bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypertension Induced by Chronic Renal Adrenergic Stimulation Is Angiotensin Dependent
Authors: Reinhart Glenn A. , Lohmeier Thomas E. , Hord C. Edward
Published: June 2012

Abstract
We designed these studies to assess the role of the renin-angiotensin system in mediating the hypertensive and renal functional effects of chronic renal adrenergic stimulation. Norepinephrine was infused at 0.1 μg/kg per minute for 7 days directly into the renal artery of uninephrectomized dogs under control conditions (n=5) or after plasma angiotensin II (Ang II) concentration was fixed at control levels (n=5) by chronic intravenous infusion of captopril (14 μg/kg per minute) and Ang II (0.58±0.04 ng/kg per minute). During the first 60 minutes of norepinephrine infusion in control dogs, mean arterial pressure increased 9±4 mm Hg in association with a twofold to threefold rise in plasma renin activity. Additionally, glomerular filtration rate, renal plasma flow, sodium excretion, and fractional sodium excretion decreased to 70±5%, 64±5%, 31±4%, and 38±6% of control, respectively, while filtration fraction increased 15±2%. In contrast to the pronounced short-term effects of norepinephrine on renal function, during chronic norepinephrine infusion, all indexes of renal function returned to control levels. However, elevations in both plasma renin activity and mean arterial pressure were sustained and on day 7 were 2.3±0.6 ng angiotensin I/mL per hour (control, 0.5±0.1) and 110±7 mm Hg (control, 90±3). In dogs with fixed plasma levels of Ang II, acute and chronic changes in renal function induced by norepinephrine were similar to those in control dogs except that acute reductions in glomerular filtration rate tended to be more severe, and changes in filtration fraction and fractional sodium excretion were either attenuated or abolished. Moreover, in the absence of a rise in plasma Ang II concentration, mean arterial pressure did not change either acutely or chronically during norepinephrine infusion. These findings suggest a critical role for Ang II in mediating the hypertension associated with elevated levels of renal adrenergic stimulation that have little or no long-term effect on renal blood flow.
Sodium-Lithium Countertransport Has Low Affinity for Sodium in Hyperinsulinemic Hypertensive Subjects
Authors: Zerbini Gianpaolo , Ceolotto Giulio , Gaboury Cynthia , Mos Lucio , Pessina Achille C. , Canessa Mitzy , Semplicini Andrea
Published: June 2012

Abstract
We recently reported that incubation of red blood cells with insulin markedly decreases the affinity for external Na
+
and increases the maximal transport rate (
V
max
) of Na
+
-Li
+
countertransport. The association of hypertension with insulin resistance and its compensatory hyperinsulinemia led us to investigate the relationship between insulin levels in vivo and the Na
+
activation kinetics of this antiporter. We studied normotensive (n=28) and hypertensive (n=25) subjects after they had fasted overnight and determined their plasma glucose and insulin concentrations. Insulin levels were higher in the hypertensive subjects (11.7±1.5 μU/mL, mean±SEM) than in the normotensive subjects (8.2±1.2 μU/mL), but glucose levels were similar and within normal limits. Antiporter activity was measured as sodium-stimulated Li
+
efflux by a new procedure that uses isosmotic conditions to raise external Na
+
to 280 mmol/L. In normotensive subjects,
V
max
was reached between 50 and 100 mmol/L Na
+
, whereas in most hypertensive subjects, Na
+
concentrations higher than 150 mmol/L were needed. This different kinetic behavior was because the Na
+
concentration for half-maximal activation (
K
m
) was twofold higher in hypertensive subjects (58.9±5.3 mmol/L) than in normotensive subjects (29.8±2.6 mmol/L,
P
<.001). Hypertensive subjects with fasting insulin levels greater than 10 μU/mL (n=12) had a higher
K
m
for Na
+
than subjects with insulin levels less than 10 μU/mL (n=13) (73.4±8.7 versus 45.6±3.9 mmol/L, respectively,
P
<.01) and similar
V
max
(0.57±0.05 versus 0.41±0.05 mmol · L
−1
· h
−1
). In contrast, normotensive subjects with insulin levels greater than 10 μU/mL (n=6) had
V
max
and
K
m
values similar to those with insulin levels less than 10 μU/mL (n=22). Simple regression analysis showed that body mass index, insulin, and blood pressure correlated with both kinetic parameters. However, stepwise multiple regression analysis showed that the main determinant of
V
max
was blood pressure and for
K
m
, blood pressure and insulin levels. The association of a low affinity for Na
+
with in vivo hyperinsulinemia and its concomitant insulin resistance observed in hypertensive subjects agrees with the in vitro effects of insulin on this antiporter.
Antihypertensive Effects of a Novel Endothelin-A Receptor Antagonist in Rats
Authors: Bird J. Eileen , Moreland Suzanne , Waldron Thomas L. , Powell James R.
Published: June 2012

