bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cardiac β-Adrenoceptor–Mediated Signaling Pathway and Its Alterations in Hypertensive Heart Disease
Authors: Castellano Maurizio , Böhm Michael
Published: June 2012

Hypertension-induced cardiac hypertrophy is a predictor of the development of cardiac failure. It is unknown which cellular markers contribute to the progression from compensated hypertrophy to failure. In heart failure, several signal transduction defects leading to adenylate cyclase desensitization have been demonstrated, such as β-adrenoceptor downregulation, increase of inhibitory G protein expression, and uncoupling of β-adrenergic receptors, presumably by an increase of receptor kinase activity. In hypertensive heart disease, most studies have been performed in rat models of hypertension. As in heart failure, heterologous adenylyl cyclase desensitization occurs. The mechanisms are often different between the heterogeneous models for acquired and genetic hypertension, but G
i
protein alterations and β-adrenoceptor downregulation have been observed frequently. The underlying mechanism for desensitization is most likely a sympathetic activation in established hypertension rather than genetic alterations of signal transduction proteins. The data available suggest that β-adrenergic desensitization could represent a mechanism that contributes to the progression from hypertrophy to failure. The key question remains whether those hypertensive patients who develop heart failure are more prone to β-adrenergic desensitization or whether early intervention to reduce sympathetic activity is more effective in preventing or delaying the transition from compensated hypertrophy to overt failure.
Effect of Calcium Channel or β-Blockade on the Progression of Diabetic Nephropathy in African Americans
Authors: Bakris George L. , Mangrum Amy , Copley J. Brian , Vicknair Nancy , Sadler Rebecca
Published: June 2012

β-Blockers are known to slow the progression of diabetic nephropathy by lowering arterial pressure. Moreover, in individuals with diabetic nephropathy, antihypertensive agents that provide sustained reductions in proteinuria slow the rate of decline in renal function compared with agents without this antiproteinuric effect. To examine whether differential effects on proteinuria affect the progression of diabetic nephropathy, we conducted a randomized study that compared the effects of a heart rate–lowering calcium channel blocker, sustained-release verapamil, with those of a β-blocker, atenolol, on the progression of diabetic renal disease. The primary end point of the study was a change in creatinine clearance slope. Thirty-four African Americans with the following inclusion criteria were randomized to one of the two groups: serum creatinine greater than 1.4 mg/dL, proteinuria greater than 1500 mg/d, longer than a 5-year history of both non–insulin-dependent diabetes mellitus and hypertension, and exclusion of other renal diseases. Goal blood pressure was less than 140/90 mm Hg. All subjects received loop diuretics as second line agents to help achieve the blood pressure goal. Twenty-four-hour urinary protein and sodium excretions as well as creatinine clearance were measured at 6-month intervals. Blood pressure was measured every 3 months. After a mean follow-up of 54±6 months, the calcium channel blocker group demonstrated both a slower rate of decline in creatinine clearance (−1.7±0.9 versus −3.7±1.4 mL/min per year per 1.73 m
2
,
P
<.01) and a greater reduction in proteinuria compared with the atenolol group. Additionally, a greater proportion of the atenolol group had a 50% or more increase in serum creatinine compared with the verapamil group (32±9% versus 16±7%,
P
<.05). These between-group differences could not be explained by differences in blood pressure control. These data support the concept that antihypertensive agents that persistently maintain reductions in both arterial pressure and proteinuria slow the progression of diabetic renal disease in African Americans to a greater extent than those agents without these effects.
Sodium Pump Isoform Specificity for the Digitalis-Like Factor Isolated From Human Peritoneal Dialysate
Authors: Tao Qing-Feng , Hollenberg Norman K. , Price Deborah A. , Graves Steven W.
Published: June 2012

We have isolated a labile, specific sodium pump inhibitor or digitalis-like factor from the peritoneal dialysate of volume-expanded renal failure patients whose levels correlated closely with volume status and blood pressure. This study characterizes the inhibitory profile of this agent compared with that of ouabain against the three α-isoforms of the sodium pump. We prepared microsomal Na,K-ATPase from rat tissues representing the highest proportion of one of the α-isoforms. Both Northern and Western blot analyses confirmed that kidney had predominantly the α
1
-isoform, skeletal muscle the α
2
-isoform, and fetal brain the α
3
-isoform. Ouabain (5×10
−6
mol/L) produced little inhibition of kidney Na,K-ATPase (3.4±2.0%) but significant inhibition of skeletal muscle (37.2±3.7%,
P
<.001) and fetal brain (38.8±3.5%,
P
<.001) activity. In contrast, the labile digitalis-like factor, causing comparable inhibition of fetal brain Na,K-ATPase activity (33.3±4.7%), produced markedly greater inhibition of kidney (42.5±5.6%,
P
<.001) and moderately greater inhibition of skeletal muscle pump activity (57.7±6.3%,
P
<.05). In addition, the labile digitalis-like factor produced a marked concentration-dependent inhibition of the α
2
- and α
3
-isoforms (
r
=.79,
P
=.00005). Experiments combining the labile digitalis-like factor and ouabain confirmed that digitalis-like factor, unlike ouabain, was an effective inhibitor of all three isoforms in rat, in particular α
2
. The different pattern of isoform sensitivity displayed by the labile digitalis-like factor and ouabain further differentiates the two agents and raises some interesting possibilities about the functional implications of the endogenous factor.
Effects of Dietary Sodium and Magnesium on Cyclosporin A–Induced Hypertension and Nephrotoxicity in Spontaneously Hypertensive Rats
Authors: Mervaala Eero M.A. , Pere Anna-Kaisa , Lindgren Leena , Laakso Juha , Teräväinen Terttu-Liisa , Karjala Kirsi , Vapaatalo Heikki , Ahonen Juhani , Karppanen Heikki
Published: June 2012

