bluuebunny/crossref_metadata_2025 huggingface dataset:
Afferent Arteriolar Vasodilation to the Sulfonimide Analog of 11,12-Epoxyeicosatrienoic Acid Involves Protein Kinase A
Authors: Imig John D. , Inscho Edward W. , Deichmann Paul C. , Reddy K. Malla , Falck John R.
Published: June 2012

Abstract
—The current study determined the contribution of protein kinase-A (PKA) and protein kinase-G (PKG) to the vasodilation elicited by the
N-
methylsulfonimide analog of 11,12-epoxyeicosatrienoic acid (11,12-EET). Experiments were performed, in vitro, using the juxtamedullary nephron preparation combined with videomicroscopy. The response of afferent arterioles to the sulfonimide analog of 11,12-EET, was determined before and after inhibition of PKA, PKG, or guanylyl cyclase. Afferent arterioles, preconstricted with 0.5 μmol/L norepinephrine, averaged 18±1 μm (n=25) at a renal perfusion pressure of 100 mm Hg. Superfusion with 0.01 to 100 nmol/L of the 11,12-EET analog caused a graded increase in diameter of the afferent arteriole. Vessel diameter increased by 11±1% and 15±1%, respectively, in response to 10 and 100 nmol/L of the 11,12-EET analog. The afferent arteriolar response to 10 and 100 nmol/L of the 11,12-EET analog was significantly attenuated during inhibition of PKA with 10 μmol/L H-89 (n=7) or 5 μmol/L myristolated PKI (n=6), such that afferent arteriolar diameter increased by only 5±2% and 2±1%, respectively, in response to 100 nmol/L of the 11,12-EET analog. In contrast, the afferent arteriolar vasodilatory response to the 11,12-EET analog was unaffected by PKG or guanylyl cyclase inhibition. In the presence of 200 μmol/L histone H2B (n=5) or 10 μmol/L ODQ (n=7), the afferent arteriolar diameter increased by 16±3% and 12±2%, respectively, in response to 100 nmol/L of the 11,12-EET analog. These results demonstrate that activation of PKA is an important mechanism responsible for the afferent arteriolar vasodilation elicited by the sulfonimide analog of 11,12-EET.
Role of 20-HETE in Elevating Chloride Transport in the Thick Ascending Limb of Dahl SS/Jr Rats
Authors: Ito Osamu , Roman Richard J.
Published: June 2012

Abstract
—This study examined the role of endogenous 20 hydroxyeicosatetraenoic acid (20-HETE) in elevating Cl
−
transport in the medullary thick ascending loop of Henle (MTAL) of 9-week-old male Dahl salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats perfused in vitro. Basal transepithelial voltage (V
te
; 14.9±0.9 versus 10.1±0.5 mV) and net lumen-to-bath Cl
−
flux (J
Cl
) (155±6 versus 127±5 pEq · min
−1
· mm
−1
) were significantly greater in MTAL isolated from SS/Jr rats (n=16) than in those obtained from SR/Jr rats (n=16). Blockade of the synthesis of 20-HETE with 17-octadecynoic acid (17-ODYA; 10 μmol/L) increased V
te
from 9.9±0.8 to 13.1±1.0 mV and J
Cl
from 127±7 to 152±8 pEq · min
−1
· mm
−1
in the MTAL of SR/Jr rats (n=8), but it had no significant effect on V
te
or J
Cl
in the MTAL of SS/Jr rats (n=8). Exogenous 20-HETE (1 μmol/L) decreased V
te
from 14.8±0.6 to 10.5±0.6 mV and J
Cl
from 155±10 to 116±6 pEq · min
−1
· mm
−1
in MTAL of SS/Jr rats (n=8), but it had no effect on V
te
or J
Cl
in the MTAL of SR/Jr rats (n=8). The expression of P4504A2 protein in the MTAL of SS/Jr rats was approximately half of that seen in the MTAL of SR/Jr rats. These results indicate that endogenously formed 20-HETE regulates transepithelial voltage and Cl
−
transport in the MTAL and that a diminished production of 20-HETE contributes to an elevation in Cl
−
transport in the MTAL of SS/Jr rats.
Neuronal Nitric Oxide Synthase-Dependent Afferent Arteriolar Function in Angiotensin II-Induced Hypertension
Authors: Ichihara Atsuhiro , Imig John D. , Navar L. Gabriel
Published: June 2012

Abstract
—This study was designed to determine the influence of neuronal nitric oxide synthase (nNOS) in tubular flow-dependent regulation of afferent arteriolar diameter in hypertensive Sprague-Dawley rats that received 60 ng/min angiotensin II (Ang II) subcutaneously for 13 days. Systolic blood pressure of control and Ang II–infused rats averaged 122±2 (n=23) and 194±2 mm Hg (n=24). Afferent arteriolar responses to the nNOS inhibitor
S
-methyl-
l
-thiocitrulline (L-SMTC; 0.1 to 10 μmol/L) and the nonselective NOS inhibitor
N
ω
-nitro-
l
-arginine (L-NNA; 1 to 100 μmol/L) were assessed in vitro using the blood-perfused juxtamedullary nephron preparation. At a perfusion pressure of 160 mm Hg, afferent arteriolar diameters from control and Ang II–infused rats averaged 18.7±1.1 μm (n=8) and 18.1±1.1 μm (n=9), respectively, and decreased by 19.9±1.5% and 11.8±1.1%, respectively, in response to 10 μmol/L L-SMTC. The L-SMTC–induced afferent arteriolar constriction was significantly greater in control than in Ang II–infused rats. In contrast, 100 μmol/L L-NNA constricted afferent arterioles similarly in both control (n=8) and Ang II–infused (n=7) rats. After transection of the loops of Henle to interrupt flow to the macula densa, the vasoconstrictor responses to L-SMTC but not to L-NNA were reversed. Increasing distal volume delivery by addition of 10 mmol/L acetazolamide to the blood perfusate significantly enhanced the afferent arteriolar constrictor responses to 10 μmol/L L-SMTC (34.5±4.8%, n=7) in normotensive rats. In contrast, in Ang II–infused rats, acetazolamide treatment did not enhance the responses to L-SMTC (n=8). These results indicate that chronic Ang II infusion reduces the ability of nNOS-derived nitric oxide to counteract the afferent arteriolar response to increased distal tubular flow.
Obesity-Induced Hypertension
Authors: Mark Allyn L. , Correia Marcelo , Morgan Donald A. , Shaffer Richard A. , Haynes William G.
Published: June 2012