Abstract
Endothelin is a potent pressor agent mediated primarily through activation of endothelin-A receptors on vascular smooth muscle. Surprisingly, there is no consensus in the literature regarding the role of endothelin itself or endothelin-A receptors in hypertension. The goal of this study was to compare the effects of the novel, selective endothelin-A receptor antagonist BMS-182874 in various models of hypertension. BMS-182874 specifically inhibited the pressor response to endothelin-1 (0.3 nmol/kg IV) in Sprague-Dawley rats in a dose-dependent manner (ED
25
=8 μmol/kg IV) but had no effect on changes in mean arterial pressure brought about by other vasoactive agents. The antihypertensive effects of BMS-182874 were evaluated in conscious deoxycorticosterone acetate (DOCA)–salt hypertensive rats, spontaneously hypertensive rats (SHR), and sodium-deplete SHR. BMS-182874 reduced blood pressure in DOCA-salt hypertensive rats when administered at a dose of 30, 100, or 300 μmol/kg IV. A maximal decrease of approximately 45 mm Hg was observed after treatment with 100 μmol/kg IV. Three days of oral or intravenous treatment with BMS-182874 (100 μmol/kg) elicited a sustained decrease in blood pressure in the DOCA-salt hypertensive rats. In SHR, BMS-182874 decreased blood pressure by approximately 30 mm Hg, but the antihypertensive effects were similar at doses of 75, 150, and 450 μmol/kg PO. In sodium-deplete SHR, BMS-182874 did not significantly reduce blood pressure. In summary, BMS-182874 is a specific, orally active endothelin-A receptor antagonist that is efficacious in mineralocorticoid hypertension in rats but has less effect in sodium-replete and sodium-deplete SHR. Thus, endothelin-A receptor activation may play a role in volume-dependent or low-renin hypertension but is unlikely to be important in all hypertensive states.
α-Adrenoceptor Modulation of Norepinephrine and ATP Release in Isolated Kidneys of Spontaneously Hypertensive Rats
Authors: Bohmann Christine , Rump Lars Christian , Schaible Ulrike , von Kügelgen Ivar
Published: June 2012

Abstract
The present study investigates sympathetic cotransmission and its α-adrenoceptor–mediated modulation in kidneys of spontaneously hypertensive rats (SHR, 12 to 14 weeks) and age-matched normotensive Wistar-Kyoto rats (WKY). In the presence of cocaine and corticosterone, renal nerve stimulation at 1 Hz (30 seconds) induced a greater outflow of norepinephrine in SHR (4.2±0.2 pmol/g kidney) than in WKY (3.0±0.2 pmol/g kidney). The α
2
-adrenoceptor antagonist rauwolscine (0.01 to 1 μmol/L) increased the stimulation-induced norepinephrine outflow to a greater extent in SHR than in WKY. In contrast, the α
1
-adrenoceptor antagonist prazosin (0.03 to 3 μmol/L) increased the stimulation-induced norepinephrine outflow to a greater extent in WKY than in SHR. This difference was not observed in the presence of the P
1
-purinoceptor antagonist 8-(
p
-sulfophenyl)theophylline (100 μmol/L). Stimulation at 4 Hz (30 seconds) induced an outflow of ATP (SHR, 12.7±3.3 pmol/g kidney; WKY, 16.7±2.1 pmol/g kidney; perfusion solution without cocaine and corticosterone). Prazosin (0.03 μmol/L) markedly reduced pressor responses to stimulation and inhibited the induced ATP outflow by 60% to 70%. When prazosin (0.03 μmol/L) was present, rauwolscine (0.1 μmol/L) increased the induced outflow of norepinephrine and ATP and markedly enhanced prazosin-resistant pressor responses. These pressor responses were abolished by the P
2
-purinoceptor antagonist suramin (300 μmol/L). The results demonstrate an increased α
2
-adrenoceptor–mediated automodulation of norepinephrine release in SHR kidneys caused by increased intrasynaptic norepinephrine levels. α
1
-Adrenoceptor–mediated transjunctional modulation of norepinephrine release by endogenous adenosine is defective in SHR kidneys and may be responsible for the greater norepinephrine release in this strain. Norepinephrine and ATP are coreleased in SHR and WKY kidneys and both mediate pressor responses to stimulation. The release of ATP is identical in SHR and WKY and is, like that of norepinephrine, modulated by α
2
-adrenoceptor–mediated autoinhibition.
Modulation of Tubuloglomerular Feedback by Angiotensin II Type 1 Receptors During the Development of Goldblatt Hypertension
Authors: Braam Branko , Navar L. Gabriel , Mitchell Kenneth D.
Published: June 2012

Abstract
It has been suggested that the increased levels of angiotensin II (Ang II) in the contralateral kidney of two-kidney, one clip (2K1C) Goldblatt hypertensive rats act to enhance tubuloglomerular feedback responsiveness and proximal tubular reabsorption and thereby exert a substantial sodium-retaining influence on the nonclipped kidney. The current study investigated the Ang II dependency of tubuloglomerular feedback responsiveness in the nonclipped kidney during the early stages of development of 2K1C hypertension. Stop-flow pressure feedback responses were assessed in the nonclipped kidney of 2K1C rats during control conditions and after systemic administration of the Ang II type 1 receptor antagonist losartan (10 mg/kg). In 1-week clipped and sham-operated rats, losartan administration decreased mean arterial pressure (from 143±6 to 123±2 mm Hg,
P
<.01, and from 129±2 to 106±5 mm Hg,
P
<.01, respectively) and attenuated the magnitude of the maximal feedback responses (from −12.9±1.2 to −3.0±0.3 mm Hg,
P
<.01, and from −13.2±1.5 to −3.6±1.1 mm Hg,
P
<.01, respectively). The decreases in mean arterial pressure were not significantly different in sham-operated and 1-week clipped rats. In 3-week clipped rats, mean arterial pressure was further elevated (163±6 mm Hg) compared with sham-operated rats (134±4 mm Hg,
P
<.01). Although maximal tubuloglomerular feedback responses were similar in 3-week clipped and sham-operated rats, the late proximal perfusion rate eliciting a half-maximal response averaged 13±2 nL/min in the 3-week clipped and 18±1 nL/min in the sham-operated rats (
P
<.05), indicating enhanced tubuloglomerular feedback responsiveness in the nonclipped kidney. After losartan administration, mean arterial pressure decreased by 32±5 and 43±3 mm Hg, and the maximal tubuloglomerular feedback responses were markedly attenuated in both the sham-operated rats (from −12.3±1.9 to −2.4±0.9 mm Hg,
P
<.01) and clipped rats (from −9.6±0.6 to −1.8±0.5 mm Hg,
P
<.01). These data indicate that during the early stages of 2K1C Goldblatt hypertension, tubuloglomerular feedback responsiveness in the nonclipped kidney is maintained or slightly enhanced and highly dependent on Ang II type 1 receptor activation.
Enhanced Pressor Response to Angiotensin I in Normotensive Men With the Deletion Genotype (DD) for Angiotensin-Converting Enzyme
Authors: Ueda Shinichiro , Elliott Henry L. , Morton James J. , Connell John M. C.
Published: June 2012