Arterial hypertension, nephrotoxicity, and magnesium loss are common side effects of the immunosuppressive agent cyclosporin A (CsA). In the present study, the effects of dietary sodium and magnesium on CsA toxicity were examined in spontaneously hypertensive rats. A 6-week treatment with CsA during a moderately low-sodium diet (Na 0.3%, Mg 0.2% of the dry weight of the chow) raised blood pressure only slightly, without evidence of nephrotoxicity. By contrast, CsA during a high-sodium diet (Na 2.6%) produced a pronounced rise in blood pressure as well as marked nephrotoxicity, comprising decreased creatinine clearance, increased levels of serum creatinine and urea, and increased urinary protein excretion. During the high-sodium diet, CsA decreased myocardial and bone magnesium concentration and increased myocardial and renal calcium concentration. Magnesium supplementation (Mg 0.6%) protected against the CsA-induced hypertension and nephrotoxicity during the high-sodium diet. Magnesium supplementation also completely prevented the CsA-induced myocardial magnesium depletion and calcium accumulation in the heart and kidney during the high-sodium diet. Our findings indicate a detrimental interaction between increased sodium intake and CsA treatment and a marked protection by concomitant oral magnesium supplementation.
Effects of Central Muscarinic-1 Receptor Stimulation on Blood Pressure Regulation
Authors: Medina Aharon , Bodick Neil , Goldberger Ary L. , Mahon Margaret Mac , Lipsitz Lewis A.
Published: June 2012

Stimulation of central nervous system muscarinic-1 (M
1
) receptors in animals increases blood pressure, heart rate, and sympathetic outflow. In Alzheimer's disease, stimulation of central M
1
receptors is reduced. When the oral formulation of the selective M
1
agonist xanomeline was tested for the treatment of Alzheimer's disease, an increased incidence of syncope was observed. Therefore, we used Alzheimer's disease as a model of relative M
1
deficiency to determine the effect of M
1
receptor stimulation on blood pressure regulation in humans. Eight Alzheimer's patients and 6 healthy age- and sex-matched subjects underwent blood pressure, heart rate, forearm vascular resistance, plasma norepinephrine, and heart rate variability measurements during 90 minutes after ingestion of xanomeline or placebo, then during 45 minutes of head-up tilt. Alzheimer's patients were studied on three occasions: after placebo, the first dose of xanomeline, and 3 days of xanomeline. Normal subjects were studied after placebo and the first dose of xanomeline. A subset of 5 Alzheimer's patients was studied with the peripheral muscarinic antagonist methscopolamine. Oral xanomeline increased supine systolic and diastolic blood pressures in normal subjects and heart rate and plasma norepinephrine in all subjects. During the placebo tilt, 0 of 8 Alzheimer's patients and 2 of 6 healthy subjects developed near-syncope, and during the first-dose xanomeline tilt, 4 of 8 Alzheimer's patients and 3 of 6 healthy subjects had near-syncope. The maximal decrease in systolic blood pressure during tilt was greater with xanomeline than placebo in both groups (
P
<.03). Methscopolamine did not prevent xanomeline-induced hypotension. Central M
1
receptor stimulation with the oral formulation of xanomeline in humans is associated with sympathetic stimulation under supine conditions and impaired baroreflex compensation during tilt. Alzheimer's patients, who presumably lack M
1
receptor activity, may have a reduced risk of tilt-induced syncope compared with normal subjects. Both groups, however, have enhanced susceptibility to hypotension and syncope when M
1
receptor activity is pharmacologically increased.
Insulin-Induced Hypertension in Rats Depends on an Intact Renin-Angiotensin System
Authors: Brands Michael W. , Harrison David L. , Keen Henry L. , Gardner Angela , Shek Eugene W. , Hall John E.
Published: June 2012

Abstract
This study tested the dependence of insulin-induced hypertension in rats on a functional renin-angiotensin system. Rats were instrumented with chronic artery and vein catheters and housed in metabolic cages. After acclimation, 10 rats began receiving the angiotensin-converting enzyme inhibitor (ACEI) benazepril at 1.8 mg · kg
−1
· d
−1
via a continuous intravenous infusion that was maintained throughout the study; 8 control rats received vehicle. Four days after starting ACEI or vehicle, all rats entered a 5-day control period that was followed by a 7-day insulin infusion at 1.5 mU · kg
−1
· min
−1
. Glucose was coinfused at 22 mg · kg
−1
· min
−1
to prevent hypoglycemia. Insulin infusion in control rats increased mean arterial pressure (MAP; measured 24 h/d) from an average of 101±1 to 113±2 mm Hg on day 1; MAP averaged 110±1 mm Hg for the 7-day infusion period. Glomerular filtration rate decreased, although not significantly, from 2.7±0.1 to 2.1±0.2 mL/min on day 3. Chronic ACEI decreased baseline MAP from an average of 97±1 to 79±1 mm Hg and markedly attenuated the increase in MAP during insulin. MAP averaged 81±1 mm Hg for the 7-day period and increased significantly, to 85±2 mm Hg, only on day 3. Likewise, the tendency for glomerular filtration rate to decrease was blunted. These results indicate that insulin-induced hypertension in rats depends on angiotensin II and suggest that a reduction in glomerular filtration rate contributes to the shift in pressure natriuresis.
Pressure Natriuresis and Renal Medullary Blood Flow in Dogs
Authors: Majid Dewan S. A. , Godfrey Murrell , Navar L. Gabriel
Published: June 2012