Abstract
—Obesity is associated with an increased risk of hypertension. In the past 5 years there have been dramatic advances into the genetic and neurobiological mechanisms of obesity with the discovery of leptin and novel neuropeptide pathways regulating appetite and metabolism. In this brief review, we argue that these mounting advances into the neurobiology of obesity have and will continue to provide new insights into the regulation of arterial pressure in obesity. We focus our comments on the sympathetic, vascular, and renal mechanisms of leptin and melanocortin receptor agonists and on the regulation of arterial pressure in rodent models of genetic obesity. We suggest 3 concepts. First, the effect of obesity on blood pressure may depend critically on the genetic-neurobiological mechanisms underlying the obesity. Second, obesity is not consistently associated with increased blood pressure, at least in rodent models. Third, the blood pressure response to obesity may be critically influenced by modifying alleles in the genetic background.
Effect of Treatment on Flow-Dependent Vasodilation of the Brachial Artery in Essential Hypertension
Authors: Muiesan Maria Lorenza , Salvetti Massimo , Monteduro Cristina , Rizzoni Damiano , Zulli Roberto , Corbellini Claudia , Brun Claudia , Agabiti-Rosei Enrico
Published: June 2012

Abstract
—The aim of our study was to evaluate the effect of antihypertensive treatment on flow-mediated dilation (FMD)of a large artery, a noninvasive estimate of endothelial function, in hypertensive patients. In 78 consecutive hypertensive patients (40%men; age range, 42 to 67 years) we measured by a high-resolution ultrasound system the changes of brachial artery diameter during reactive hyperemia and after sublingual glyceryl trinitrate (400 μg); brachial artery flow velocity was measured by pulsed Doppler. The results of 2 studies are reported. In the first study, this procedure was repeated in 58 patients after 6 and 12 months of treatment with a combination of antihypertensive drugs; in a second study, the FMD was assessed in 20 patients after 2 months of monotherapy with either nifedipine or hydrochlorothiazide. In the first study, FMD was significantly increased after treatment compared with baseline (from 3.1±3% at baseline to 6.5±4.5% at 6 months and to 8.12±4.6% at 12 months;
P
<0.001 by ANOVA), concomitant with blood pressure reduction (from 162±24/102±13 mm Hg to 141±12/89±6 mm Hg and to 141±9/89±6 mm Hg;
P
<0.001 by ANOVA); significant changes of endothelium-independent dilation were also observed, but only after 12 months of treatment (from 14.2±4.8 at baseline to 15.5±4.7 at 6 months and 16.8±5.9% at 12 months;
P
=0.03 by ANOVA). In the second study, FMD was significantly increased during nifedipine treatment as compared with baseline (from 5±6.18% at baseline to 9.45±3.94%,
P
<0.001), while it did not change in patients receiving hydrochlorothiazide (from 5.15±5.28% at baseline to 4.69±4.34%, NS). No significant changes of endothelium–independent dilation were observed with both drugs (from 17.10±2.4% to 18.14±3.76% and from 18.73±4.07% to 17.46±4.27% during nifedipine and hydrochlorothiazide, respectively, NS). Thus, in essential hypertensive patients an improvement of the impaired FMD of the brachial artery, evaluated by noninvasive ultrasound, may be observed after long-term, effective blood pressure reduction, suggesting a beneficial effect of antihypertensive treatment on endothelial function. It seems that beyond blood pressure control, a calcium antagonist may be more effective than a diuretic in this respect.
Direct Effects of Colchicine on Myocardial Function
Authors: Cicogna Antonio C. , Robinson Kathleen G. , Conrad Chester H. , Singh Krishna , Squire Robyn , Okoshi Marina P. , Bing Oscar H. L.
Published: June 2012

Abstract
—The aging spontaneously hypertensive rat (SHR) is a model in which the transition from chronic stable left ventricular hypertrophy to overt heart failure can be observed. Although the mechanisms for impaired function in hypertrophied and failing cardiac muscle from the SHR have been studied, none accounts fully for the myocardial contractile abnormalities. The cardiac cytoskeleton has been implicated as a possible cause for myocardial dysfunction. If an increase in microtubules contributes to dysfunction, then myocardial microtubule disruption by colchicine should promote an improvement in cardiac performance. We studied the active and passive properties of isolated left ventricular papillary muscles from 18- to 24-month-old SHR with evidence of heart failure (SHR-F, n=6), age-matched SHR without heart failure (SHR-NF, n=6), and age-matched normotensive Wistar-Kyoto rats (WKY, n=5). Mechanical parameters were analyzed before and up to 90 minutes after the addition of colchicine (10
−5
, 10
−4
, and 10
−3
mol/L). In the baseline state, active tension (AT) developed by papillary muscles from the WKY group was greater than for SHR-NF and SHR-F groups (WKY 5.69±1.47 g/mm
2
[mean±SD], SHR-NF 3.41±1.05, SHR-F 2.87±0.26; SHR-NF and SHR-F
P
<0.05 versus WKY rats). The passive stiffness was greater in SHR-F than in the WKY and SHR-NF groups (central segment exponential stiffness constant, K
cs
: SHR-F 70±25, SHR-NF 44±17, WKY 41±13 [mean±SD]; SHR-F
P
<0.05 versus SHR-NF and WKY rats). AT did not improve after 10, 20, and 30 minutes of exposure to colchicine (10
−5
, 10
−4
, and 10
−3
mol/L) in any group. In the SHR-F group, AT and passive stiffness did not change after 30 to 90 minutes of colchicine exposure (10
−4
mol/L). In summary, the data in this study fail to demonstrate improvement of intrinsic muscle function in SHR with heart failure after colchicine. Thus, in the SHR there is no evidence that colchicine-induced cardiac microtubular depolymerization affects the active or passive properties of hypertrophied or failing left ventricular myocardium.
Evidence for Peroxynitrite Formation in the Vasculature of Women With Preeclampsia
Authors: Roggensack Anne M. , Zhang Yunlong , Davidge Sandra T.
Published: June 2012

