated marked increase in MAP to ≈160 mm Hg. Irbesartan ICV did not affect pressor responses to angiotensin II IV, but irbesartan administered subcutaneously or by gavage markedly inhibited these responses. Irbesartan ICV or by gavage partially inhibited pressor responses to angiotensin II ICV and the development of hypertension. Irbesartan subcutaneously at the higher dose more completely inhibited pressor responses to angiotensin II ICV and fully prevented the salt-induced hypertension. The degree of central but not peripheral AT
1
receptor blockade parallels the antihypertensive effect of irbesartan, indicating that inhibition of the brain renin-angiotensin system can contribute to a significant extent to the therapeutic effectiveness of AT
1
receptor blockers such as irbesartan when administered in sufficiently high doses to cause central AT
1
receptor blockade.
Hypothesis
Authors: Aviv Abraham
Published: June 2012

Abstract
—In exploration of the association between pulse pressure and longevity in humans, 3 hypotheses are briefly discussed: the fetal origin hypothesis, antagonistic pleiotropy, and the telomere hypothesis of cellular aging. The implications of these hypotheses serve to draw a critical distinction between biologic age (aging) and chronological age and, thereby, offer an answer to a question that presently matters most in the field of hypertension: Why has it been so difficult to disentangle the genetic components of essential hypertension and to identify the variant genes responsible for elevated blood pressure in a large segment of the human population?
Fenestrations of the Carotid Internal Elastic Lamina and Structural Adaptation in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Boumaza Saliha , Arribas Silvia M. , Osborne-Pellegrin Mary , McGrath John C. , Laurent Stéphane , Lacolley Patrick , Challande Pascal
Published: June 2012

Abstract
—Our aim was to determine the structural factors that determine the mechanical adaptation of the carotid arterial wall in stroke-prone hypertensive rats (SHRSP). Distensibility-pressure and elastic modulus–stress curves assessed by in vivo echo-tracking measurements indicated a reduction in arterial stiffness in 13-week-old SHRSP compared with Wistar-Kyoto rats (WKY). Elastin and collagen contents determined biochemically were not different between SHRSP and WKY. Confocal microscopy showed that the mean area of fenestrations and fraction of area occupied by fenestrations of the internal elastic lamina (IEL) were smaller in SHRSP than in WKY, which indicated a reduction in stress-concentration effects within the IEL. Immunohistologic staining of EIIIA fibronectin isoform and total fibronectin (also as determined by Western blot) was greater in SHRSP, which suggested increased cell-matrix interactions. We suggest that these structural modifications of the vascular wall play a synergistic role in the mechanical adaptation to a high level of stress in SHRSP.
Lacidipine Prevents Endothelial Dysfunction in Salt-Loaded Stroke-Prone Hypertensive Rats
Authors: Krenek Peter , Salomone Salvatore , Kyselovic Jan , Wibo Maurice , Morel Nicole , Godfraind Théophile
Published: June 2012

Abstract
—Endothelium-dependent vasorelaxation is defective in hypertensive rats, especially in conduit arteries. In the stroke-prone spontaneously hypertensive rat, impaired endothelium-dependent vasorelaxation appears to contribute to the pathogenesis of stroke independent of blood pressure. Because treatment with lacidipine, a long-acting calcium channel blocker, protects against stroke and cardiovascular remodeling in this model, we investigated the effect of this treatment on endothelium-dependent vasorelaxation in the aorta. Stroke-prone rats were exposed to a salt-rich diet (1% NaCl in drinking water) with or without lacidipine (1 mg · kg
−1
· d
−1
) for 6 weeks. A high-sodium diet (1) increased systolic blood pressure, aortic weight, and wall thickness and plasma renin activity (
P
<0.05); (2) markedly reduced nitric oxide (NO)-mediated, endothelium-dependent relaxation of aortic rings to acetylcholine and the sensitivity to the relaxing effect of
S
-nitroso-
N
-acetylpenicillamine, an NO donor (
P
<0.001); and (3) induced an elevation of preproendothelin-1 mRNA levels in aortic tissue (
P
<0.01) without affecting endothelial NO synthase mRNA levels. Lacidipine treatment prevented the salt-dependent functional and structural alterations of the aorta, including the overexpression of the preproendothelin-1 gene, and increased endothelial NO synthase mRNA levels in aortic tissue (
P
<0.01). In conclusion, lacidipine protects stroke-prone hypertensive rats against the impairment of endothelium-dependent vasorelaxation evoked by a salt-rich diet, and this effect may contribute to its beneficial effect against end-organ damage and stroke.
Gender Differences in the Regulation of Blood Pressure
Authors: Reckelhoff Jane F.
Published: June 2012

Abstract
—Men are at greater risk for cardiovascular and renal disease than are age-matched, premenopausal women. Recent studies using the technique of 24-hour ambulatory blood pressure monitoring have shown that blood pressure is higher in men than in women at similar ages. After menopause, however, blood pressure increases in women to levels even higher than in men. Hormone replacement therapy in most cases does not significantly reduce blood pressure in postmenopausal women, suggesting that the loss of estrogens may not be the only component involved in the higher blood pressure in women after menopause. In contrast, androgens may decrease only slightly, if at all, in postmenopausal women. In this review the possible mechanisms by which androgens may increase blood pressure are discussed. Findings in animal studies show that there is a blunting of the pressure-natriuresis relationship in male spontaneously hypertensive rats and in ovariectomized female spontaneously hypertensive rats treated chronically with testosterone. The key factor in controlling the pressure-natriuresis relationship is the renin-angiotensin system (RAS). The possibility that androgens increase blood pressure via the RAS is explored, and the possibility that the RAS also promotes oxidative stress leading to production of vasoconstrictor substances and reduction in nitric oxide availability is proposed.
Maternal Diastolic Dysfunction and Left Ventricular Geometry in Gestational Hypertension
Authors: Valensise Herbert , Novelli Gian Paolo , Vasapollo Barbara , Di Ruzza Giancarlo , Romanini Maria Elisabetta , Marchei Massimo , Larciprete Giovanni , Manfellotto Dario , Romanini Carlo , Galante Alberto
Published: June 2012