Abstract
The insertion (I)/deletion (D) polymorphism of the human angiotensin-converting enzyme gene has emerged as a genetic risk factor for ischemic heart disease. However, the functional consequences of this polymorphism in humans are not known. Ten normotensive men with the DD genotype and 10 with the II genotype participated in a study in which pressor responses to stepwise infusions of incremental doses of angiotensin I (Ang I) and Ang II and Ang II production during Ang I infusion were measured. Pressor responses were expressed as PD
20
, which reflects the angiotensin dose required to raise mean blood pressure by 20 mm Hg. The PD
20
for Ang I in subjects with the DD genotype was significantly lower than that in II genotype subjects (8.8 versus 14.8 ng/kg per minute,
P
=.0091), whereas the PD
20
for Ang II between the two groups did not differ significantly. The ratio of PD
20
for Ang I and Ang II in DD subjects was significantly lower than that in II subjects (0.85 versus 0.96,
P
=.0452), and the venous levels of Ang II during Ang I infusion in DD subjects were significantly higher than those in II subjects (
P
<.01). Our study has shown increased pressor responsiveness to Ang I, probably as a consequence of the generation of increased Ang II levels, in subjects homozygous for the DD allele of the angiotensin-converting enzyme gene. This result may be relevant to the reported adverse cardiovascular risk conferred by the D allele, as it provides a mechanistic rationale for the association between this polymorphism and cardiovascular disease.
Noninvasive Determination of Shear-Rate Distribution Across the Arterial Lumen
Authors: Hoeks Arnold P. G. , Samijo Steven K. , Brands Peter J. , Reneman Robert S.
Published: June 2012

Abstract
In vitro experiments have shown that the shear stress exerted by flowing blood on the endothelial surface affects the morphology of the vascular wall and the release of vasoactive substances and growth factors by that wall. It is believed that the caliber of a vessel adjusts to the local shear stress to maintain a specific value of the shear stress. The local shear stress follows from local shear rate by multiplying shear rate by the local blood viscosity. The present article describes a method in which ultrasound techniques are used to assess transcutaneously the time-dependent wall shear rate in vivo in arteries. This method is applied to the assessment of wall shear rate in the common carotid artery of volunteers, presumed to be healthy, in two age categories (young age group, 20 to 30 years old, n=8; old age group, 60 to 70 years old, n=6). Although the peak shear rate in the young age group is markedly higher than in the old age group, the mean shear rate averaged over a cardiac cycle has the same value of 210 s
−1
for both groups, corroborating earlier observations that mean shear rate and, hence, mean shear stress are maintained at a particular value. Conversion of the observed shear rates to shear stresses, assuming a blood viscosity of 3.5 mPa.s for both age groups, gives shear stresses of approximately 0.7 Pa. This is a factor of two lower than the shear stresses estimated from the relation between volume flow and artery caliber (1.5 Pa).
Regulation and Differential Expression of Neutral Endopeptidase 24.11 in Human Endothelial Cells
Authors: Graf Kristof , Koehne Petra , Gräfe Michael , Zhang Minzhong , Auch-Schwelk Wolfgang , Fleck Eckart
Published: June 2012

Abstract
Neutral endopeptidase 24.11, a membrane-bound metallopeptidase, cleaves and degrades vasoactive peptides such as atrial natriuretic peptide, endothelin, angiotensin I, substance P, and bradykinin. Therefore, the presence of this metallopeptidase may contribute to the regulation of vascular tone and local inflammatory responses in the vascular endothelium and elsewhere. We determined neutral endopeptidase in cultured human endothelial cells from different vascular beds and studied its regulation by protein kinase C. Neutral endopeptidase was detected in all cultured endothelial cell types. Lowest concentrations were measured in human endothelial cells from umbilical veins (360±14 pg/mg protein), followed by pulmonary and coronary arteries; higher concentrations were found in endothelial cells from the cardiac microcirculation (1099±73 pg/mg protein). Neutral endopeptidase content increased during cell growth but was not affected by endothelial cell growth factor or modifications of the growth medium. Stimulation of protein kinase C with 1-oleoyl-2-acetyl-rac-glycerol (0.1 to 1 μmol/L) and phorbol 12-myristate 13-acetate (0.01 to 0.1 μmol/L) induced a time- and concentration-dependent increase of endothelial cells that was inhibited by cycloheximide (5 μmol/L), an inhibitor of protein synthesis. Incubation with phospholipase C (1 μmol/L) and thrombin (10 IU/mL) induced upregulation of neutral endopeptidase, resulting in 158±26% and 150±22% increases, respectively, compared with controls. The thrombin effect was inhibited by calphostin C (1 μmol/L), an inhibitor of protein kinase C. Endothelial neutral endopeptidase is constitutively expressed in endothelial cells from different origins and is inducible by thrombin via activation of the protein kinase C pathway.
Sympathetic Modulation of Radial Artery Compliance in Congestive Heart Failure
Authors: Grassi Guido , Giannattasio Cristina , Failla Monica , Pesenti Antonio , Peretti Giovanni , Marinoni Edoardo , Fraschini Nicoletta , Vailati Sabrina , Mancia Giuseppe
Published: June 2012