Abstract
—Preeclampsia is a multisystemic disorder of pregnancy in which the normal vascular adaptations to pregnancy are compromised. Oxidative stress as well as endothelial cell dysfunction have been implicated as pathophysiological features of preeclampsia. Endothelial cells produce the vasorelaxant nitric oxide (NO). However, NO is also known to react with superoxide anions (produced under conditions of oxidative stress), yielding peroxynitrite that may impair vascular function. Our objective was to use immunohistochemical techniques to determine whether there is evidence of peroxynitrite formation in the maternal systemic vasculature of women with preeclampsia. Vessels were obtained from a biopsy of subcutaneous fat at the time of cesarean section from normal pregnant (n=7) and preeclamptic (n=7) women or at the time of hysterectomy from nonpregnant women (n=5). There were significantly more vessels staining with greater intensity for nitrotyrosine and endothelial NO synthase in the endothelium of vessels from women with preeclampsia compared with that of normal pregnant women or nonpregnant women. Both endothelial and smooth muscle cells from all vessels showed evidence for the presence of superoxide dismutase (SOD), an enzyme that scavenges superoxide anions. However, the intensity of staining for SOD in the endothelium was significantly lower in the preeclamptic and nonpregnant women than in normal pregnant women. These data of increased endothelial NO synthase, decreased SOD, and increased nitrotyrosine immunostaining in the maternal vasculature of women with preeclampsia suggest increased peroxynitrite formation. We speculate that peroxynitrite is involved in endothelial cell dysfunction in preeclamptic women and contributes to the pathophysiology of this pregnancy disorder.
Effect of Alcohol Abstinence on Blood Pressure
Authors: Teresa Aguilera María , de la Sierra Alejandro , Coca Antonio , Estruch Ramón , Fernández-Solá Joaquín , Urbano-Márquez Alvaro
Published: June 2012

Abstract
—Several studies have shown that cessation of alcohol drinking reduces blood pressure (BP). However, attempts to reproduce these findings by ambulatory BP monitoring (ABPM) have shown inconsistent results. The aim of the present study was to assess the effect of 1 month of proven abstinence from alcohol on the 24-hour BP profile in heavy alcohol drinkers. Forty-two men who were heavy drinkers (>100 g of pure ethanol per day) were consecutively admitted to a general ward for voluntary alcohol detoxification. On the day of admission, they received a total dose of 2 g/kg of ethanol diluted in orange juice in 5 divided doses, and a 24-hour ABPM was performed. A new 24-hour BP monitoring in the same environmental conditions was performed after 1 month of proven alcohol abstinence while the subjects were receiving the same amount of fluid but without the addition of alcohol. After 1 month of proven alcohol abstinence, BP and heart rate (HR) significantly decreased. The reduction was 7.2 mm Hg for 24-hour systolic BP (SBP) (95% CI, 4.5 to 9.9), 6.6 mm Hg for 24-hour diastolic BP (DBP) (95% CI, 4.2 to 9.0), and 7.9 bpm for HR (95% CI, 5.1 to 10.7). The proportion of alcoholic patients considered hypertensive on the basis of 24-hour BP criteria (daytime SBP ≥135 mm Hg or daytime DBP ≥85 mm Hg) fell from 42% during alcohol drinking to 12% after 1 month of complete abstinence. Abstinence did not modify either the long-term BP variability, assessed by SD of 24-hour BP, or its circadian profile. We conclude that abstinence in heavy alcohol drinkers significantly reduces BP assessed by 24-hour ABPM and that this reduction is clinically relevant. These results show that heavy alcohol consumption has an important effect on BP, and thus cessation of alcohol consumption must be recommended as a priority for hypertensive alcohol drinkers.
Genetic and Gender Influences on Sensitivity to Focal Cerebral Ischemia in the Stroke-Prone Spontaneously Hypertensive Rat
Authors: Carswell Hilary V. O. , Anderson Niall H. , Clark James S. , Graham Delyth , Jeffs Baxter , Dominiczak Anna F. , Macrae I. Mhairi
Published: June 2012

Abstract
—We have investigated genetic transmission of increased sensitivity to focal cerebral ischemia and the influence of gender in the stroke-prone spontaneously hypertensive rat (SHRSP). Halothane-anesthetized, 3- to 5-month-old male and female Wistar-Kyoto rats (WKY), SHRSP, and the first filial generation rats (F
1
crosses 1 and 2) underwent distal (2 mm) permanent middle cerebral artery occlusion (MCAO) by electrocoagulation. Infarct volume was measured by using hematoxylin-eosin–stained sections and image analysis 24 hours after ischemia and expressed as a percentage of the volume of the ipsilateral hemisphere. Infarct volume in males and females grouped together were significantly larger in SHRSP, F
1
cross 1 (SHRSP father), and F
1
cross 2 (WKY father), at 36.6±2.3% (mean±SEM,
P
<0.001, n=15), 25.4±2.4% (
P
<0.01, n=14), and 33.9±1.6% (
P
<0.001, n=18), respectively, compared with WKY (14±2%, n=17). Male F
1
cross 1 (18.9±2.4%, n=6) developed significantly smaller infarcts than male F
1
cross 2 (32.8±2%, n=8,
P
<0.005). Females, which underwent ischemia during metestrus, developed larger infarcts than respective males. A group of females in which the cycle was not controlled for developed significantly smaller infarcts than females in metestrus. Thus, the increased sensitivity to MCAO in SHRSP is retained in both F
1
cross 1 and cross 2 hybrids, suggesting a dominant or codominant trait; response to cerebral ischemia appears to be affected by gender and stage in the estrous cycle. In addition, the male progenitor of the cross (ie, SHRSP versus WKY) influences stroke sensitivity in male F
1
cohorts.
Insulin Sensitivity Is Related to Physical Fitness and Exercise Blood Pressure to Structural Vascular Properties in Young Men
Authors: Fossum Eigil , Høieggen Aud , Moan Andreas , Rostrup Morten , Kjeldsen Sverre E.
Published: June 2012