Abstract
—The objective of this study was to evaluate diastolic parameters and left ventricular geometry in gestational hypertension. Twenty-one consecutive pregnant women with gestational hypertension and 21 normotensive women matched for age and gestational age were enrolled in the third trimester of gestation. Echocardiographic and uterine color Doppler evaluations were performed. Systolic, diastolic, and mean blood pressure, total vascular resistance (TVR), and uterine resistance index were higher in hypertensive women than in control subjects (
P
<0.01). Left atrial function and cardiac output were significantly lower in gestational hypertension (
P
<0.01). Patients with gestational hypertension had longer left ventricular isovolumetric relaxation time (IVRT) (
P
<0.0001); lower velocity-time integral of the A wave (
P
<0.05) and of the diastolic pulmonary vein flow (
P
<0.05); and higher velocity-time integral of the reverse pulmonary vein flow (
P
<0.05). Systolic fraction of the pulmonary vein flow was higher in women with gestational hypertension than in control subjects (
P
<0.01); the difference in duration of pulmonary vein flow and A wave was closer to 0 in gestational hypertension (
P
<0.0001). Altered left ventricular geometry was found in 100% of hypertensive patients and in 19.05% of normotensive patients (
P
<0.001). IVRT, left ventricular end-systolic volume, atrial function, and uterine resistance index were directly related to TVR (
P
<0.01); deceleration time of the E wave showed a quadratic correlation with TVR (
P
<0.01). Gestational hypertension is characterized by an altered cardiac geometric pattern of concentric hypertrophy. The altered geometric pattern assessed during gestational hypertension is associated, in our study, with depressed systolic function, high TVR, altered diastolic function, and left atrial dysfunction. Deceleration time of the E wave, IVRT, and left atrial fractional area change, found in concomitance with the highest TVR, may be useful in the evaluation of cardiac function and hemodynamics present in pregnancy-induced hypertension.
Activation of Cardiac c-Jun NH
2
-Terminal Kinases and p38-Mitogen–Activated Protein Kinases With Abrupt Changes in Hemodynamic Load
Authors: Fischer Thomas A. , Ludwig Stephan , Flory Egbert , Gambaryan Stepan , Singh Krishna , Finn Peter , Pfeffer Marc A. , Kelly Ralph A. , Pfeffer Janice M.
Published: June 2012

Abstract
—The role of mitogen-activated protein kinase (MAPK) pathways as signal transduction intermediates of hemodynamic stress leading to cardiac hypertrophy in the adult heart is not fully established. In a rat model of pressure-overload hypertrophy, we examined whether activation of MAPK pathways, namely, the extracellular signal–regulated protein kinase (ERK), c-Jun NH
2
-terminal kinase (JNK), and the p38-MAPK pathways, occurs during rapid changes in hemodynamic load in vivo. A slight activation of ERK2 and marked increases in JNK1 and p38-MAPK activities were observed 30 minutes after aortic banding. The increase in p38-MAPK activity was accompanied by an increase in the phosphorylation of the p38 substrate MAPK–activated protein kinases 2 and 3. Activation of these kinases was coincident with an increase in phosphorylation of c-Jun and activating transcription factor-2 (ATF-2) and enhanced DNA binding of activator protein-1 factors. Thus, hemodynamic stress of the adult rat heart in vivo results in rapid activation of several parallel MAPK kinase cascades, particularly stress-activated MAPK and p38-MAPK and their target transcription factors c-Jun and ATF-2.
Hypotensive and Natriuretic Actions of Adrenomedullin in Subjects With Chronic Renal Impairment
Authors: McGregor David O. , Troughton Richard W. , Frampton Christopher , Lynn Kelvin L. , Yandle Timothy , Richards A. Mark , Nicholls M. Gary
Published: June 2012

Abstract
—Plasma levels of adrenomedullin are increased in chronic renal failure. The significance of this finding is uncertain, because the biological effects of adrenomedullin in renal impairment are unknown. Therefore, we studied the effects of adrenomedullin infusion in subjects with chronic renal impairment. Eight males with IgA nephropathy and plasma creatinine of 0.19±0.03 mmol/L (mean±SEM) were studied in a vehicle-controlled crossover design. Each subject was studied twice; subjects were administered either adrenomedullin at a low dose and then a high dose (2.9 and 5.8 pmol/kg per minute, respectively, for 2 hours each) or a 4-hour vehicle control (Hemaccel), in random order, on day 4 of controlled metabolic diets. Adrenomedullin infusion achieved plasma adrenomedullin concentrations in the pathophysiological range after the low (31.2±5.1 pmol/L) and high (47.4±4.3 pmol/L) dose, and plasma cAMP was increased. Compared with vehicle control, high-dose adrenomedullin increased peak heart rate (+21.7±3.3 bpm,
P
<0.01) and cardiac output (+2.9±0.2 L/min,
P
<0.01) and lowered both systolic and diastolic blood pressures by >10 mm Hg (
P
<0.05). Plasma renin activity, angiotensin II, and norepinephrine increased by up to 50% above baseline levels (
P
<0.05 for all), whereas aldosterone and epinephrine were unchanged. Urinary volume and sodium excretion increased significantly (
P
<0.05) with low-dose adrenomedullin, whereas creatinine clearance was stable, and proteinuria tended to decrease. In subjects with chronic renal impairment due to IgA nephropathy, adrenomedullin infusion lowered blood pressure, stimulated sympathetic activity and renin release, and caused diuresis and natriuresis. Adrenomedullin may have a role in modulating blood pressure and kidney function in renal disease.
Reversibility of Chronic Experimental Syndrome X by Diet Modification
Authors: Roberts Christian K. , Vaziri Nosratola D. , Liang Kai Hui , Barnard R. James
Published: June 2012