Abstract
In the present study, we evaluated the effects of changes in arterial pressure on regional renal blood flows and sodium excretion in anesthetized dogs during control conditions and after 5% volume expansion with isotonic saline. Medullary and cortical blood flow responses were determined with laser-Doppler needle flow probes inserted into the midmedullary and midcortical regions, and whole-kidney blood flow was assessed with an electromagnetic flow probe. Volume expansion in six dogs caused marked increases in urine flow (20.2±5.5 to 82.5±22.7 μL·min
−1
·g
−1
) and sodium excretion (3.2±0.5 to 11.1±2.7 μmol·min
−1
·g
−1
), with slight increases in glomerular filtration rate (0.92±0.03 to 1.01±0.02 mL·min
−1
·g
−1
) but no significant changes in total renal blood flow (4.7±0.3 to 5.2±0.6 mL·min
−1
·g
−1
), medullary blood flow (+6±9%), or cortical blood flow (+12±10%). During stepwise reductions in renal arterial pressure (150 to 75 mm Hg) elicited with a renal arterial occluder, both before and after volume expansion, medullary, cortical, and total renal blood flows as well as glomerular filtration rate exhibited efficient autoregulation, with slopes not significantly different from zero over this range of arterial pressure. There were marked increases in the slopes of the relationships between arterial pressure and urine flow (0.18±0.05 to 0.78±0.27 μL·min
−1
·g
−1
·mm Hg
−1
) as well as sodium excretion (0.03±0.004 to 0.10±0.03 μmol·min
−1
·g
−1
·mm Hg
−1
) during volume expansion. These data demonstrate that medullary blood flow is efficiently autoregulated in dogs during control and volume-expanded states and indicate that the mechanism responsible for the arterial pressure–induced changes in sodium excretion does not depend on coincident alterations in medullary blood flow.
Long-term Effects of Neonatal Sodium Restriction on Blood Pressure
Authors: Geleijnse Johanna M. , Hofman Albert , Witteman Jacqueline C. M. , Hazebroek Alice A. J. M. , Valkenburg Hans A. , Grobbee Diederick E.
Published: June 2012

Abstract
In 1980, a randomized trial was conducted among 476 Dutch newborn infants to study the effect of a low or normal sodium diet on blood pressure during the first 6 months of life. At the end of the trial, systolic blood pressure in the low sodium group (n=231) was 2.1 mm Hg lower than in the control group (n=245). To investigate whether contrasting levels of sodium intake in infancy are associated with blood pressure differences in adolescence, we measured blood pressure in 167 children from the original cohort (35%) after 15 years of follow-up. We assessed the differences in systolic and diastolic blood pressure levels between the diet groups using a multivariate regression model with adjustment for potential confounders. The adjusted systolic blood pressure at follow-up was 3.6 mm Hg lower (95% confidence interval, −6.6 to −0.5) and the diastolic pressure was 2.2 mm Hg lower (95% confidence interval, −4.5 to 0.2) in children who had been assigned to the low sodium group (n=71) compared with the control group (n=96). These findings suggest that sodium intake in infancy may be important in relation to blood pressure later in life.
Ultrasonic Videodensitometric Analysis of Two Different Models of Left Ventricular Hypertrophy
Authors: Di Bello Vitantonio , Pedrinelli Roberto , Giorgi Davide , Bertini Alessio , Talarico Luigi , Caputo Maria Teresa , Massimiliano Bianchi , Dell’Omo Giulia , Paterni Marco , Giusti Costantino
Published: June 2012

Abstract
Absolute or relative increases in intramyocardial fibrosis accompany hypertrophy development in human hypertension. Myocardial texture analysis of two-dimensional echocardiographic gray-level distribution has been shown to identify alterations attributed to abnormal collagen content in several conditions. Therefore, this echocardiographic tool might help to identify those hypertensive individuals with abnormal interstitial collagen deposition, a condition that may promote and/or aggravate morbidity in this group of people who are at high risk for cardiovascular events. We compared male essential hypertensive subjects who had marked cardiac hypertrophy (left ventricular mass index adjusted for height >2 SD of mean of control group) (group 1) with normotensive elite veteran athletes who had comparable cardiac hypertrophy (group 2) and sedentary normotensive subjects as controls (group 3). The groups (n=14 each) were matched for age (±2 years) and sex. We analyzed echocardiographic digitized data quantitatively by means of a calibrated 256 gray level digitization system to calculate midseptal and midposterior end-diastolic and end-systolic mean gray levels and to derive the so-called cyclic variation index, ie, the percent mean gray level variation during the cardiac cycle. Echocardiographic parietal and septal thicknesses and masses were evaluated according to the Penn convention. Left ventricular mass index (adjusted for height) overlapped between groups 1 and 2 (187.1±17.5 and 181.3±19.3 g/m, respectively;
P
=NS), whereas it was obviously smaller in control subjects (93.1±18.6 g/m;
P
<.001 for both). According to inclusion criteria, both septal and posterior wall thicknesses were comparable in athletes and hypertensive subjects, and they were higher than in the control group (
P
<.0001). The hypertensive subjects showed a significantly lower cyclic variation index than the control and athlete groups for both the septum (
P
<.001) and posterior wall (
P
<.001); no statistical difference was found between athletes and control subjects for this parameter. In conclusion, abnormalities of two-dimensional echocardiographic gray-level distribution are present in hypertensive hypertrophied individuals but seem unrelated to the degree of echocardiographic hypertrophy as such. An altered collagen network distribution or a decrease in capillary distribution in severe myocardial hypertrophy, secondary to pressure-volume overload in hypertension with other yet unknown mechanisms, could help to explain our findings. Further work is needed to establish the prognostic, clinical, and therapeutic implications of these findings.
Angiotensinogen Gene Variation Associated With Variation in Blood Pressure in Aboriginal Canadians
Authors: Hegele Robert A. , Harris Stewart B. , Hanley Anthony J. G. , Sun Fang , Connelly Philip W. , Zinman Bernard
Published: June 2012