Abstract
—Insulin resistance is related to physical inactivity, which is a risk factor for cardiovascular disease and death. Moreover, blood pressure responses during the first 6 minutes of an exercise test (600 kilo/pound/meter [kpm] per min) are more predictive for cardiovascular morbidity and mortality than blood pressure at rest, which could reflect that exercise blood pressure correlates more closely to peripheral structural vascular changes than casual blood pressure. We have recently shown a correlation between insulin resistance and minimal forearm vascular resistance (MFVR) in young men recruited from the highest blood pressure percentiles during a military draft session. In the present study, we tested the hypotheses that insulin sensitivity relates to physical fitness and that blood pressure responses during an exercise test relate to peripheral structural vascular changes in these men; we also tested whether these findings were interrelated. We assessed insulin sensitivity and physical fitness in 27 young men randomly selected from the cohort having a blood pressure of 140/90 mm Hg or higher during the compulsory military draft session in Oslo. Insulin sensitivity correlated with physical fitness (
r
=0.58,
P
=0.002). Systolic blood pressure after 6 minutes of exercise (600 kpm/min) correlated with MFVR (
r
=0.46,
P
=0.015). MFVR and physical fitness independently explained 60% of the variation in insulin sensitivity, and MFVR independently explained 19% of the variation of systolic blood pressure after 6 minutes of exercise. In conclusion, insulin sensitivity is related to physical fitness and exercise blood pressure to structural vascular properties in these young men.
Assessment of Arterial Compliance by Carotid Midwall Strain-Stress Relation in Hypertension
Authors: Bella Jonathan N. , Roman Mary J. , Pini Riccardo , Schwartz Joseph E. , Pickering Thomas G. , Devereux Richard B.
Published: June 2012

Abstract
—To elucidate the relations between arterial hypertrophy and compliance in hypertension, we studied 205 unmedicated hypertensive patients (129 men and 76 women) and 82 normotensive adults (56 men and 26 women) from an employed population by carotid ultrasound, noninvasive applanation tonometry, and echocardiography. Carotid midwall strain and circumferential stress were calculated at end diastole and peak systole. The relations of luminal and midwall strain to the increment in circumferential stress from end diastole to peak systole (Δcarotid stress in normal subjects) were used to calculate ratios of observed/predicted carotid luminal and midwall strain. Mean stress-corrected luminal strain (82±26%) and midwall strain (78±23%) were lower (both
P
<0.001) in hypertensive patients than in normal adults. Stress-corrected luminal strain identified 14% of hypertensive patients with low arterial compliance, while stress-corrected midwall strain was low in 18% of patients. Patients with subnormal carotid midwall strain were older (61±12 versus 54±12 years,
P
<0.01) and had larger carotid diameters (6.6±0.8 versus 5.7±0.8 mm,
P
=0.002) and higher brachial pulse pressures (71±25 versus 63±17 mm Hg,
P
<0.05) than other patients. Patients with arterial hypertrophy had lower stress-corrected midwall strain than those without hypertrophy (70±24% versus 79±23%,
P
=0.05), whereas no difference was observed in stress-corrected luminal strain (
P
=0.40). Stress-corrected midwall strain tended to be lower in patients with discrete atherosclerotic plaques than in those without (74±20% versus 79±24%,
P
=0.15). Compared with patients with normal left ventricular geometry, those with concentric hypertrophy had larger carotid diameters (6.6±0.7 versus 5.8±0.9 mm,
P
<0.05) and lower stress-corrected luminal strain (62±11% versus 85±25%,
P
<0.05) and midwall strain (59±10% versus 81±22%,
P
<0.05). Therefore, stress-corrected midwall strain identifies patients with reduced arterial compliance, increased arterial wall thickness, and abnormal left ventricular geometry better than conventional measures based on arterial lumen diameters.
Effects of an Angiotensin-Converting Enzyme Inhibitor and a β-Blocker on Cerebral Arterioles in Rats
Authors: Chillon Jean-Marc , Baumbach Gary L.
Published: June 2012

Abstract
—We examined the effects of an angiotensin-converting enzyme inhibitor, perindopril, and a β-blocker, propranolol, on cerebral arterioles in stroke-prone spontaneously hypertensive rats (SHRSP). The structure and mechanics of cerebral arterioles were examined in untreated Wistar-Kyoto rats (WKY) and SHRSP that were untreated or treated for 3 months with a high (2 mg/kg per day) or a low (0.3 mg/kg per day) dose of perindopril or propranolol (250 mg/kg per day) alone or in combination with the low dose of perindopril. We measured pressure, external diameter, and cross-sectional area of the vessel wall (CSA) in maximally dilated (with EDTA) cerebral arterioles. Treatment of SHRSP with the high dose of perindopril or the combination of propranolol and the low dose of perindopril normalized cerebral arteriolar mean pressure (50±1 [mean±SEM] and 43±2 mm Hg vs 50±1 mm Hg in WKY and 94±3 mm Hg in untreated SHRSP;
P
<0.05), pulse pressure (15±1 and 16±1 mm Hg vs 13±1 mm Hg in WKY and 35±1 mm Hg in untreated SHRSP;
P
<0.05), and CSA (1103±53 and 1099±51 μm
2
, respectively, vs 1057±49 μm
2
in WKY and 1281±62 μm
2
in untreated SHRSP;
P
<0.05). In contrast, treatment of SHRSP with the low dose of perindopril or propranolol alone did not normalize arteriolar pulse pressure (24±1 and 21±1 mm Hg) and failed to prevent increases in CSA (1282±77 and 1267±94 μm
2
). Treatment with either dose of perindopril or the combination of propranolol and perindopril significantly increased external diameter in cerebral arterioles of SHRSP (99±3, 103±2, and 98±3 μm vs 87±2 μm in untreated SHRSP;
P
<0.05), whereas propranolol alone did not (94±3 μm;
P
>0.05). These findings suggest that effects of angiotensin-converting enzyme inhibitors on cerebral arteriolar hypertrophy in SHRSP may depend primarily on their effects on arterial pressure, particularly pulse pressure, whereas their effects on cerebral arteriolar remodeling (defined as a reduction in external diameter) may be pressure independent.
Prospective Analysis of Traits Related to 6-Year Change in Sodium-Lithium Countertransport
Authors: Cirillo Massimo , Laurenzi Martino , Panarelli Walter , Trevisan Maurizio , Stamler Jeremiah
Published: June 2012