Abstract
Animal studies have suggested that arterial compliance can be modulated by adrenergic influences. Whether this adrenergic modulation also occurs in humans is still a matter of debate. In the present article we address this issue by examining the relationships between sympathetic tone and arterial compliance in a variety of physiological and pathophysiological conditions. We have found that cigarette smoking, ie, an action that produces a marked sympathetic activation, causes a significant reduction in radial artery compliance, as measured by an echotracking device capable of providing continuous beat-to-beat evaluation of this hemodynamic variable. When expressed as compliance index, ie, as the ratio between the area under the compliance-pressure curve and pulse pressure, the reduction amounted to 35.7±4.8% (mean±SEM) and was independent of the smoking-related blood pressure increase. Furthermore, pharmacological stimulation of adrenergic receptors located in the arterial wall was also shown to affect arterial compliance because the radial artery compliance index was markedly reduced (−29.5±3.9%) during phenylephrine infusion in the brachial artery at doses devoid of any systemic blood pressure effect. Evidence was also obtained that the relationship between sympathetic activation and arterial compliance has pathophysiological relevance, because in 17 patients with congestive heart failure (New York Heart Association classes II through IV) there was a significant inverse correlation (
r
=.62,
P
<.01) between muscle sympathetic nerve activity (directly measured by microneurography in the peroneal nerve) and radial artery compliance. Finally, we have recently observed that anesthesia of the brachial plexus, a maneuver that induces a transient blockade of nerve conduction to the upper limb, markedly increases radial artery compliance (change in compliance index, +30.0±5.0%). Thus, at least at the radial artery level arterial compliance is under a pronounced tonic restraint by sympathetic influences and can be modulated in either direction by reflex or central alterations in sympathetic drive. This modulation has pathophysiological implications.
Prevalence and Determinants of Cardiac and Vascular Hypertrophy in Hypertension
Authors: Roman Mary J. , Pickering Thomas G. , Pini Riccardo , Schwartz Joseph E. , Devereux Richard B.
Published: June 2012

Abstract
Hypertrophy of the capacitance arteries has recently been documented in hypertensive patients by noninvasive ultrasound techniques. To better define the prevalence and determinants of vascular hypertrophy and its potential association with ventricular hypertrophy in hypertension, we compared carotid and cardiac ultrasound findings in 172 normotensive and 172 unmedicated hypertensive subjects matched for age and sex. Despite similar body size, hypertension was associated with increased left ventricular wall thicknesses, mass, and mass index (89 versus 80 g/m
2
,
P
<.0001 for all comparisons) and increased carotid wall thickness (0.82 versus 0.77 mm) and cross-sectional area (17.1 versus 15.3 mm
2
,
P
<.005 for both comparisons). Among the 172 normotensive subjects, left ventricular hypertrophy was noted in 9 (5.2%) and arterial hypertrophy was found in 9 (5.2%), whereas ventricular hypertrophy was found in 21 (12.2%) and arterial hypertrophy in 19 (11%) hypertensive subjects. Arterial hypertrophy was found in 9% of hypertensive subjects with normal ventricular mass and in 24% with left ventricular hypertrophy (
P
<.05). Among hypertensive subjects carotid wall thickness and cross-sectional area were most strongly related to age and systolic pressure (
P
<.0001 for all comparisons), with little contribution from body size. Carotid relative wall thickness was only related to increasing age (
P
<.01). In contrast, left ventricular wall thickness and mass were strongly related to body size and systolic pressure (
P
<.0001 for all comparisons) but not to age (
P
=NS). Thus, among otherwise healthy, asymptomatic hypertensive subjects, left ventricular and arterial hypertrophy are similarly prevalent (when the latter is defined by methods that take into account the influence of aging) and are associated with each other. Although both arterial and left ventricular size are strongly related to blood pressure, aging is the most important determinant of arterial size, even in hypertension, whereas body size is the most important determinant of left ventricular mass.
β-Adrenergic, Angiotensin II, and Bradykinin Receptors Enhance Neurotransmission in Human Kidney
Authors: Rump Lars C. , Bohmann Christine , Schaible Ulrike , Schultze-Seemann Wolfgang , Schollmeyer Peter J.
Published: June 2012

Abstract
The aim of this study was to investigate angiotensin II (Ang II) receptor–, bradykinin receptor–, and β-adrenergic receptor–mediated modulation of norepinephrine release from human renal sympathetic nerves and to characterize the respective receptor subtypes involved. Human cortical kidney slices were incubated with [
3
H]norepinephrine, placed in superfusion chambers between two platinum electrodes, and superfused with Krebs-Henseleit solution. The sympathetic nerves were stimulated electrically at 2.5 Hz for 1 minute, and the stimulation-induced outflow of radioactivity was taken as an index of endogenous norepinephrine release. Ang II and its precursor Ang I (both 0.01 to 1 μmol/L) enhanced stimulation-induced outflow of radioactivity in a concentration-dependent manner, with EC
50
values of 0.03 and 0.05 μmol/L, respectively. The enhancement by Ang I but not that by Ang II was inhibited by the angiotensin-converting enzyme inhibitor captopril (3 μmol/L). The concentration-response curves of Ang I and Ang II were shifted to the right by EXP 3174 (0.01 μmol), the in vitro active form of the Ang II type 1 receptor antagonist losartan, with affinity estimates of 8.72 and 9.30, respectively. A higher concentration of EXP 3174 (0.1 μmol/L) abolished the facilitatory effects of Ang I and Ang II. The Ang II type 2 receptor antagonist PD 123319 (10 μmol/L) did not alter the facilitation by Ang II. In the absence of other drugs, bradykinin (0.01 to 1 μmol/L) failed to modulate stimulation-induced outflow of radioactivity but in the presence of captopril (3 μmol/L) enhanced it in a concentration-dependent manner, with an EC
50
of 0.1 μmol/L. This facilitatory effect of bradykinin was prevented by the bradykinin type 2 receptor antagonist Hoe 140 (0.3 μmol/L). The β
1
/β
2
-adrenergic receptor agonist isoproterenol (0.001 to 0.1 μmol/L) also enhanced stimulation-induced outflow of radioactivity in a concentration-dependent manner, with an EC
50
of 0.008 μmol/L. The facilitatory effect of isoproterenol was abolished by the β
2
-adrenergic receptor antagonist ICI 118551 (0.03 μmoL/L) but unaltered by the β
1
-adrenergic receptor antagonist atenolol (3 μmol/L), captopril (3 μmol/L), or EXP 3174 (0.1 μmol/L). We conclude that activation of prejunctional Ang II type 1, bradykinin type 2, and β
2
-adrenergic receptors facilitates renal norepinephrine release in humans. Ang II can be formed locally within the human renal cortex from Ang I by angiotensin-converting enzyme to activate prejunctional Ang II type 1 receptors. The β
2
-adrenergic receptor–mediated effect is likely to function independently of a local renin-angiotensin system. However, the facilitatory bradykinin type 2 receptor mechanism can be demonstrated only when bradykinin degradation is prevented by the angiotensin-converting enzyme (kininase II) inhibitor captopril.
Amylin Stimulates Plasma Renin Concentration in Humans
Authors: Cooper Mark E. , McNally Paul G. , Phillips Paddy A. , Johnston Colin I.
Published: June 2012