Abstract
We measured blood pressure and related clinical phenotypes in 497 adult native Canadians from an isolated community in Northern Ontario. We analyzed their DNA for genotypes of angiotensinogen. We found that the frequency of the T235 variant of the angiotensinogen gene was 0.89 in this sample. This variant was associated with a significantly increased systolic pressure but not diastolic pressure. We also found that sex and body mass were each highly significantly associated with variation in both systolic and diastolic pressures. We found a significant association between age and variation in systolic pressure but not diastolic pressure. We also found a highly significant association between plasma apolipoprotein B concentration and variation in diastolic pressure but not systolic pressure. The high frequency of the angiotensinogen T235 variant suggests that subjects in this young, essentially normotensive population might be predisposed to hypertension, which may become more apparent in the presence of secondary factors.
Mechanical Load Opposes Angiotensin-Mediated Decrease in Vascular α
1
-Adrenoceptors
Authors: Clements Mary L. , Faber James E.
Published: June 2012

Abstract
α
1
-Adrenergic receptor contraction of vascular smooth muscle is augmented by increases in angiotensin II and also in several forms of hypertension. Whether angiotensin directly modulates α
1
-adrenoceptor subtype expression to contribute to this effect is unknown. In a previous study, we demonstrated that increased mechanical load (pressure) per se does not alter expression of α
1B
- and α
1D
-adrenoceptors in rat aortic smooth muscle in cell culture, in vitro or in vivo. However, findings in aortic coarctation hypertension suggested that a humoral factor, possibly angiotensin, selectively reduces α
1B
-adrenoceptors and that increased mechanical load opposes this decrease. The present study examined this hypothesis by determining the effect of angiotensin alone and in the presence of mechanical loading on the expression of α
1D
- and α
1B
-adrenergic receptor mRNAs and α
1
-receptor density in cultured aortic smooth muscle cells. α
1D
mRNA content, per smooth muscle cell, concentration-dependently decreased after 3 hours of exposure to 0.3 nmol/L to 1 μmol/L angiotensin but by 24 hours had returned to control levels. In contrast, α
1B
mRNA concentration-dependently declined at a later time (24 hours) and remained decreased at 48 hours to 27±6% of control with 1 μmol/L angiotensin. Angiotensin also decreased α
1
-adrenoceptor density in a dose-dependent manner. Angiotensin had no effect on cell number in these confluent, quiescent cells but did increase cell protein and total RNA. This cellular hypertrophy and the decreases in α
1
-adrenoceptor mRNAs were blocked by the angiotensin type 1 receptor antagonist losartan. Cyclic mechanical loading of smooth muscle cells opposed the angiotensin-mediated hypertrophy and decrease in α
1B
mRNA expression and α
1
-adrenergic receptor density. These data suggest that angiotensin and intravascular pressure interact to affect cell growth and expression of α
1B
-adrenergic receptors by vascular smooth muscle.
Endothelin-1 Upregulation in the Kidney of Uninephrectomized Spontaneously Hypertensive Rats and Its Modification by the Angiotensin-Converting Enzyme Inhibitor Quinapril
Authors: Largo Raquel , Gómez-Garre Dulcenombre , Liu Xue Hui , Alonso Javier , Blanco Julia , Plaza Juan J. , Egido Jesús
Published: June 2012

Abstract
Endothelin (ET-1) is a potent vasoconstrictor that plays an important role in the control of renal circulation and tubular function. The contribution of this peptide to the pathogenesis of systemic hypertension and renal failure remains largely undefined. In spontaneously hypertensive rats (SHR) uninephrectomized at 20 weeks of age (UNX-SHR) and followed until 45 weeks of age, we determined ET-1 gene expression in renal tissue by reverse transcription–polymerase chain reaction and its localization by in situ hybridization in paraffin-embedded kidney sections. Age-matched SHR and normotensive Wistar-Kyoto (WKY) rats were chosen as controls. At the end of the follow-up, UNX-SHR had high systolic blood pressure, intense proteinuria, mesangial expansion, focal and segmental glomerular sclerosis, and tubulointerstitial lesions. In relation to WKY and SHR, UNX-SHR exhibited an increase in ET-1 gene expression in renal cortex and medulla. By in situ hybridization and immunoperoxidase staining, an overexpression of ET-1 gene and protein were seen in mesangial and glomerular epithelial cells and in some proximal tubules and vessels. Angiotensin-converting enzyme (ACE) activity was significantly increased in the renal brush border. Since in mesangial cells, angiotensin II induces ET-1 synthesis, a group of UNX-SHR received the ACE inhibitor quinapril from the time of UNX. These animals had a decrease in blood pressure, proteinuria, and serum and brush border ACE activity and in the expression and synthesis of ET-1 in all renal areas. On the whole, these data show that UNX-SHR have an upregulation of ET-1 gene and protein in several structures of the kidney compared with SHR and WKY rats. Quinapril diminished ACE activity and ET-1 expression and synthesis coincidentally with an improvement in proteinuria and morphological lesions. The beneficial effects of ACE inhibitors may be due to the diminution of both angiotensin II and ET-1 generation.
Chronic Dietary
l
-Arginine Prevents Endothelial Dysfunction Secondary to Environmental Tobacco Smoke in Normocholesterolemic Rabbits
Authors: Hutchison Stuart J. , Reitz Megan S. , Sudhir Krishnankutty , Sievers Richard E. , Zhu Bo-Qing , Sun Yi-Ping , Chou Tony M. , Deedwania Prakash C. , Chatterjee Kanu , Glantz Stanton A. , Parmley William W.
Published: June 2012