Abstract
—This study was designed to examine whether abnormalities that comprise the metabolic syndrome, including insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia, and obesity, are reversible by diet. Female Fischer rats were placed on either a high-fat, refined-carbohydrate (HFS) diet or low-fat, complex-carbohydrate (LFCC) diet for a period of 20 months. After 20 months, a group of HFS rats were switched to the LFCC diet (HFS/LFCC) for a period of 2 months. Skeletal muscle glucose transport, plasma insulin, systolic blood pressure, and plasma lipids were measured in all groups after 22 months. Energy intake and body weight were measured weekly. In the HFS group, insulin-stimulated glucose transport was significantly reduced (67±4 versus 98±4 pmol · mg
−
1
· 15 s
−
1
), whereas plasma insulin (300±49 versus 82±8 pmol/L), blood pressure (147±4 versus 123±4 mm Hg), plasma triglycerides (2.58±0.31 versus 0.39±0.04 mmol/L), LDL cholesterol (C) (3.45±0.40 versus 0.89±0.06 mmol/L), LDL-C to HDL-C ratio (2.9±0.1 versus 2.2±0.1), VLDL-C (1.53±0.23 versus 0.37±0.07 mmol/l), Total-C (5.56±0.58 versus 1.49±0.10 mmol/L), and body weight (360±11 versus 260±5 g) were all significantly elevated compared with the LFCC. Energy intake did not differ significantly; however, the LFCC had a much poorer feed efficiency. Conversion to a LFCC diet for 2 months led to normalization of glucose transport, blood pressure, plasma insulin, and VLDL-C and significant amelioration of obesity and other lipid abnormalities. These results demonstrate that syndrome X induced by an inappropriate diet is reversed with implementation of a low-fat, unrefined-carbohydrate diet without caloric restriction and suggest that diet may be a possible treatment for multiple simultaneous cardiovascular risk factors.
Quantification of Mechanical and Neural Components of Vagal Baroreflex in Humans
Authors: Hunt Brian E. , Fahy Lisamarie , Farquhar William B. , Taylor J. Andrew
Published: June 2012

Abstract
—Traditionally, arterial baroreflex control of vagal neural outflow is quantified by heart period responses to falling and/or rising arterial pressures (ms/mm Hg). However, it is arterial pressure–dependent stretch of barosensory vessels that determines afferent baroreceptor responses, which, in turn, generate appropriate efferent cardiac vagal outflow. Thus, mechanical transduction of pressure into barosensory vessel stretch and neural transduction of stretch into vagal outflow are key steps in baroreflex regulation that determine the conventional integrated input-output relation. We developed a novel technique for direct estimation of gain in both mechanical and neural components of integrated cardiac vagal baroreflex control. Concurrent, beat-by-beat measures of arterial pressures (Finapres), carotid diameters (B-mode ultrasonography), and R-R intervals (ECG lead II) were made during bolus vasoactive drug infusions (modified Oxford technique) in 16 healthy humans. The systolic carotid diameter/pressure relationship (
r
2
=0.79±0.008, mean±SEM) provided a gain estimate of dynamic mechanical transduction of pressure into a baroreflex stimulus. The R-R interval/systolic diameter relationship (
r
2
=0.77±0.009) provided a gain estimate of afferent-efferent neural transduction of baroreflex stimulus into a vagal response. Variance between repeated measures for both estimates was no different than that for standard gain (
P
>0.40). Moreover, in these subjects, the simple product of the 2 estimates almost equaled standard baroreflex gain (ms/mm Hg=0.98x+2.27;
r
2
=0.93,
P
=0.001). This technique provides reliable information on key baroreflex components not distinguished by standard assessments and gives insight to dynamic mechanical and neural events during acute changes in arterial pressure.
Central Orexin-A Augments Sympathoadrenal Outflow in Conscious Rabbits
Authors: Matsumura Kiyoshi , Tsuchihashi Takuya , Abe Isao
Published: June 2012