Abstract
Although insulin resistance and hypertension are commonly associated, the underlying cause for this association remains unknown. Plasma concentrations of the recently described hormone amylin, which is cosecreted with insulin by the pancreatic β cell, are reported to be elevated in various states of insulin resistance, including hypertension and obesity. Preliminary studies by our group have suggested that there are amylin binding sites in the kidney. In nine healthy humans an infusion of human amylin that resulted in steady state plasma amylin levels in the subnanomolar range led to significant increases in plasma renin and aldosterone concentrations. These changes occurred in the absence of significant changes in plasma electrolytes, catecholamines, vasopressin, total renin, or osmolality. Diastolic pressure at 30 minutes and plasma glucose at 60 minutes rose modestly. Since amylin has both metabolic and renal actions, this peptide may be an important link between hypertension, insulin resistance, and the renin-angiotensin system.
Combined Renal Effects of Overweight and Hypertension
Authors: Ribstein Jean , du Cailar Guilhem , Mimran Albert
Published: June 2012

Abstract
The existence of a direct relationship between body mass and arterial pressure is well recognized; however, the effect of obesity on known target organs of hypertension is not clearly understood. We undertook the present studies to assess the influence of obesity on renal function and urinary albumin excretion in 40 normotensive subjects and 80 never-treated hypertensive patients matched for age, sex, arterial pressure level, and known duration of hypertension in whom an oral glucose tolerance test was within normal limits. Glomerular filtration rate and effective renal plasma flow (expressed as absolute values or values normalized for height) were increased in overweight compared with lean subjects whether normotensive or hypertensive. Glomerular filtration rate was positively correlated with protein intake (as assessed from urinary excretion of urea) and fasting serum insulin level. Urinary excretion of albumin but not IgG and β
2
microglobulin was higher in hypertensive patients compared with normotensive subjects. The overweight condition clearly enhanced the influence of arterial pressure on albuminuria; in fact, a steeper regression line between albumin excretion rate and arterial pressure was found in overweight compared with lean subjects. These results indicate that the overweight condition is associated with renal hyperfiltration and hyperperfusion, irrespective of the presence of hypertension, and that obesity magnifies the effect of hypertension on albuminuria, thus raising the possibility of an increased susceptibility of obese hypertensive patients to the development of renal damage.
G Protein Alterations in Hypertension and Aging
Authors: Feldman R.D. , Tan C.M. , Chorazyczewski J.
Published: June 2012

Abstract
Defective vasodilator function could be important in the pathogenesis and/or maintenance of the hypertensive state and the predisposition of the elderly to hypertension. Impaired β-adrenergic–mediated vasodilation and reduced lymphocyte β-adrenergic activation of adenyl cyclase have been demonstrated both in aging and with hypertension. The cellular mechanisms responsible for these alterations remain unclear. To determine if these defects may be due to alterations in guanine nucleotide regulatory proteins (G proteins) that link receptor activation with effector function, we assessed (1) human lymphocyte adenyl cyclase activity, (2) stimulatory G proteins by cholera toxin–mediated [
32
P]ADP ribosylation and, in hypertensive subjects, with α
s
-specific and β-subunit antisera, and (3) inhibitory G proteins by pertussis toxin–mediated [
32
P]ADP ribosylation and, in older subjects, with α
i1,2
- and β-subunit–specific antisera. Lymphocytes from older subjects and from hypertensive subjects demonstrated a comparable reduction in isoproterenol-stimulated adenyl cyclase. However, aluminum fluoride–stimulated activity was reduced only in lymphocytes from hypertensive subjects. Furthermore, aluminum fluoride–stimulated activity was inversely correlated with mean arterial pressure. In lymphocytes from younger hypertensive subjects, cholera toxin–mediated labeling was significantly reduced; however, stimulatory G protein labeling by immunodetection was unaltered. In lymphocytes from older subjects, cholera toxin–mediated labeling was not altered; however, pertussis toxin–mediated labeling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. Overall, the study suggests alterations of G protein function in hypertension and aging. In both conditions, stimulation of adenyl cyclase is impaired. However, these defects are associated with divergent alterations in stimulatory and inhibitory G proteins.
A Randomized Controlled Trial of Stress Reduction for Hypertension in Older African Americans
Authors: Schneider Robert H. , Staggers Frank , Alexander Charles N. , Sheppard William , Rainforth Maxwell , Kondwani Kofi , Smith Sandra , King Carolyn Gaylord
Published: June 2012