Abstract
—Sodium-lithium countertransport (Na-Li CT) activity in red blood cells relates cross-sectionally and longitudinally to blood pressure and hypertension. Lifestyle and metabolic factors relate cross-sectionally to this sodium transporter. The aim of this study was to conduct a prospective analysis of 6-year Na-Li CT change and of traits related to Na-Li CT change. In 2183 participants in the Gubbio Population Study (972 men and 1211 women; baseline ages, 18 to 74 years), the following data collected at baseline and 6-year follow-up were analyzed: Na-Li CT; gender; age; body mass index (BMI); blood pressure; antihypertensive treatment; alcohol intake; smoking habits; urinary sodium-to-potassium ratio; and plasma cholesterol, glucose, uric acid, sodium, potassium, and triglycerides (measured only at follow-up). Six-year changes were defined as follow-up minus baseline values. Na-Li CT was higher at follow-up than at baseline in both genders (
P
<0.001). Baseline Na-Li CT; baseline and change values of BMI; and change values of alcohol intake, plasma potassium, and plasma glucose related to Na-Li CT change significantly and independently with control for other variables. Follow-up plasma triglyceride levels also related independently to Na-Li CT change. Coefficients were positive for BMI, alcohol intake, and plasma glucose and triglyceride levels and were negative for baseline Na-Li CT and plasma potassium levels. Baseline and change values of other variables did not relate significantly to Na-Li CT change. In conclusion, in prospective analyses, BMI, alcohol intake, plasma glucose, and lipids were directly related to Na-Li CT change; baseline Na-Li CT and plasma potassium levels were inversely related. The data support the concept that lifestyle and related metabolic factors influence Na-Li CT.
Erythropoietin Depresses Nitric Oxide Synthase Expression by Human Endothelial Cells
Authors: Wang Xiu Q. , Vaziri Nosratola D.
Published: June 2012

Abstract
—We have recently shown that erythropoietin (EPO)-induced hypertension is unrelated to the rise in hematocrit and is marked by elevated cytosolic [Ca
+2
] and nitric oxide (NO) resistance. The present study was done to determine the effect of EPO on NO production and endothelial NO synthase (eNOS) expression by endothelial cells. Human coronary artery endothelial cells were cultured to subconfluence and then were incubated for 24 hours in the presence of either EPO (0, 5, and 20 U/mL) alone or EPO plus the calcium channel blocker felodipine. The experiments were carried out with quiescent (0.5% FCS) and proliferating (5% FCS) cells. Total nitrate and nitrite, eNOS protein, DNA synthesis (thymidine incorporation), and cell proliferation (cell count) were determined. In addition, NO production in response to acetylcholine stimulation was tested. EPO resulted in a dose-dependent inhibition of basal and acetylcholine-stimulated NO production and eNOS protein expression and also led to a significant dose-dependent stimulation of DNA synthesis in endothelial cells. The inhibitory effects of EPO on NO production and eNOS expression were reversed by felodipine. Thus, EPO downregulates basal and acetylcholine-stimulated NO production, depresses eNOS expression, and stimulates proliferation in isolated human endothelial cells. The suppressive effects of EPO on NO production and on eNOS expression are reversed by calcium channel blockade.
Salt-Sensitive Hypertension Develops After Short-Term Exposure to Angiotensin II
Authors: Lombardi Donna , Gordon Katherine L. , Polinsky Patti , Suga Shinichi , Schwartz Stephen M. , Johnson Richard J.
Published: June 2012

Abstract
—We hypothesized that short-term exposure to angiotensin II (Ang II) could result in structural and functional changes in the kidney that would favor sodium retention and the development of sustained hypertension. To test this hypothesis, rats were exposed to pressor doses (435 ng · kg
−1
· min
−1
) of Ang II for 2 weeks. The infusion of Ang II was associated with acute hypertension, renal dysfunction, proteinuria, and focal tubulointerstitial and vascular damage. At sites of the tubulointerstitial damage, there was a reduction in peritubular capillary endothelial cell staining. By use of immunostaining, we found focal loss of endothelial nitric oxide synthase (eNOS) in the peritubular capillaries at sites of injury and a generalized reduction in eNOS in collecting ducts, thin loops of Henle, and vascular bundles in the medulla. When the Ang II infusion ended, the rats became normotensive and renal function returned toward normal. However, exposure of the rats to high salt diet (4% NaCl) resulted in the redevelopment of hypertension after 3 to 4 weeks. Rats maintained on a high salt diet with no prior exposure to Ang II and rats placed on low salt diet (0.1% NaCl) after exposure to Ang II remained normotensive. Thus, we report a new model of salt-sensitive hypertension induced by transient exposure to pressor doses of Ang II. The mechanism may relate to microvascular injury with peritubular capillary loss coupled with functional changes, such as a loss in intrarenal nitric oxide formation, that could alter the ability of the kidney to excrete a salt load.
Dopamine-1 Receptor Coupling Defect in Renal Proximal Tubule Cells in Hypertension
Authors: Sanada Hironobu , Jose Pedro A. , Hazen-Martin Debra , Yu Pei-Ying , Xu Jing , Bruns David E. , Phipps John , Carey Robert M. , Felder Robin A.
Published: June 2012