Abstract
—We determined the cardiovascular and neurohormonal responses to intracerebroventricular administration of orexin-A in conscious rabbits. Intracerebroventricular injection of orexin-A elicited dose-related increases in mean arterial pressure and renal sympathetic nerve activity. Peak values of mean arterial pressure and renal sympathetic nerve activity induced by intracerebroventricular injection of 100 pmol of orexin-A (14.0±0.7 mm Hg and 55.4±14.9%, respectively) were obtained at 40 and 25 minutes after injection, respectively. Plasma epinephrine and glucose concentrations were significantly increased at 60 and 90 minutes after intracerebroventricular injection of orexin-A (control versus 90 minutes; for epinephrine, 38.0±12.8 versus 167.5±42.5 pg/mL,
P
<0.01; for glucose, 6.66±0.18 versus 7.75±0.14 mmol/L,
P
<0.01). Plasma norepinephrine and insulin concentrations increased at 60 and 90 minutes but did not attain significant values. Intracerebroventricular injection of orexin-A also caused significant increases in plasma vasopressin concentrations. However, pretreatment with an intravenous injection of pentolinium (5 mg/kg), a ganglion-blocking agent, abolished these cardiovascular and neurohormonal responses. On the other hand, intravenous injection of the same dose of orexin-A (100 pmol) used in the intracerebroventricular experiment failed to cause any cardiovascular and renal sympathetic nerve responses. These results suggest that intracerebroventricular orexin-A acts in the central nervous system and activates sympathoadrenal outflow, resulting in increases in arterial pressure and plasma glucose levels in conscious rabbits.
Endothelin Mediates Some of the Renal Actions of Acutely Administered Angiotensin II
Authors: Riggleman Amy , Harvey Jeff , Baylis Chris
Published: June 2012

Recent studies suggest that endogenous endothelin mediates much of the vasoconstrictor activity and vascular fibrotic damage caused by chronic administration of angiotensin II. The present study uses the mixed endothelin-A and endothelin-B receptor antagonist bosentan and the endothelin-A-selective blocker BQ-123 to study the contribution of endogenous endothelin to the pressor and renal action of acutely administered angiotensin II in conscious, chronically catheterized rats. Exposure to angiotensin II at 0.48 pmol 0.5 ng/100 g body weight per min IV (low dose) and 1.91 pmol 2.0 ng/100 g body weight per min IV (high dose) raised mean arterial blood pressure (18±4 mm Hg,
P
<0.01, and 39±4 mm Hg,
P
<0.005, respectively) while also increasing renal vascular resistance (4.3±1 mm Hg/mL per min,
P
<0.001, and 10±1 mm Hg/mL per min,
P
<0.001, respectively). In the presence of bosentan, pressor and renal vasoconstrictor responses to low-dose angiotensin II were blunted (
P
<0.02 and
P
<0.01, respectively), and the results with BQ-123 were similar. In contrast, these parameters were unaffected during high-dose angiotensin II infusion+bosentan, although BQ-123 did selectively reduce the rise in renal vascular resistance, possibly via an endothelin B-mediated nitric oxide effect. In contrast, high-dose angiotensin II caused natriuretic and diuretic effects that were completely prevented by bosentan. These results show that endothelin (via endothelin A) contributes to the pressor and renal vasoconstrictor actions of acutely administered low-dose angiotensin II. Furthermore, our data suggest that the previously described angiotensin II-induced natriuresis and diuresis observed with a high pressor dose of angiotensin II is mediated by endothelin.
Link of Nonhemodynamic Factors to Hemodynamic Determinants of Left Ventricular Hypertrophy
Authors: de Simone Giovanni , Pasanisi Fabrizio , Contaldo Franco
Published: June 2012

Despite current evidence suggesting that hemodynamic load is the fundamental stimulus to begin the sequence of biological events leading to the development of left ventricular hypertrophy, genotype, gender, body size, and less easily recognizable environmental factors may contribute to generate the cascade of molecular changes that eventually yield the increase in protein synthesis needed to increase left ventricular mass. However, even nonhemodynamic factors such as gender and body size eventually regulate the growth of left ventricular mass by at least in part influencing loading conditions. Consideration of measurable factors, such as gender, body size, and hemodynamic load, allows evaluation of individual echocardiographic left ventricular mass as the deviation from the level that would be required to face a gender-specific hemodynamic load at a given body size. Values of left ventricular mass that are inappropriately high for individual gender, body size, and hemodynamic load are associated with a high cardiovascular risk phenotype, even independent of the presence of arterial hypertension. Thus, the condition of inappropriately high left ventricular mass may be recognized as a more advanced stage of pathological structural changes initially induced by overload, going beyond the compensatory needs. The biological process that yields inappropriate left ventricular mass is probably linked to the protracted activity over time of biological mediators of left ventricular hypertrophy, such as proto-oncogenes and other growth factors, neurohormones, and cytokines, inducing structural modifications that initially compensate imposed overload but eventually change the structure of myocardial tissue and the composition of motor units.
Genomic Scan for Exercise Blood Pressure in the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study
Authors: Rankinen Tuomo , An Ping , Rice Treva , Sun Guang , Chagnon Yvon C. , Gagnon Jacques , Leon Arthur S. , Skinner James S. , Wilmore Jack H. , Rao D.C. , Bouchard Claude
Published: June 2012