Abstract
Our goal was to determine whether environmental tobacco smoke causes endothelial dysfunction in the absence of hypercholesterolemia and whether such an effect can be prevented by supplementation with
l
-arginine. Environmental tobacco smoke exposure is associated with an increase in coronary artery disease events and mortality. We have previously demonstrated that environmental tobacco smoke causes endothelial dysfunction and atherosclerosis in rabbits with diet-induced hypercholesterolemia and atherosclerosis and that chronic dietary
l
-arginine supplementation prevents this. The effects of
l
-arginine supplementation (2.25% solution ad libitum) and environmental tobacco smoke (smoking chambers for 10 weeks) were examined with a 2×2 design in 32 rabbits fed a normal diet. Acetylcholine, calcium ionophore A23187, and nitroglycerin-induced vasorelaxation were assessed in aortic rings precontracted with phenylephrine. Endothelial
l
-arginine levels were measured by chromatography. Chronic
l
-arginine supplementation increased serum (
P
<.001) and endothelial (
P
=.003)
l
-arginine levels. Environmental tobacco smoke reduced endothelium-dependent acetylcholine-induced relaxation, and
l
-arginine blocked this adverse effect (
P
=.04). Environmental tobacco smoke tended to increase phenylephrine-induced contraction (
P
=.06). Neither environmental tobacco smoke nor
l
-arginine influenced A23187-induced relaxation nor endothelium-independent nitroglycerin-induced relaxation. Endothelial dysfunction secondary to environmental tobacco smoke may occur in the absence of diet-induced hypercholesterolemia and atherosclerosis. Chronic dietary supplementation with a nitric oxide donor such as
l
-arginine offsets the endothelial dysfunction associated with environmental tobacco smoke in normocholesterolemic rabbits, possibly through substrate loading of the nitric oxide pathway.
Effects of Alcohol on Sympathetic Activity, Hemodynamics, and Chemoreflex Sensitivity
Authors: van de Borne Philippe , Mark Allyn L. , Montano Nicola , Mion Decio , Somers Virend K.
Published: June 2012

Abstract
Alcohol intake has been shown to worsen obstructive sleep apnea and increase nocturnal hypoxemia. The mechanisms of this action are unclear. Animal studies suggest that a reduction in chemoreflex sensitivity may be implicated. Using a double-blind, randomized, vehicle-controlled design, we tested the hypothesis that oral alcohol intake depresses chemoreflex sensitivity in humans. We examined the effects of oral alcohol intake (1.0 g/kg body wt) on blood pressure, heart rate, heart rate variability, muscle sympathetic nerve activity, forearm vascular resistance, and minute ventilation in 16 normal male subjects. Peripheral and central chemoreflex sensitivity were measured in response to hypoxia (n=10) and hypercapnia (n=6), respectively. Plasma alcohol increased from 0 to 23.2±1.5 mmol/L (107±7 mg/dL) at 60 minutes and 20.2±1 mmol/L (93±4 mg/dL) at 85 minutes after alcohol intake (
P
<.0001). Alcohol induced an increase in heart rate from 59±2 to 66±2 beats per minute (
P
<.01) and increased the ratio of low- to high-frequency variability of heart rate (
P
<.05). Although alcohol increased sympathetic nerve activity by up to 239±22% of baseline values (
P
<.01), forearm vascular resistance after alcohol was lower than that after vehicle (
P
<.05). Blood pressure did not increase compared with the vehicle session. Oxygen saturation during hypoxia after alcohol was 4±1% lower than it was during hypoxia after vehicle (
P
<.05) although arterial blood P
o
2
was unchanged. Alcohol did not affect the cardiovascular, sympathetic, or ventilatory responses to either hypoxia or hypercapnia. Acute increases in plasma alcohol increase heart rate and sympathetic nerve activity; blood pressure is not increased, probably because of vasodilator effects of alcohol. Alcohol does not alter chemoreflex responses to hypoxia or hypercapnia; thus, alterations in chemoreflex sensitivity are unlikely to explain the effects of alcohol on sleep apnea. Alcohol may reduce the affinity of hemoglobin for oxygen.
Possible Participation of Nitric Oxide in the Increase of Norepinephrine Release Caused by Angiotensin Peptides in Rat Atria
Authors: Gironacci M. M. , Lorenzo P. S. , Adler-Graschinsky E.
Published: June 2012

Abstract
In rat atria isolated with their cardioaccelerans nerves and labeled with [
3
H]norepinephrine, exposure to 1×10
−7
mol/L angiotensin II (Ang II) and 1×10
−7
mol/L Ang-(1-7) increased the release of radioactivity elicited by nerve stimulation (0.5-millisecond-long square-wave pulses at 2 Hz during 2 minutes) by 90% and 60%, respectively. The facilitatory effect on noradrenergic neurotransmission caused by both peptides was stereospecifically prevented by
N
ω
-nitro-
l
-arginine methyl ester (1×10
−4
mol/L), an inhibitor of nitric oxide synthase that catalyzes the conversion of
l
-arginine to nitric oxide, as well as by 1×10
−5
mol/L methylene blue, a substance that inhibits the guanylate cyclase considered as the final target of nitric oxide action. On the other hand, the precursor of nitric oxide synthesis,
l
-arginine (1×10
−3
mol/L), reversed the prevention produced by
N
ω
-nitro-
l
-arginine methyl ester on the increased release of norepinephrine caused by Ang II and Ang-(1-7). The present results suggest that nitric oxide could be involved in the neuromodulatory function elicited by both Ang II and Ang-(1-7) in rat atria. The physiological role of this observation is still under study.
Whole-body venous capacity and effective total tissue compliance in SHR.
Authors: Trippodo N C , Yamamoto J , Frolich E D
Published: June 2012