Abstract
We tested the short-term efficacy and feasibility of two stress education approaches to the treatment of mild hypertension in older African Americans. This was a randomized, controlled, single-blind trial with 3 months of follow-up in a primary care, inner-city health center. Of 213 African American men and women screened, 127 individuals (aged 55 to 85 years with initial diastolic pressure of 90 to 109 mm Hg, systolic pressure of ≤189 mm Hg, and final baseline blood pressure of ≤179/104 mm Hg) were selected. Of these, 16 did not complete follow-up blood pressure measurements. Mental and physical stress-reduction approaches (Transcendental Meditation and progressive muscle relaxation) were compared with a lifestyle modification education control program and with each other. The primary outcome measures were changes in clinic diastolic and systolic pressures from baseline to final follow-up, measured by blinded observers. The secondary measures were linear blood pressure trends, changes in home blood pressure, and intervention compliance. Adjusted for significant baseline differences and compared with control, Transcendental Meditation reduced systolic pressure by 10.7 mm Hg (
P
<.0003) and diastolic pressure by 6.4 mm Hg (
P
<.00005). Progressive muscle relaxation lowered systolic pressure by 4.7 mm Hg (
P
=.054) and diastolic pressure by 3.3 mm Hg (
P
<.02). The reductions in the Transcendental Meditation group were significantly greater than in the progressive muscle relaxation group for both systolic blood pressure (
P
=.02) and diastolic blood pressure (
P
=.03). Linear trend analysis confirmed these patterns. Compliance was high in both stress-reduction groups. Home systolic but not diastolic pressure changes were similar to clinic changes. Selected mental and physical stress-reduction techniques demonstrated efficacy in reducing mild hypertension in this sample of older African Americans. Of the two techniques Transcendental Meditation was approximately twice as effective as progressive muscle relaxation. Long-term effects and generalizability to other populations require further evaluation.
Effects of Long-term Nitric Oxide Synthesis Inhibition on Plasma Volume Expansion and Fetal Growth in the Pregnant Rat
Authors: Salas Sofía P. , Altermatt Fernando , Campos Mauricio , Giacaman Andrea , Rosso Pedro
Published: June 2012

Abstract
We conducted the present study to investigate whether the vasodilator nitric oxide plays a role in plasma volume homeostasis during pregnancy. Pregnant Sprague-Dawley rats were randomly assigned to a control group (n=18) or to groups receiving 0.69 mmol/L (n=11) or 1.7 mmol/L (n=14)
N
ω
-nitro-
l
-arginine, a competitive inhibitor of nitric oxide synthetase, from gestational days 7 through 21. On day 20 systolic pressure was measured. On day 21 blood samples were taken for plasma volume, hematocrit, and hormonal measurements. Fetal and placental weights also were determined. Systolic pressure was significantly higher in experimental rats (101±6 and 115±6 mm Hg in the 0.69 and 1.7 mmol/L groups, respectively) than in controls (79.7±7.5 mm Hg), and plasma volume was lower (18.4±1.1 and 17.1±0.5 mL) than in controls (21.5±0.8 mL). Both experimental groups had increased hematocrit levels. Plasma renin activity was significantly lower in the experimental groups (11.5±3 and 7.2±1.5 ng angiotensin I/mL per hour) than in controls (21.9±2.7 ng angiotensin I/mL per hour); however, no changes were observed in aldosterone levels. Experimental groups had lower fetal weight (4.6±0.1 and 5.1±0.1 g) than controls (5.5±0.1 g). In addition, fetal hindlimb hypoplasia was observed in the experimental groups. In conclusion, the present data indicate that long-term
N
ω
-nitro-
l
-arginine administration to pregnant rats leads to increased blood pressure, reduced plasma volume expansion, lower plasma renin activity, and fetal growth retardation. These results suggest that nitric oxide may play an important role in maternal systemic vasodilatation and indirectly in plasma volume homeostasis and fetal growth.
Endothelin Subtype B Receptor–Mediated Calcium and Contractile Responses in Small Arteries of Hypertensive Rats
Authors: Touyz Rhian M. , Deng Li Yuan , Schiffrin Ernesto L.
Published: June 2012

Abstract
Endothelin-1 elicits vasoconstrictor responses through endothelin subtype A receptors, which are located on vascular smooth muscle cells, and vasodilator responses through endothelin subtype B receptors, which occur predominantly on endothelial cells. Endothelin subtype B receptors also may be present on vascular smooth muscle cells, in which they may mediate vasoconstriction. The aims of this study were to determine the presence of vascular smooth muscle vasoconstrictor endothelin subtype B receptors in mesenteric resistance arteries and to assess whether endothelin subtype B receptor–mediated responses differ between spontaneously hypertensive rats and Wistar-Kyoto rats. Contractile responses to the endothelin subtype B receptor agonist sarafotoxin S6c and endothelin-1 were measured simultaneously with [Ca
2+
]
i
in endothelium-denuded mesenteric resistance arteries from adult spontaneously hypertensive rats and Wistar-Kyoto rats. To simulate in vivo conditions matched as closely as possible to in vitro conditions, vessels were mounted in a vessel flow chamber in which intraluminal pressure was maintained at 60 mm Hg. Contraction was determined by video imaging to record lumen diameter, and [Ca
2+
]
i
was measured by the fura 2 method. Basal [Ca
2+
]
i
was significantly higher (
P
<.01) in hypertensive (170±4 nmol/L) compared with normotensive rats (134±3 nmol/L). The endothelin subtype B receptor agonist sarafotoxin S6c increased [Ca
2+
]
i
in a concentration-dependent manner. Sarafotoxin S6c–induced [Ca
2+
]
i
and contractile responses were significantly lower in hypertensive compared with normotensive rats. These data demonstrate that endothelin subtype B receptors are present in vascular smooth muscle of small arteries and that endothelin subtype B receptor–mediated vasoconstriction occurs through intracellular calcium signaling pathways. Although the contribution of endothelin subtype B receptor–induced contraction is small, responses mediated by this receptor subtype in spontaneously hypertensive rats are attenuated compared with age-matched Wistar-Kyoto rats.
Augmented Calcium Currents in Mesenteric Artery Branches of the Spontaneously Hypertensive Rat
Authors: Cox Robert H. , Lozinskaya Irina M.
Published: June 2012