A genome-wide linkage scan was performed for genes affecting submaximal exercise systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the sedentary state and their responses to a standardized endurance training program. A total of 344 polymorphic markers were used, and 344 pairs of siblings from 99 white nuclear families and 102 sibling pairs from 105 black family units were available for the study. All subjects were healthy but sedentary at baseline. SBP and DBP were measured during exercise tests at 2 different intensities: 50 W (SBP50 and DBP50) and 80% of maximal oxygen consumption (SBP80 and DBP80). Baseline blood pressure phenotypes were adjusted for age, gender, and body mass index, and the training responses (after training minus baseline [Δ]) were adjusted for age, gender, baseline body mass index, and baseline blood pressure. Two analytical strategies were used: a multipoint variance-components linkage analysis using all the family data and a single-point linkage analysis using pairs of siblings. In whites, promising linkages (lod score >1.75) were detected for baseline SBP80 on 10q23-q24 and for ΔSBP50 on 8q21. In addition, several chromosomal regions with suggestive evidence of linkage (lod score 1.0 to 1.75) were observed for SBP50 (22q11.2-q13), DBP50 (6q23-q27), SBP80 (2p24, 2q21, 14q11.1-q12, and 16q21), DBP80 (6q13-q21), ΔSBP50 (7p12-p13), and ΔDBP50 (5q31-q32). In blacks, DBP50, DBP80, and ΔDBP80 showed promising quantitative trait loci on 18p11.2, 11q13-q21, and 10q21-q23, respectively. Suggestive linkages were evident for DBP50 on 2p22-p25, 11p15.5, and 18q21.1; for SBP80 on 6q21-q21, 6q31-q36, 12q12-q13, 15q12-q13, and 17q11-q12; and for DBP80 on 8q24, 10q21-q24, and 12p13. All the detected chromosomal regions include several potential candidate genes and therefore warrant further studies in the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) cohort and other studies.
Src Is an Important Mediator of Extracellular Signal–Regulated Kinase 1/2–Dependent Growth Signaling by Angiotensin II in Smooth Muscle Cells From Resistance Arteries of Hypertensive Patients
Authors: Touyz Rhian M. , He Gang , Wu Xiao-Hua , Park Jeong Bae , Mabrouk Mohammed El , Schiffrin Ernesto L.
Published: June 2012

The role of c-Src in growth signaling by angiotensin (Ang) II was investigated in vascular smooth muscle cells (VSMCs) from arteries of hypertensive patients. c-Src and extracellular signal–regulated kinase 1/2 (ERK1/2) activity, proto-oncogene expression, activating protein-1 (AP-1) DNA-binding activity, and DNA and protein synthesis were studied in Ang II–stimulated VSMCs derived from small peripheral resistance arteries of normotensive subjects (NTs, n=5) and age-matched untreated hypertensive patients (HTs, n=10). Ang II type 1 (AT
1
) and type 2 (AT
2
) receptor status was also assessed. Ang II dose-dependently increased the synthesis of DNA and protein, with enhanced effects in VSMCs from HTs. PD 098,059, a selective inhibitor of the ERK1/2 pathway, attenuated Ang II–stimulated growth in HTs. The effects of PD 098,059 were greater in HTs than in NTs. In NTs, Ang II transiently increased ERK1/2 phosphorylation, whereas in HTs, Ang II–stimulated actions were augmented and sustained. PP2, a selective Src inhibitor, reduced ERK1/2 activity and normalized ERK1/2 responses in HTs. Ang II–induced c-Src phosphorylation was 2- to 3-fold greater in HTs than in NTs. In HTs but not NTs, kinase activation was followed by overexpression of c-
fos
and enhanced AP-1 DNA-binding activity. PD 098,059 and PP2 attenuated these responses. AT
1
receptor expression was similar in NTs and HTs. In HT cells transfected with c-
fos
antisense oligodeoxynucleotide, Ang II–stimulated growth was reduced compared with sense oligodeoxynucleotide. Our findings suggest that augmented Ang II–stimulated VSMC growth is mediated via hyperactivation of c-Src–regulated ERK1/2-dependent pathways, leading to overexpression of c-
fos
mRNA and enhanced AP-1 DNA-binding activity. Because AT
1
receptor expression was unaltered in HTs, increased Ang II signaling may be a postreceptor phenomenon. These data define a signal transduction pathway whereby Ang II mediates exaggerated growth in VSMCs from HTs.
Transepithelial Sodium Absorption Is Increased in People of African Origin
Authors: Baker Emma H. , Ireson Nicola J. , Carney Christine , Markandu Nirmala D. , MacGregor Graham A.
Published: June 2012

Salt-sensitive hypertension is more common and has more severe consequences in urban black populations than in white populations. Increased renal sodium reabsorption through epithelial sodium channels may underlie the development of high blood pressure in black people. Increased sodium channel activity has been detected in subjects with Liddle’s syndrome by nasal potential difference measurements. Nasal potential difference measurements were made in 39 black normotensive, 106 black hypertensive, 51 white normotensive, and 61 white hypertensive subjects. Blood pressure, body mass index, and 24-hour urinary sodium excretion were also measured. Maximum potential difference was significantly higher in black subjects than in white subjects (
P
=0.009) but was not significantly different between normotensive and hypertensive subjects after adjustment for age, gender, current smoking status, body mass index, and 24-hour urinary sodium excretion (black normotensive, −21.6±1.0 mV; black hypertensive, −21.5±0.7 mV; white normotensive, −18.5±1.0 mV; and white hypertensive subjects, −18.9±0.9 mV). Nasal potential difference did not correlate with blood pressure or biochemical variables within ethnic and blood pressure groups. Nasal potential difference, an index of nasal sodium channel activity, is greater in black than in white people but does not differ between normotensive and hypertensive groups. Increased nasal potential difference measurements may reflect generalized upregulation of sodium transport in black people compared with white people, which may help to explain the high prevalence of hypertension in black people but would not explain differences in blood pressure within separate ethnic groups.
Acute Effect of Caffeine on Arterial Stiffness and Aortic Pressure Waveform
Authors: Mahmud Azra , Feely John
Published: June 2012