Whole-body venous capacity was examined in conscious 4-month-old male spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive (WKY) rats by determining mean circulatory filling pressure (MCFP) and blood volume. The MCFP was determined in conscious animals after briefly arresting the circulation by inflating an indwelling balloon in the right atrium. Blood volume was determined by dilution of 125I-albumin and 51Cr-red cells. Although blood volume was not significantly different between SHR (60.9 +/- 0.7 ml/kg, SE) and WKY (59.6 +/- 0.8 ml/kg), MCFP was slightly, but significantly elevated in the SHR (9.5 +/- 0.3 vs 8.5 +/- 0.2 mm Hg, mean +/- SE, p less than 0.05). Increased MCFP with normal blood volume suggests decreased venous capacity in the SHR. In addition, effective total tissue compliance (ETTC) was measured in conscious 5-month-old female SHR and WKY. A decrease in tissue fluid volume was induced by i.v. infusion of hyperoncotic albumin solution. Changes in interstitial fluid pressure were monitored continuously with implanted tissue capsules. Changes in tissue fluid volume were estimated from changes in plasma volume and urine volume. In SHR 3 hours postinfusion, tissue fluid volume decreased by 38.7 +/- 2.7 ml/kg and interstitial fluid pressure decreased from -1.4 +/- 0.3 to -6.6 +/- 1.5 mm Hg. In WKY, tissue fluid volume decreased by 32.5 +/- 2.7 ml/kg and interstitial fluid pressure decreased from -1.4 +/- 0.4 to -3.9 +/- 0.5 mm Hg. The linear regression line for delta interstitial fluid pressure and delta fluid volume was estimated for each rat and the inverse of this slope represented ETTC, which averaged 7.4 +/- 1.0 and 9.6 +/- 2.1 ml/kg/mm Hg (p greater than 0.3) in SHR and WKY respectively. Thus, there were no significant differences in interstitial fluid pressure or ETTC between female SHR and WKY. The results of this study confirm a decreased venous capacity in male SHR with established hypertension and provide new information indicating no measurable abnormalities in interstitial fluid pressure or effective total tissue compliance in adult female SHR as compared with WKY.
Pediatric blood pressure: ethnic comparisons in a primary care center.
Authors: Gutgesell M , Terrell G , Labarthe D
Published: June 2012

This study reviews the blood pressure (BP) determinations previously recorded in a primary care center serving a low socioeconomic population and compares the systolic blood pressure (SBP) and diastolic blood pressure (DBP) distributions within the clinic population among the three major ethnic groups represented, and also between this clinic population and a recently reported standard population (Task Force for Blood Pressure Control in Children, NHLBI). The study group consisted of 2810 children 3-17 years of age, of whom 49.2% were of Spanish surname, 23.4% black, and 27.4% white. As a standard clinic procedure, BP readings were obtained from the right arm with the subject seated. Comparisons of the average SBP by 3-year age groups, by sex, within the clinic population showed that blacks had higher SBPs than children with Spanish surnames or whites in all of the five male subgroups and in four of the five female subgroups. Black males had higher DBPs than Spanish or whites in four of the five subgroups; black females had higher DBPs in three of the five subgroups. In comparison with the standard population, the overall 95th percentile values for both SBP and DBP were lower. The prevalence of readings above the 95th percentile values reported for the standard population over all age groups was as follows: SBP, 1.53%; DBP, 1.60%; and both SBP and DBP, 0.57%. Proportionately, elevated readings were most common among blacks and least common among whites. However, these differences between ethnic groups could be accounted for statistically, to a great extent, by adjusting for height and weight, since blacks were the tallest and heaviest of the three groups. These results suggest that, even in childhood, blacks presenting at a primary care center have higher BPs than Spanish or whites, but that this differences is largely related to body size.
Effect of salt on prostaglandin metabolism in hypertension-prone and -resistant Dahl rats.
Authors: Limas C , Goldman P , Limas C J , Iwai J
Published: June 2012

The effect of high salt intake on vascular and renomedullary prostaglandin (PG) synthesis was compared in Sprague-Dawley and salt-sensitive (S) and -resistant (R) Dahl rats. Animals were given a diet containing either 0.6% or 8% NaCl starting at 5 weeks of age, and were sacrificed 6 weeks later. Systolic blood pressure of S rats increased to 220 +/- 7 mm Hg but was unaffected in R and Sprague-Dawley rats. Prostaglandin synthesis was studied in aortic rings and renomedullary microsomes using 14C-arachidonate as substrate. [3H]PGE2 degradation was measured in the renocortical cytosol. In Sprague-Dawley and R rats, aortic PGI2 synthesis was not affected by high salt intake, while a significant increase compared to animals on 0.6% NaCl (from 608 +/- 84 to 992 +/-108 pmoles/60 min, p less than 0.05) was noted in S rats. Enhancement of PGI2 synthesis in S rats may be secondary to the hypertension. Salt-loading consistently stimulated renomedullary PGE2 synthesis in all three animal groups. S rats, however, had the lowest PG synthesis in renal medullas compared to Sprague-Dawley and R rats when placed on either diet. Thus, even after 6 weeks on high salt, S rats did not reach the levels of PGE2 synthesis seen in R or Sprague-Dawley rats on regular diet. The activity of cortical 15-hydroxyprostaglandin dehydrogenase was increased by salt-loading in S and Sprague-Dawley, but not in R rats. R rats had lower dehydrogenase activity than the other two groups when placed on either diet. The observed differences in PG synthesis and catabolism will tend to maintain the net output of renal PGs highest in R and lowest in S rats. These differences correlate with the reported differences in renal papillary flow between these two rat strains and may be relevant to their susceptibility or resistance to hypertension in response to salt.
Converting enzyme inhibition during chronic angiotensin II infusion in rats. Evidence against a nonangiotensin mechanism.
Authors: Textor S C , Brunner H R , Gavras H
Published: June 2012