Abstract
—The ability of the dopamine-1 (D
1
)-like receptor to stimulate adenylyl cyclase (AC) and phospholipase C (PLC), inhibit sodium transport in the renal proximal tubule (RPT), and produce natriuresis is attenuated in several rat models of hypertension. Since the inhibitory effect of D
1
-like receptors on RPT sodium transport is also reduced in some patients with essential hypertension, we measured D
1
-like receptor coupling to AC and PLC in cultures of human RPT cells from normotensive (NT) and hypertensive (HT) subjects. Basal cAMP concentrations were the same in NT (n=6) and HT (n=4). However, the D
1
-like receptor agonist fenoldopam increased cAMP production to a greater extent in NT (maximum response=67±1%) than in HT (maximum response=17±5%), with a potency ratio of 105. Dopamine also increased cAMP production to a greater extent in NT (32±3%) than in HT (14±3%). The fenoldopam-mediated increase in cAMP production was blocked by
SCH23390
(a D
1
-like receptor antagonist) and by antisense D
1
oligonucleotides in both HT and NT, indicating action at the D
1
receptor. The stimulatory effects of forskolin and parathyroid hormone–related protein of cAMP accumulation were not statistically different in NT and HT, indicating receptor specificity and an intact G-protein/AC pathway. The fenoldopam-stimulated PLC activity was not impaired in HT, and the primary sequence and expression of the D
1
receptor were the same in NT and HT. However, D
1
receptor serine phosphorylation in the basal state was greater in HT than in NT and was not responsive to fenoldopam stimulation in HT. These studies demonstrate the expression of D
1
receptors in human RPT cells in culture. The uncoupling of the D
1
receptor in both rats (previously described) and humans (described here) suggests that this mechanism may be involved in the pathogenesis of hypertension; the uncoupling may be due to ligand-independent phosphorylation of the D
1
receptor in hypertension.
Different Frequencies of Inducible Nitric Oxide Synthase Genotypes in Older Hypertensives
Authors: Glenn Cheryl L. , Wang William Y. S. , Morris Brian J.
Published: June 2012

Abstract
—A locus for essential hypertension has been found recently on chromosome 17 in the general vicinity of the inducible nitric oxide synthase (iNOS) gene (
NOS2A
at 17cen-q11.2). We therefore tested
NOS2A
markers for association and linkage with hypertension in affected Australian Anglo-Caucasians. Patients for the association study (n=112) were from our cohort of hypertensives (systolic/diastolic=175±25 SD/112±19 mm Hg) who were the offspring of 2 hypertensive parents; control subjects (n=164) were normotensives whose parents were both normotensive. The linkage study involved 156 hypertensive sib-pairs. Genotypes for an 8-allele pentameric repeat located 2.6 kb upstream of
NOS2A
and of a biallelic tetranucleotide repeat 0.7 kb upstream were determined by polymerase chain reaction and automated gene scan analysis. In the association study, the frequency of the minor allele of the biallelic marker was 0.18 in the hypertensives and 0.14 in the normotensives (χ
2
1 df
=1.1,
P
=0.3). Allele frequencies for the multiallelic marker were also similar in each group (χ
2
7 df
=9.8,
P
=0.2). Furthermore, no genotypic differences in blood pressure were apparent. In the sib-pair study, SPLINK APM, and MAPMAKERS/SIBS did not indicate excess allele sharing. We also examined genotype as a function of age. In the younger (< 60 years) hypertensives as well as younger or older normotensives, genotype and allele frequency of the biallelic marker was similar (0.12 to 0.14). However, in hypertensives ≥60 years of age, frequency of the minor allele was 0.28 (χ
2
=7.4,
P
=0.006). Homozygotes for this allele were rare. Frequency of heterozygotes was 0.19 for normotensives but 0.39 for the older hypertensives (χ
2
=8.0,
P
=0.018) and was 0.40 for hypertensive sibs ≥60 years of age with a diastolic pressure ≥100 mm Hg. Furthermore, homozygotes for the major allele were 7 years younger than heterozygotes (
P
=0.05 by ANOVA). In conclusion, the present study shows (1) no evidence for a role of
NOS2A
in hypertension and (2) a genotypic difference in frequency of a
NOS2A
promoter variant in older hypertensives, seen in 2 different cohorts. A possible interpretation of the latter observation is that
NOS2A
genotype could affect longevity, at least in patients at high risk by having moderate to severe hypertension.
Lack of Evidence for Association Between the Endothelial Nitric Oxide Synthase Gene and Hypertension
Authors: Kato Norihiro , Sugiyama Takao , Morita Hiroyuki , Nabika Toru , Kurihara Hiroki , Yamori Yukio , Yazaki Yoshio
Published: June 2012

Abstract
—Significant association between a Glu298Asp polymorphism of the endothelial nitric oxide synthase
(eNOS)
gene and essential hypertension was recently reported in Japanese populations, with the 298Asp variant showing a higher prevalence in hypertensive patients (10.3% to 12.0%) than in normotensive subjects (5.0% to 5.8%). In contrast, another study demonstrated that the 298Glu variant was significantly associated with hypertension in a Caucasian population. We therefore undertook an extensive association study in Japanese to resolve these contradictory claims. A total of 1165 individuals were selected from clinic outpatients and hospital staff in a single institution. The relevance of the Glu298Asp polymorphism to hypertension in this population was tested in 2 ways. First, a case-control study was conducted in 549 hypertensive and 513 normotensive subjects within the study population, with the χ
2
statistic used to test the significance of an association between
eNOS
genotype and the presence of hypertension. Second, an ANOVA was used to test the significance of an association between
eNOS
genotype and the level of blood pressure within the entire population except for 167 hypertensive subjects who had been under treatment for hypertension. No significant association was observed in either of the statistics tested. Allele frequencies of 298Asp were concordant across the panels: 8.4% in hypertensive subjects, 8.2% in normotensive subjects, and 7.9% and 9.5% in 2 additional sample populations used as reference panels. Taken together, our results do not support the previous observation that the molecular variant of the
eNOS
gene may confer principal susceptibility for essential hypertension but rather suggest the existence of sampling variation.
Descriptive Epidemiology of Blood Pressure Response to Change in Body Position
Authors: Nardo Christopher J. , Chambless Lloyd E. , Light Kathleen C. , Rosamond Wayne D. , Sharrett A. Richey , Tell Grethe S. , Heiss Gerardo
Published: June 2012