Caffeine acutely increases blood pressure and peripheral vascular resistance, in part because of sympathetic stimulation. Its effects on large artery properties are largely unknown. In a double-blind crossover study, 7 healthy subjects 26±2.6 years of age (mean±SEM) were studied for 90 minutes while in the supine position on 2 occasions separated by a week in random order after ingestion of 250 mL caffeinated (150 mg) and decaffeinated (<2 mg) coffee. Compared with baseline, arterial stiffness measured by carotid femoral pulse wave velocity increased progressively from 7.2±0.41 to 8.0±0.6 m/s (
P
<0.05) at 90 minutes after caffeine intake, an effect that may be independent of changes in blood pressure. In addition, arterial wave reflection, measured by applanation tonometry from the aortic pressure waveform, also increased from −5.7±7.6% to 5.28%±5.6 (
P
<0.01). No such changes were seen with decaffeinated coffee intake. Although the integral of the brachial systolic and diastolic blood pressure values over the 90 minutes was larger (
P
<0.05) after caffeinated than decaffeinated coffee intake, the effect on aortic systolic and diastolic blood pressures was more pronounced (
P
<0.05) than on the brachial artery. These results show a significant effect of caffeine intake on arterial tone and function and suggest that caffeine acutely increases arterial stiffness.
Cardiac βARK1 Upregulation Induced by Chronic Salt Deprivation in Rats
Authors: Iaccarino Guido , Barbato Emanuele , Cipolleta Ersilia , Esposito Antonio , Fiorillo Antonia , Koch Walter J. , Trimarco Bruno
Published: June 2012

The β-adrenergic receptor (βAR) kinase (βARK1) is a G protein-coupled receptor kinase (GRK) that controls cardiac βAR signaling via receptor phosphorylation, leading to desensitization. We have observed in mice that chronic isoproterenol administration results in increased myocardial levels of βARK1 activity, suggesting that adrenergic activation can regulate cardiac βARK1 expression. Thus, we evaluated left ventricular (LV) βARK1 levels and activity in response to 3 weeks of a low-sodium (0.05%) diet, which is known to chronically activate the sympathetic nervous system. Wistar-Kyoto rats were subjected to either low or regular sodium (2%) intake. To prove the association of βARK1 expression and low sodium-induced adrenergic activation, a group of rats was subjected to atenolol treatment (1 mg/kg per day) during the low-sodium diet. LV βARK1 expression was assessed by protein immunoblotting and βARK1 activity by in vitro GRK phosphorylation assays. We verified the LV protein levels of GRK5, which is abundantly expressed in the heart. A low-sodium diet reduced body weight and cardiac size so that the heart-to-body weight ratio did not change. On the contrary, low-sodium diet increased by 50% both LV βARK1 protein (densitometry units: normal sodium, 26.5±0.9; low sodium, 35.7±1.6;
P
<0.05) and activity (fmol/mg per minute: normal sodium, 6.49±1.17; low sodium, 9.15±0.93;
P
<0.05). Atenolol treatment prevented the increase in both protein expression (low sodium plus atenolol, 27.6±5.33,
P
=NS versus normal sodium) and activity (6.54±1.19,
P
=NS versus normal sodium). GRK5 expression was not affected by a low-sodium diet (17.2±0.2 versus 18.4±0.4,
P
=NS). Our data indicate that cardiac βARK1 is regulated by sympathetic action on βARs as tested by reducing dietary salt and βAR blockade.
Age-Related Reduction of NO Availability and Oxidative Stress in Humans
Authors: Taddei Stefano , Virdis Agostino , Ghiadoni Lorenzo , Salvetti Guido , Bernini Giampaolo , Magagna Armando , Salvetti Antonio
Published: June 2012

Age-related endothelial dysfunction could be caused by an alteration in the
l
-arginine-NO system and the production of oxidative stress in both normotensive and hypertensive individuals. In 47 normotensive subjects and 49 patients with essential hypertension, we evaluated forearm blood flow (by strain-gauge plethysmography) modifications induced by intrabrachial sodium nitroprusside (1, 2, and 4 μg/100 mL per minute) and acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-independent vasodilator and an endothelium-dependent vasodilator, respectively. Acetylcholine was repeated in the presence of the NO synthase inhibitor
N
G
-monomethyl-
l
-arginine (L-NMMA, 100 μg/100 mL per minute), the antioxidant vitamin C (8 mg/100 mL per minute), or both. Vasodilation to acetylcholine, but not to sodium nitroprusside, was lower (
P
<0.01) in hypertensive patients compared with control subjects. Moreover, in both groups, endothelium-dependent vasodilation declined with aging. In normotensive subjects, the inhibiting effect of L-NMMA on response to acetylcholine decreased in parallel with advancing age, whereas vitamin C increased vasodilation to acetylcholine in only the oldest group (age >60 years). In young hypertensive patients (age <30 years), vasodilation to acetylcholine was sensitive to L-NMMA, whereas in hypertensive patients age >30 years, vitamin C enhanced endothelium-dependent vasodilation and restored the inhibiting effect of L-NMMA on response to acetylcholine. In normotensive individuals, an earlier primary dysfunction of the NO system and a later production of oxidative stress cause age-related reduction in endothelium-dependent vasodilation. These alterations are similar but anticipated in hypertensive patients compared with normotensive subjects.
Overweight and Sympathetic Overactivity in Black Americans
Authors: Abate Nicola I. , Mansour Yasser H. , Tuncel Meryem , Arbique Debbie , Chavoshan Bahman , Kizilbash Ali , Howell-Stampley Temple , Vongpatanasin Wanpen , Victor Ronald G.
Published: June 2012