Abstract
The greater efficacy of organic channel blockers in lowering peripheral resistance and blood pressure in hypertensive subjects has been suggested to be the result of augmented calcium influx through L-type calcium channels in arterial smooth muscle. These studies were performed to determine whether differences exist in voltage-gated calcium channels of mesenteric artery branches from 20-week-old spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). Single myocytes were acutely isolated by collagenase and elastase treatment and studied at room temperature (≈20°C) with the use of whole-cell, patch-clamp methods. Maximum values of calcium current measured at 0 mV from a holding potential of −90 mV were larger in SHR myocytes (105±11 versus 149±15 pA). Values of cell capacitance were smaller in SHR (29.5±1.3 pF) compared with WKY (35.0±1.5 pF) myocytes. Cell capacitance measures surface membrane area and, when used to normalize calcium currents, magnified the difference between WKY and SHR to approximately 47%. There was a larger percent reduction of maximum calcium current at holding potentials of −60 and −40 mV in SHR compared with WKY myocytes: for example, at −40 mV calcium current was reduced from values at −90 mV by −73±2% in SHR compared with −58±1% in WKY. When divided by the maximum current for each holding potential, the voltage dependence of normalized calcium currents for the two groups was completely superimposed. Difference currents were calculated by subtracting currents measured from holding potentials of −90 and −40 mV. The voltage dependence of difference currents was identical to that of the calcium currents measured from the two values of holding potential. The results of this study indicate that (1) only L-type calcium currents are present in freshly isolated mesenteric artery myocytes from 20-week-old WKY and SHR, and (2) these currents are larger in SHR. These differences in calcium currents may contribute to augmented contractile responses that have been previously reported.
Effects of Dehydroepiandrosterone Sulfate on Cellular Calcium Responsiveness and Vascular Contractility
Authors: Barbagallo Mario , Shan Jie , Pang Peter K.T. , Resnick Lawrence M.
Published: June 2012

Abstract
Dehydroepiandrosterone sulfate (DHEAS) is an endogenous steroid having a wide variety of biological effects, but its physiological role remains undefined. Since an age-related decline of DHEAS corresponds to the progressive onset of atherosclerosis, cardiovascular diseases, and overall mortality, we investigated a possible protective role of DHEAS in vascular disease by studying the effects of this hormone (10
−7
to 10
−5
mol/L) on cytosolic free calcium and contractility in different in vitro vascular tissue preparations. DHEAS produced a significant, dose-dependent relaxation of isolated helical strips of rat tail artery precontracted with KCl (60 mmol/L) (89.7±18.7%,
P
<.01), arginine vasopressin (3 nmol/L) (27.3±7.1%,
P
<.01), and norepinephrine (0.1 μmol/L) (49.2±18.2%,
P
<.01). In isolated vascular smooth muscle cells DHEAS reversibly inhibited KCl (30 mmol/L)–induced elevations of cytosolic free calcium to 69.8±8.4% and 43.8±7.4% of the control response at 5×10
−7
and 5×10
−6
mol/L, respectively (
P
<.05 at both doses). These results provide evidence of a direct vascular action of DHEAS, in doses reflecting circulating levels in vivo, and suggest the possibility that these effects are mediated by modulation of intracellular calcium metabolism. We hypothesize that physiologically, DHEAS may serve to buffer vascular responsiveness to a wide variety of depolarizing and constrictor hormonal stimuli.
Effects of Losartan on Blood Pressure, Metabolic Alterations, and Vascular Reactivity in the Fructose-Induced Hypertensive Rat
Authors: Navarro-Cid Josefa , Maeso Rosaura , Perez-Vizcaino Francisco , Cachofeiro Victoria , Ruilope Luis M. , Tamargo Juan , Lahera Vicente
Published: June 2012

Abstract
Fructose feeding induces a moderate increase in blood pressure levels in normal rats that is associated with insulin resistance, hyperinsulinemia, and hypertriglyceridemia. The sympathetic nervous system seems to participate in the alterations of this model. To further explore the mechanisms underlying fructose-induced hypertension, the effects of the AT
1
receptor antagonist losartan on blood pressure, insulin resistance, renal function, and vascular reactivity in mesenteric vascular beds were studied. Sprague-Dawley rats were fed for 4 weeks with diets containing 60% fructose or 60% starch (control), and half of each group received losartan (1 mg/kg per day) in the drinking water. Fructose-fed rats showed higher (
P
<.05) blood pressure levels and plasma concentrations of triglycerides and insulin than those of controls. Losartan treatment prevented both blood pressure elevation and hyperinsulinemia in fructose-fed rats but not elevation of plasma triglycerides. Plasma glucose and insulin levels in response to an oral glucose load were higher (
P
<.05) in fructose-fed rats than in controls. These exaggerated responses were prevented by losartan treatment. No differences in the constrictor responses of mesenteric vascular beds to KCl (60 μmol), angiotensin II (1 nmol), phenylephrine (10
−5
mol/L), or endothelin-1 (10 pmol) were found between the two groups. Relaxing responses to acetylcholine or sodium nitroprusside in phenylephrine-precontracted mesenteric vascular beds and constrictor response to the nitric oxide synthesis inhibitor
N
G
-nitro-
l
-arginine methyl ester (100 nmol) were comparable in both groups. Losartan blunted angiotensin II constriction and reduced (
P
<.05) responses to phenylephrine in all groups. In conclusion, these results suggest that angiotensin II plays an important role in the blood pressure elevation and in the insulin resistance induced by fructose feeding in rats. The mechanisms underlying these effects appear to be dependent on neither a vascular hyperreactivity to constrictor factors nor an endothelial dysfunction related to a decreased production of nitric oxide.
Stress-Induced Elevation of Ouabainlike Compound in Rat Plasma and Adrenal
Authors: Goto Atsuo , Yamada Kaoru , Nagoshi Hiroshi , Terano Yoshitake , Omata Masao
Published: June 2012