Abstract
—The epidemiology of a common measure of cardiovascular reactivity, the change in systolic blood pressure (ΔSBP) from the supine to the standing position, is described in a cohort of 13 340 men and women aged 45 to 65 years enrolled in the Atherosclerosis Risk in Communities (ARIC) Study. The distribution of ΔSBP was found to be symmetrical and unimodal, with a mean value near zero (−0.45 mm Hg). The range of ΔSBP was from −63.2 to 54.3 mm Hg, and the standard deviation was 10.8. Stratification of ΔSBP by race and gender shows a slight shift in distribution toward higher values for black men and women. ΔSBP was categorized into deciles. Participants in the top 30% and bottom 30% of the distribution were compared with individuals in the middle 40% of the distribution, who had little or no change in SBP on standing. Participants in the bottom 30% (ie, SBP decreased on standing) were significantly older, had a greater prevalence of hypertension and peripheral vascular disease, had higher values of SBP, and had more cigarette-years of smoking. Among participants in the top 30% (ie, SBP increased on standing), a significantly larger proportion were black, mean seated SBP was higher, and the predicted risk of developing coronary heart disease after 8 years was greater. The response of SBP to change in posture showed considerable variability in a population sample of middle-aged adults. Cardiovascular morbidity, sociodemographic factors, and cigarette smoking were associated with the magnitude and direction of the postural change.
Human Obesity Is Characterized by a Selective Potentiation of Central Chemoreflex Sensitivity
Authors: Narkiewicz Krzysztof , Kato Masahiko , Pesek Catherine A. , Somers Virend K.
Published: June 2012

Abstract
—The chemoreflexes are an important mechanism for regulation of both breathing and autonomic cardiovascular function. Obesity is associated with an increased risk of alveolar hypoventilation and carbon dioxide retention, suggesting that abnormalities in chemoreflex control mechanisms may be implicated. We tested the hypothesis that chemoreflex function is altered in obesity. We compared ventilatory, sympathetic, heart rate, and blood pressure responses to hypercapnia, hypoxia, and the cold pressor test in 14 obese subjects and 14 normal-weight subjects matched for age and gender. During hypercapnia, the increase in minute ventilation was significantly greater in obese subjects (7.0±0.3 L/min) than in normal-weight subjects (3.3±1.1 L/min;
P
=0.03). Despite higher minute ventilation during hypercapnia in obese subjects, the increase in muscle sympathetic nerve activity was similar in obese and normal-weight subjects. When the inhibitory influence of breathing during hypercapnia was eliminated by apnea, the increase in sympathetic nerve activity in obese subjects (99±16%) was greater than in normal-weight subjects (44±16%;
P
=0.02). The magnitude of the ventilatory and autonomic responses to hypoxia and the cold pressor test was similar in obese and normal-weight subjects. We conclude that chemoreflex responses to hypercapnia are potentiated in eucapnic obese subjects. In contrast, responses to hypoxia and to the excitatory cold pressor stimulus in obese subjects are similar to those in normal-weight subjects. Thus, obesity is characterized by selective potentiation of central chemoreflex sensitivity.
The Lys198Asn Polymorphism in the Endothelin-1 Gene Is Associated With Blood Pressure in Overweight People
Authors: Tiret Laurence , Poirier Odette , Hallet Vincent , McDonagh Theresa A. , Morrison Caroline , McMurray John J. V. , Dargie Henry J. , Arveiler Dominique , Ruidavets Jean-Bernard , Luc Gérald , Evans Alun , Cambien François
Published: June 2012

Abstract
—There is accumulating evidence that endothelin-1 plays an important role in vascular pathophysiology. Our objective was to examine whether molecular variations at the endothelin-1 locus were involved in susceptibility to myocardial infarction and variation in blood pressure. The entire coding sequence and 1.4 kb of the 5′ flanking region were screened. Five polymorphisms were detected, which were genotyped in the ECTIM (Etude Cas-Témoin de l’Infarctus du Myocarde) Study, a multicenter study comparing 648 male patients who had survived a myocardial infarction and 760 population-based controls. The polymorphisms were not associated with myocardial infarction, nor did they contribute to blood pressure levels in the population at large. However, a G/T polymorphism predicting an Lys/Asn change (ET1/C198) strongly interacted (
P
<0.001) with body mass index in the determination of blood pressure levels. There was a steeper increase of blood pressure with body mass index in carriers of the
T
allele than in
GG
homozygotes. As a consequence, the
T
allele was associated with an increase of blood pressure in overweight subjects (body mass index ≥26 kg/m
2
), while no significant effect was observed in lean subjects (body mass index <26 kg/m
2
). To determine whether this finding could be replicated, the ET1/C198 was genotyped in the Glasgow Heart Scan Study, a population-based study including 619 men and 663 women. Subjects homozygous for the
T
allele had higher resting blood pressure levels than others (
P
<0.05). A similar interaction between the
T
allele and body mass index was observed on the maximum blood pressure achieved during a treadmill exercise test (
P
<0.001). In conclusion, results from 2 independent studies suggest that the ET1/C198 polymorphism is associated with blood pressure levels in overweight people.
The 825C/T Polymorphism of the G-Protein Subunit β3 Is Not Related to Hypertension
Authors: Brand Eva , Herrmann Stefan-Martin , Nicaud Viviane , Ruidavets Jean-Bernard , Evans Alun , Arveiler Dominique , Luc Gerald , Plouin Pierre-François , Tiret Laurence , Cambien François
Published: June 2012