Interpretation of results obtained with angiotensin-converting enzyme inhibition in hypertensive patients has been obscured by the possibility of nonangiotensin-mediated mechanisms, particularly rats, we have compared the effects of converting enzyme inhibition (CEI) by oral captopril administration to those of dextrose. In this setting of constant angiotensin II levels, any apparent effects of CEI must be mediated by a nonangiotensin-related mechanism. Angiotensin II infusion at 30 ng/min increased mean blood pressure by an average of 22 mm Hg. Following 7 days of CEI, effective blockade of converting enzyme was established both by a 10-fold elevation of vasodepressor sensitivity to exogenous bradykinin and a markedly decreased plasma converting enzyme activity. On the ninth day of angiotensin II infusion, mean arterial pressure, heart rate, and plasma renin activity were not different between CEI and dextrose-treated groups. Similarly, blockade of angiotensin II by saralasin induced a comparable fall in blood pressure in both groups. Metabolic studies also revealed no long-term differences in water and food intake, weight change, or sodium and potassium metabolisms. These findings suggest that, in the continued presence of angiotensin II, there is no detectable hemodynamic or metabolic effect of chronic converting enzyme inhibition, and therefore that bradykinin plays little or no role in its long-term antihypertensive action.
Impaired cardiac contractile response to isoproterenol in the spontaneously hypertensive rat.
Authors: Saragoca M , Tarazi R C
Published: June 2012

To test the ability of the hypertrophied ventricle to increase its contractility in response to sympathetic stimulation, we compared the chronotropic, inotropic, and relaxation responses to graded in fusions of isoproterenol in spontaneously hypertensive rats (SHR) with responses of matched Wistar-Kyoto (WKY) controls. A closed-chested, direct ventricle puncture was used for the study. The SHR required a higher threshold dose (0.04 vs 0.01 micrograms/kg/min) for a significant chronotropic response, and their maximal response of heart rate was smaller than in WKY (delta HR = +12.5 +/- 5.4 vs +22.8 +/- 10.7 beats/min, p less than 0.01). Contractility indices did not increase in the SHR after isoproterenol infusion: (delta dP/dt +2224.3 +/- 1304.7 mm Hg/sec; delta dP/dt/P = +5.1 +/- 9.3 sec-1, p greater than 0.05) in sharp contrast with the marked increases observed in WKY (delta dP/dt = +4682.1 +/- 435.0 mm Hg/sec, p less than 0.01; delta dP/dt/P +78.6 +/- 8.0 sec-1, p less than 0.001). Left ventricular relaxation rate was marked diminished by isoproterenol in SHR (delta neg dP/dt = -2598.6 +/- 855.0 mm Hg/sec) whereas it was not altered significantly in normotensive rats. Thus, cardiac contractile and chronotropic responses were markedly diminished in SHR, possibly as a result of diminished beta adrenoreceptor mediation; further, the impairment of the relaxation rate induced by isoproterenol in SHR might also interfere with contractile cardiac performance during stress.
Left ventricular hypertrophy in children with blood pressures in the upper quintile of the distribution. The Muscatine Study.
Authors: Schieken R M , Clarke W R , Lauer R M
Published: June 2012

From echocardiography measurements of left heart dimensions, cardiac output was estimated in 264 school children whose systolic blood pressure persisted in the lowest, middle, or highest quintile of the distribution for their age and sex. Children with blood pressure in the upper quintile were taller, heavier, and more obese. Echocardiographically determined left ventricular wall mass, corrected for body size, was significantly greater in these children than those in the lower quintiles of blood pressure. These children displayed a continuum of cardiac output. Those with the highest cardiac output in the upper blood pressure quintile had the greatest left ventricular wall mass.
Increased Transforming Growth Factor-β Production and Gene Expression by Peripheral Blood Monocytes of Hypertensive Patients
Authors: Porreca Ettore , Di Febbo Concetta , Mincione Gabriella , Reale Marcella , Baccante Giovanna , Guglielmi Maria Domenica , Cuccurullo Franco , Colletta Giulia
Published: June 2012

Abstract
Cultured human peripheral blood monocytes are known to secrete and express transforming growth factor-β (TGF-β), a multifunctional cytokine that can be involved in myocardial and vascular remodeling. In addition, monocytes/macrophages have been demonstrated to be colocalized with fibrosis of hypertrophied heart and in the vascular wall of hypertensive vessels. In this study, we tested TGF-β production and mRNA expression in peripheral blood monocytes from hypertensive patients with myocardial hypertrophy and increased carotid myointimal thickness with respect to healthy normotensive control subjects. We found an increased TGF-β activity in the conditioned medium of monocytes from hypertensive patients compared with control subjects as evaluated by inhibition of [
3
H]thymidine incorporation by mink lung epithelial cells (−83% and −18% in hypertensive and normotensive subjects;
P
<.001). Western blot analysis confirmed a significant difference in the amount of TGF-β protein secreted in the conditioned medium of hypertensive patients compared with that of normotensive subjects. Finally, we also observed a 4.2- and 5.5-fold increase in the amount of TGF-β
1
and TGF-β
2
transcripts, respectively. Our results indicate an upregulation of the TGF-β system in the peripheral blood monocytes of hypertensive patients with cardiovascular structural changes, suggesting a possible role of TGF-β monocyte production in hypertensive disease.
Regulation of Vascular Type 1 Angiotensin Receptors by Cytokines
Authors: Sasamura Hiroyuki , Nakazato Yuichi , Hayashida Tomoko , Kitamura Yudai , Hayashi Matsuhiko , Saruta Takao
Published: June 2012