A large body of clinical investigation implicates an important role for the sympathetic nervous system in linking obesity with hypertension. However, the experimental support for this hypothesis is derived from strictly white cohorts. The goal of this study was to determine whether being overweight begets sympathetic overactivity in black Americans, the ethnic minority at highest risk for hypertension. We recorded postganglionic sympathetic nerve discharge with microelectrodes in muscle nerve fascicles of the peroneal nerve in 92 normotensive young adult black men and women within a wide range of body mass index. The same experiments were performed in a control group of 45 normotensive white men and women of similar ages and body mass indices. The major new findings are 2-fold. First, in young, normotensive, overtly healthy black women, being overweight begets sympathetic overactivity (
r
=0.45,
P
=0.0009), a putative intermediate phenotype for incident hypertension. Second, in black men, sympathetic nerve discharge is dissociated from body mass index (
r
=0.03,
P
=NS). This dissociation is explained in part by a 20% to 40% higher rate of sympathetic nerve discharge in lean black men compared with lean white men and lean black and white women (28±3 versus 18±2, 21±2, and 17±2 bursts/min, respectively;
P
<0.05). Sympathetic nerve discharge in lean black men is comparable to that of overweight black men and women as well as white men and women. These data provide the first microneurographic evidence for tonic central sympathetic overactivity in blacks, both adiposity-related sympathetic overactivity in black women and adiposity-independent sympathetic overactivity in black men.
Thyrotropin-Releasing Hormone Receptor (TRHR) Gene Is Associated With Essential Hypertension
Authors: García Silvia I. , Porto Patricia I. , Dieuzeide Guillermo , Landa María S. , Kirszner Tobias , Plotquin Yanquel , Gonzalez Claudio , Pirola Carlos J.
Published: June 2012

Abstract
—

— In essential hypertension, a polygenic and multifactorial syndrome, several genes interact with the environment to produce high blood pressure. Thyrotropin-releasing hormone (TRH) plays an important role in central cardiovascular regulation. We have described that TRH overexpression induces hypertension in a normal rat, which was reversed by TRH antisense treatment. This treatment also reduces the central TRH hyperactivity in spontaneously hypertensive rats and normalizes blood pressure. Human TRH receptor (TRHR) belongs to the G protein-coupled seven-transmembrane domain receptor superfamily. Mutations of these receptors may result in constitutive activation. As it has been demonstrated that hypertensive patients have a blunted TSH response to TRH injection, suggesting a defect in the TRHR, we postulate that the TRHR gene is involved in human hypertension. We studied 2 independent populations from different geographic regions of our country: a sample of adult subjects from a referral clinic and a population-based sample of high school students. In search of molecular variants of TRHR, we disclosed that a polymorphic TG dinucleotide repeat (STR) at −68 bp and a novel single nucleotide polymorphism, a G→C conversion at −221 located in the promoter of the TRHR are associated with essential hypertension. As STRs detected in gene promoters are potential Z-DNA-forming sequences and seem to affect gene expression, we studied the potentially different transcriptional activity of these TRHR promoter variants and found that the S/−221C allele has a higher affinity than does the L/G−221 allele to nuclear protein factor(s). Our findings support the hypothesis that the TRHR gene participates in the etiopathogenesis of essential hypertension.
Brain endo-oligopeptidase B: a post-proline cleaving enzyme that inactivates angiotensin I and II.
Authors: Greene L J , Spadaro A C , Martins A R , Perussi De Jesus W D , Camargo A C
Published: June 2012

Rabbit brain endo-oligopeptidase B inactivates angiotensin I (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) and angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) by hydrolysis of the Pro7-Phe8 peptide bond. The site of hydrolysis was determined in preparative and analytical experiments in which both products were recovered in a molar ratio of 1:1, and the sum of the products plus unhydrolyzed substrate accounted for the starting material. The enzyme has a Km of 6.3 x 10(-5) M for angiotensin II at pH 8.3 and is activated 30-fold with 4.8 mM dithiothreitol. BPP9a ( less than Gln-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro, SQ 20,881) inhibits the inactivation of angiotensin II with an I50 of 5 x 10(-5) M. BPP5a (less than Gln-Lys-Trp-Ala-Pro, SQ 20,475) is less active and D-3-mercapto-2-methylpropanoyl-L-proline (captopril, SQ 14,225) has essentially no activity. These endo-oligopeptidase B in angiotensin I and II metabolism remains to be established.
Effect of lesions of the anteroventral third ventricle (AV3V) on the development of hypertension in spontaneously hypertensive rats.
Authors: Gordon F J , Haywood J R , Brody M J , Johnson A K
Published: June 2012

Lesions of the anteroventral third ventricle (AV3V), an angiotensin and osmosensitive region of the anterior hypothalamus, prevent or abort hypertension in a number of rat models. To determine if AV3V lesions alter hypertension in spontaneously hypertensive rats (SHR), lesions and control sham lesions were made in young SHR at 28 days of age. AV3V lesions had no effect on the development of hypertension in SHR. However, lesioned rats demonstrated significantly reduced pressor responses to intracerebroventricular injections of angiotensin II (AII) and hypertonic NaCl, and drinking produced by centrally administered AII. The depressor effect of central AII receptor blockade was also significantly attenuated in lesioned SHR. These effects appeared to be of central origin since the lesion did not affect the pressor action of intravenous AII or norepinephrine (NE). It is concluded that unlike other models of experimental hypertension (steroid-salt, one-and two-kidney renal, neurogenic) the development of hypertension in SHR does not depend upon the integrity of the AV3V region.
Dopaminergic modulation of pressor and hormonal responses in essential hypertension.
Authors: Sowers J R , Golub M S , Berger M E , Whitfield L A
Published: June 2012