Abstract
Recent observations demonstrate the presence of neurosteroids and their rapid increase in response to acute stress. In view of a steroidal nature of ouabainlike compound, we tested the hypothesis that ouabainlike compound may participate in a homeostatic response to acute stress. Male Wistar rats were subjected to acute stress by swimming in water (22°C) for 10 minutes. The levels of ouabainlike compound in plasma, hypothalamus, pituitary, and adrenal at 10, 40, and 70 minutes (n=8 for each) after the end of swim stress were compared with nonstressed control levels (n=10). Ouabainlike compound was measured by a radioimmunoassay for ouabain. Plasma levels of corticosterone and catecholamines were also measured. Plasma corticosterone concentrations increased rapidly at 10 minutes (
P
<.01) and then declined. A trend for a rise in plasma catecholamines was found at 10 minutes. Adrenal levels of ouabainlike compound concomitantly increased at 10 minutes (
P
<.01, control: 58.9±5.9 pmol ouabain equivalents per gram; 10 minutes: 92.5±4.8; 40 minutes: 47.3±9.6; 70 minutes: 45.1±6.3). In contrast, the response of plasma ouabainlike compound was slow and doubled at 40 minutes (
P
<.01, control: 115±12 pmol ouabain equivalents per liter; 10 minutes: 132±23; 40 minutes: 226±53; 70 minutes: 117±16). Ouabainlike compound levels in hypothalamus and pituitary remained unaltered. These findings suggest that ouabainlike compound may function as a stress hormone.
Diabetes Mellitus and Associated Hypertension, Vascular Disease, and Nephropathy
Authors: Sowers James R. , Epstein Murray
Published: June 2012

Abstract
Because considerable important information has been published since our previous review, this update concentrates on new findings with regard to cardiovascular and renal risk factors contributing to the striking morbidity and mortality of these coexisting diseases. For example, a large body of investigative data has recently emerged suggesting or delineating a pathogenic role for hyperglycemic-related glycosylation and oxidation of lipoproteins and vascular and renal tissues. Great strides have recently been made in the understanding of platelet, coagulation, lipoprotein, and endothelial abnormalities in the pathogenesis of cardiovascular and renal disease associated with diabetes mellitus and hypertension. Major progress has been made in clarifying the pathophysiology of glomerulosclerosis and other processes involved in the progression of diabetic nephropathy. Furthermore, accumulating data surveyed in this review address new and promising pharmacological interventions that specifically address these pathophysiological mechanisms.
Heritability of Conventional and Ambulatory Blood Pressures
Authors: Fagard Robert , Brguljan Jana , Staessen Jan , Thijs Lutgarde , Derom Catherine , Thomis Martine , Vlietinck Robert
Published: June 2012

Abstract
Conventional and 24-hour ambulatory blood pressures were measured in 26 pairs of monozygotic twins and 27 pairs of dizygotic twins, all male, ages 18 to 38 years, to determine the heritability of blood pressure measured under various conditions. Conventional pressure was the average of three well-standardized measurements in the supine position, and ambulatory pressure was recorded during the subjects’ normal activities by use of the SpaceLabs 90202 device. Heritability was assessed by classic methods and by model fitting and path analysis. In the latter approach, the percent genetic variance was 70% for mean 24-hour systolic pressure and 73% for diastolic pressure, which was similar to the results for the conventional pressures (64% and 73%, respectively). During the night, these estimates were 72% and 51% for systolic and diastolic pressures, respectively, and also the average pressures of the total awake daytime period were under partial genetic control (63% and 55%, respectively). The remaining variances could be attributed primarily to unique environmental influences. However, shared and nonshared environmental factors were predominant for the pressures during a fixed 6-hour afternoon period. We conclude that the heritability of blood pressure is relatively high in young adult healthy men, for standardized conventional pressure and the average 24-hour pressure. Genetic variance is somewhat higher for the asleep pressure than for the awake systolic pressure.
Contrasting Effect of Antihypertensive Treatment on the Renal Response to
l
-Arginine
Authors: Mimran Albert , Ribstein Jean , DuCailar Guilhem
Published: June 2012

Abstract
We assessed the renal hemodynamic response to
l
-arginine infusion (30 g within 60 minutes) in normotensive subjects, patients with never-treated essential hypertension, and hypertensive patients controlled by long-term (more than 2 years) treatment with or without an angiotensin-converting enzyme inhibitor. The renal vasodilator response to
l
-arginine observed in normotensive subjects (15±4% increase in effective renal plasma flow) was abolished in untreated hypertensive patients and restored only in the group treated by angiotensin-converting enzyme inhibition. In the whole population a positive correlation between the change in effective renal plasma flow and the change in urinary cGMP was obtained. It is suggested that abnormalities of the renal nitric oxide pathway not corrected by increased availability of
l
-arginine and reversible only on long-term treatment by angiotensin-converting enzyme inhibition may underlie the abnormal renal resistance observed in essential hypertension.