Abstract
—A polymorphism at position 825 (C→T) of the cDNA that encodes the β3 subunit (GNB3) of the pertussis toxin–sensitive G protein was recently shown to be associated with human hypertension. To verify this finding and to investigate whether this polymorphism could also be associated with coronary heart disease, we analyzed the GNB3 variant in subjects from 2 previously described studies: Projet d’Etude des Gènes de l’hypertension Artérielle Sévère à modérée Essentielle (PEGASE), a case-control study of moderate to severe hypertension (681 cases and 308 controls), and Etude Cas-Témoins de l’Infarctus du Myocarde (ECTIM), a case-control study of myocardial infarction (MI) (564 cases and 633 controls). Genotyping was performed with allele-specific oligonucleotides. Genotype and allele frequencies were in Hardy-Weinberg equilibrium in all groups. Allele and genotype frequencies did not differ significantly between case patients with essential hypertension or MI and control subjects. In the ECTIM study, the 825T allele frequencies in cases and controls from Belfast, Northern Ireland, were 0.31 and 0.30 (
P
=0.79), respectively; the corresponding frequencies in cases and controls from France were 0.33 and 0.31 (
P
=0.30), respectively. In the PEGASE study, the 825T allele frequency was 0.35 in female and male cases and 0.31 in male normotensive controls (
P
=0.12). The odds ratios for hypertension (PEGASE) and MI (ECTIM) associated with T-allele carrying were 1.23 (95% confidence interval, 0.94 to 1.62;
P
=0.13) and 1.11 (95% confidence interval, 0.88 to 1.39;
P
=0.37), respectively. There was no association of the GNB3 polymorphism with early onset of hypertension, familial history of hypertension, or blood pressure level. We conclude that the 825C/T polymorphism of the GNB3 gene did not contribute in any important way to the risk of essential hypertension or MI in these studies.
p53-Mediated Upregulation of
BAX
Gene Transcription Is Not Involved in Bax-α Protein Overexpression in the Left Ventricle of Spontaneously Hypertensive Rats
Authors: Fortuño María Antonia , Zalba Guillermo , Ravassa Susana , D’Elom Eva , Beaumont Francisco J. , Fortuño Ana , Díez Javier
Published: June 2012

Abstract
—An association of increased apoptosis with overexpression of the proapoptotic protein Bax-α has been reported in the left ventricle of adult spontaneously hypertensive rats (SHR). Both alterations were corrected in SHR that received long-term treatment with the AT
1
antagonist losartan. To gain insight into the regulation of cardiac Bax-α protein in genetic hypertension, we investigated the expression of the protein p53 (a
BAX
gene transcription factor) and BAX mRNA in the left ventricle of 30-week-old Wistar-Kyoto rats (WKY), SHR, and SHR treated with losartan (20 mg · kg
−1
· d
−1
) during 14 weeks before death. The expression of p53 and Bax proteins was assessed by Western blot analysis. The expression of BAX mRNA was assessed by Northern blot analysis. The density of apoptotic cells was assessed by direct immunoperoxidase detection of biotin-labeled deoxyuridine nucleotides. Compared with WKY, untreated SHR exhibited increased apoptosis (
P
<0.05), increased Bax-α protein (
P
<0.05), and similar levels of p53 protein and BAX mRNA. Losartan given long term was associated with the normalization of apoptosis and Bax-α protein expression. The expression of BAX mRNA was decreased (
P
<0.05) in treated SHR compared with untreated SHR. No changes in the expression of p53 protein were observed in losartan-treated SHR. These results suggest that overexpression of the Bax-α protein seen in the left ventricle of adult SHR with increased apoptosis is not related to a p53-mediated upregulation of
BAX
gene transcription. Our data also suggest that normalization of Bax-α protein observed in SHR after long-term blockade of angiotensin II type 1 receptors may be due to the inhibition of
BAX
gene transcription.
Muscular Strength Training Is Associated With Low Arterial Compliance and High Pulse Pressure
Authors: Bertovic David A. , Waddell Tamara K. , Gatzka Christoph D. , Cameron James D. , Dart Anthony M. , Kingwell Bronwyn A.
Published: June 2012

Abstract
—Aerobic exercise training increases arterial compliance and reduces systolic blood pressure, but the effects of muscular strength training on arterial mechanical properties are unknown. We compared blood pressure, whole body arterial compliance, aortic impedance, aortic stiffness (measured by β-index and carotid pulse pressure divided by normalized systolic expansion [Ep]), pulse wave velocity, and left ventricular parameters in 19 muscular strength–trained athletes (mean±SD age, 26±4 years) and 19 sedentary controls (26±5 years). Subjects were healthy, non-steroid-using, nonsmoking males, and athletes had been engaged in a strength-training program with no aerobic component for a minimum of 12 months. There was no difference in maximum oxygen consumption between groups, but handgrip strength (mean±SEM, 44±2 versus 56±2 kg;
P
<0.01) and left ventricular mass (168±8 versus 190±8 g;
P
<0.05) were greater in athletes. Arterial stiffness was higher in athletes, as evidenced by lower whole body arterial compliance (0.40±0.04 versus 0.54±0.04 arbitrary compliance units;
P
=0.01), higher aortic characteristic impedance (1.55±0.13 versus 1.18±0.08 mm Hg · s · cm
−1
;
P
<0.05), β-index (4.6±0.2 versus 3.8±0.4;
P
<0.05), and ln Ep (10.86±0.06 versus 10.60±0.08;
P
<0.01). Femoral–dorsalis pedis pulse wave velocity was also higher in the athletes, but carotid-femoral pulse wave velocity was not different. Furthermore, both carotid (56±3 versus 44±2 mm Hg;
P
<0.001) and brachial (60±3 versus 50±2 mm Hg;
P
<0.01) pulse pressures were higher in the athletes, but mean arterial pressure and resting heart rate did not differ between groups. These data indicate that both the proximal aorta and the leg arteries are stiffer in strength-trained individuals and contribute to a higher cardiac afterload.