Hormonal and mean arterial pressure (MAP) responses to posture, isometric handgrip, angiotensin II (AII), adrenocorticotrophic hormone (ACTH), and metoclopramide (MCP), a dopamine (DA) antagonist, were examined in nine men with essential hypertension and nine age- and weight-matched normotensive men on a constant 100 mEq sodium and 80 mEq potassium intake before and after 4 days of administration of the DA agonist, bromocriptine (BEC; 2.5 mg three times a day). BEC depressed supine basal MAP in the hypertensives, and decreased MAP response to posture and isometric exercise in both groups. Hypertensives displayed greater (p less than 0.01) NE responses to posture and exercise than the normotensives. BEC decreased the NE response to 10 minutes of upright posture and exercise more in hypertensives (p less than 0.01) than in normotensives, but following BEC, the responses were similar. BEC did not affect basal PRA or PRA responses to posture and exercise in the two groups. PA responses to ACTH and MCP were similar in both groups, but the hypertensives displayed greater (p less than 0.01) PA responses to AII. BEC suppressed PA responses to AII (p less than 0.01) and to high dose ACTH (p less than 0.05) to a similar extent in both groups. The prolactin as well as the PA response to DA antagonism with MCP was similar in the two groups. These results suggest that dopaminergic control of NE secretion may be altered in essential hypertension. Blood pressure lowering effects of BEC in patients with essential hypertension may be related, in part, to depression of sympathetic nervous system activity.
Selective effects of alpha-methyldopa on myocardial cell components independent of cell size in normotensive and genetically hypertensive rats.
Authors: Tomanek R J
Published: June 2012

Alpha methyldopa has been shown to modify left ventricular mass and normalize mitochondria/myofibrils volume ratio in spontaneously hypertensive rats (SHR) when administered during the stage of developing cardiac hypertrophy (Tomanek et al., Cardiovas Res 23: 173, 1979). To evaluate the long-term effects of this antihypertensive agent, the drug was administered to SHR and normotensive (WKY) rats between the ages of 1 and 12 months. In another group of SHR and WKY, treatment was delayed until the age of 12 months and the animals were then treated for 3 months. Treatment with alpha-methyldopa had similar effects on systolic blood pressures in both SHR groups; group means (+/- SEM) were 151 +/- 1 in the long-term treatment group and 157 +/- 5 in the delayed treatment group compared to 178 +/- 4 and 176 +/- 3 for their respective controls. While left ventricular weight and cell size were significantly lower after early long-term treatment (compared to nontreated SHR), delayed treatment had no significant effect on these indices of left ventricular mass. Despite the effectiveness of early long-term treatment in modifying left ventricular mass, the relative volumes of mitochondria and myofibrils, as well as other cellular components (sarcoplasm), were not altered. In contrast, delayed treatment caused a significant increase (approximately twofold) in relative sarcoplasmic volume and a decrease in relative myofibrillar volume in both SHR and WKY. These findings indicate that shifts in the relative volumes of intracellular components after alpha-methyldopa are independent of cell size and blood pressure. Furthermore, the data suggest that the effects of alpha-methyldopa on the myocardial cell are dependent on or influenced by factors associated with the development or stabilization of hypertrophy and/or age.
Aldosterone binding sites in aortic cell cultures from spontaneously hypertensive rats.
Authors: Nichols N R , Hall C E , Meyer W J
Published: June 2012

Spontaneously hypertensive rats and rats made hypertensive by deoxycorticosterone-salt treatment have in common increased Na+ and K+ permeability and transport in their aortic cells. These changes may be important factors in the development of the hypertensive state and may be mediated by mineralocorticoid binding to intracellular sites in the aorta. Therefore, we examined 3H-aldosterone binding in aortic cell cultures from spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. Vascular corticoid binding sites in the two strains were compared by Scatchard analysis of Kd and Bmax, pH and temperature stability, and subcellular binding. By all of these criteria normotensive rats. These results indicate that the underlying genetic defect in spontaneous hypertension is not an intrinsic cellular defect which alters mineralocorticoid binding in the aorta.
Estimating dietary sodium intake in individuals receiving a randomly fluctuating intake.
Authors: Luft F C , Fineberg N S , Sloan R S
Published: June 2012

Previous investigations examining techniques to estimate sodium intake in free-living persons failed to consider a varying intake or were not conducted under circumstances in which the intake was actually known. To examine the utility of 24-hour and nocturnal urine collections as estimation of sodium intake under such conditions, we studied 43 white and black men and women ingesting a known sodium intake for 10 days that was randomly varied daily, with a mean intake of 150 mEq/day + 2 SD (range, 50 to 250 mEq/day). The mean 24-hour sodium excretion (UNaV) per day was and 24-hour UNaV estimated that day's sodium intake accurately for the entire 10 days, the average of several 24-hour collections was required. Nine collections were optimal (r = 0.75). Nocturnal specimens were not helpful; the average of all 10 collections correlated weakly (r = 0.30) with sodium intake. These data suggest that to estimate mean sodium intake accurately in free-living persons, only 24-hour collections are useful, although nocturnal collections are helpful in evaluating compliance with low sodium intake.