Abstract
Although various cytokines are known to be expressed in atherosclerotic lesions, it is not known how these cytokines affect receptors for the peptide hormone angiotensin II (Ang II). We therefore examined the effects of interleukin-1α (220 U/mL [10 ng/mL]), tumor necrosis factor-α (280 U/mL [100 ng/mL]), and interferon gamma (100 U/mL) on Ang II type 1 (AT
1
) receptors expressed in rat vascular smooth muscle cells. Treatment with interleukin-1α caused a 1.4- to 1.7-fold increase in AT
1
binding after 24 hours (
P
<.01) and a 2.3-fold increase in AT
1
mRNA (
P
<.05). Tumor necrosis factor-α and interferon gamma did not cause a significant change in AT
1
binding when administered alone but caused a 30% reduction in binding when administered together (
P
<.05). The maximal decrease in AT
1
binding (60%,
P
<.01) was seen with the combination of interleukin-1α with tumor necrosis factor-α and interferon gamma. Although the upregulation of AT
1
by interleukin-1α was unaffected by pretreatment of cells with
N
-monomethyl-
l
-arginine or indomethacin, downregulation of AT
1
by interleukin-1α combined with tumor necrosis factor-α/interferon gamma was inhibited by
N
-monomethyl-
l
-arginine (
P
<.01). Interleukin-1α treatment enhanced Ang II–induced [
3
H]uridine incorporation, whereas treatment with interleukin-1α combined with tumor necrosis factor-α/interferon gamma attenuated Ang II–induced [
3
H]uridine and [
3
H]leucine incorporation. These results demonstrate that interleukin-1α upregulates AT
1
receptors and enhances Ang II–stimulated hypertrophic responses. However, a combination of interleukin-1α with tumor necrosis factor-α and interferon gamma downregulates AT
1
receptors by a nitric oxide–dependent mechanism and reduces Ang II–stimulated trophic responses in vascular smooth muscle cells.
Neurovascular Compression of the Rostral Ventrolateral Medulla Related to Essential Hypertension
Authors: Morimoto Satoshi , Sasaki Susumu , Miki Shigeyuki , Kawa Tetsuyoshi , Itoh Hiroshi , Nakata Tetsuo , Takeda Kazuo , Nakagawa Masao , Kizu Osamu , Furuya Seiichi , Naruse Shoji , Maeda Tomoho
Published: June 2012

Abstract
The rostral ventrolateral medulla (RVLM) is thought to serve as a final common pathway for the integration of central cardiovascular information and to be important for the mediation of central pressor responses. An association between essential hypertension and neurovascular compression of the RVLM has been reported. To confirm this relationship and to quantitatively measure the distances between the RVLM and the neighboring arteries, we performed magnetic resonance imaging using a high-resolution 512×512 matrix and magnetic resonance angiography in 49 subjects (21 patients with essential hypertension, 10 patients with secondary hypertension, and 18 normotensive subjects). One patient with essential hypertension was excluded from the evaluations because of inadequate assessment due to poor images. Neurovascular compression of the RVLM was observed in 15 of 20 (75%) patients with essential hypertension. In contrast, neurovascular compression was observed in only 1 of 10 (10%) patients with secondary hypertension and only 2 of 18 (11%) normotensive subjects. The rate of observed neurovascular compression in the essential hypertension group was significantly higher than that in the secondary hypertension group and the normotensive group (
P
<.01 for both). The distances between the RVLM and the nearest arteries in the essential hypertension group were significantly shorter than those in the other groups (
P
<.05 for all). On the other hand, the distances between the surface of the medulla oblongata and the nearest arteries did not differ among these three groups. These results suggest that neurovascular compression of the RVLM, but not of the other regions of the medulla oblongata, is particularly related to essential hypertension.
Endogenous Retroviral Transcripts in Myocytes From Spontaneously Hypertensive Rats
Authors: Sirokman Geza , Humphries Donald E. , Bing Oscar H. L.
Published: June 2012

Abstract
The spontaneously hypertensive rat (SHR) is a well studied animal model of genetic hypertension and heart disease of unknown cause. With the use of differential display, a transcript was found in SHR myocardium that on sequence analysis was identified as an endogenous retrovirus (ERV). ERV gene expression was greater than an order of magnitude increased in adult SHR hearts relative to age-matched normotensive Wistar-Kyoto rats and was further increased in hearts from SHR with heart failure. In situ hybridization studies demonstrated that increased ERV gene expression was localized to myocardial cells. Increases in ERV transcripts in SHR suggest a possible link between inherited proviral elements and genetic hypertensive heart disease.
Elevation of Ouabainlike Compound Levels With Hypertonic Sodium Chloride Load in Rat Plasma and Tissues
Authors: Yamada Kaoru , Goto Atsuo , Nagoshi Hiroshi , Terano Yoshitake , Omata Masao
Published: June 2012

Abstract
A major biologically active endogenous digitalis-like factor in the mammalian body may be an isomer of ouabain (ouabainlike compound, OLC). However, the exact role of OLC in sodium homeostasis is still unclear, and acute isotonic volume expansion does not enhance the secretion of OLC. We tested the hypothesis that OLC may be more important in the response to acute hypertonic NaCl load rather than isotonic volume expansion. We injected intraperitoneally 2 mL of 20% NaCl solution into male Wistar rats (n=34) and measured OLC levels in plasma, hypothalamus, pituitary, and adrenal at baseline (n=10) and 1, 2, and 4 hours (n=8 for each). In response to hypertonic NaCl loading, plasma Na-K ratio was elevated at 2 and 4 hours (
P
<.01). OLC levels in pituitary increased (
P
<.01) at 1 hour. Thereafter, plasma OLC levels increased at 2 and 4 hours (
P
<.05; basal, 75±11 pmol/L [±SEM]; 1 hour, 55±11; 2 hours, 130±24; 4 hours, 156±20). Concomitantly, OLC levels in adrenal increased at 2 and 4 hours (
P
<.01; basal, 1.7±0.2 pmol/g; 1 hour, 4.5±0.9; 2 hours, 5.0±0.7; 4 hours, 6.8±2.2). A significant correlation was observed between OLC levels in plasma and adrenal (
P
<.05). Plasma Na-K ratio positively correlated with OLC levels in plasma (
r
=.51,
P
<.01) and adrenal (
r
=.48,
P
<.01). Similar injection of physiological saline solution or hypertonic sucrose solution in physiological saline did not increase OLC levels in plasma and tissues. These findings indicate the elevation of OLC levels in plasma, pituitary, and adrenal in response to acute hypertonic NaCl load in rats and suggest that OLC may be involved in the response to the hypernatremic state.