bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional Regulation of the Rat Renin Gene by Regulatory Elements in Intron I
Authors: Voigtländer Till , Ganten Detlev , Bader Michael
Published: June 2012

Abstract
—Renin catalyzes the rate-limiting step in the enzymatic cascade leading to the vasoactive peptide angiotensin II. Therefore, the activity of the renin-angiotensin system in a tissue is regulated significantly at the level of transcription of the renin gene. Besides transcription factor binding sites in the promoter region, the renin genes of human and rat contain regulatory elements also in intron I. Inclusion of intron I in reporter gene constructs with the renin promoter leads to a marked down-regulation of gene expression in nonrenin expressing 293 human embryonic kidney cells but has hardly any effect in renin-expressing L8 rat skeletal myoblasts. In combination with the cytomegalovirus immediate early gene promoter, the silencing occurs in both cell lines but is less pronounced in L8 cells. By partially deleting intron I in these constructs, we describe 5 negative (I-NRE) and 2 positive (I-PRE) regulatory elements responsible for these effects. Using gel-retardation and methylation-interference assays with 293-nuclear extracts, we detected a pseudo-palindromic protein-binding sequence between position +159 and +171 relative to the transcriptional start site. Binding of transcription factors to this sequence may be important for the tissue-specific silencing of the renin gene outside the juxtaglomerular cells of the kidney.
Sympathoinhibitory Effects of Central Nifedipine in Spontaneously Hypertensive Rats on High Versus Regular Sodium Intake
Authors: Huang Bing S. , Leenen Frans H. H.
Published: June 2012

Abstract
—The putative central sympathoinhibitory actions of the dihydropyridine calcium antagonist nifedipine and the effect of dietary sodium on these actions were investigated in spontaneously hypertensive rats (SHR). Regular or high dietary salt was administered from 4 to 8 weeks of age. At 8 weeks, blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity were recorded in conscious rats at rest as well as in response to intravenous (50 μg/kg) and intracerebroventricular (5 and 50 μg/kg) injections of nifedipine and intracerebroventricular injections of vehicle. Resting mean arterial pressure was higher in SHR on high versus regular salt (159±3 versus 135±4 mm Hg;
P
<0.05). Nifedipine administered intracerebroventricularly decreased BP as well as renal sympathetic nerve activity and HR in a dose-related manner. The responses reached their peak at 3 to 5 minutes and lasted ≈30 minutes. Peak decreases in BP, renal sympathetic nerve activity, and HR in response to both doses of nifedipine were significantly larger in SHR on high versus regular salt. Nifedipine administered intravenously also decreased BP but, in contrast, caused (reflex) increases in renal sympathetic nerve activity and HR. On both diets, intracerebroventricular vehicle did not affect mean arterial pressure, renal sympathetic nerve activity, or HR. These data indicate that in contrast to its peripheral vasodilator effect, centrally administered nifedipine may decrease sympathetic outflow and therefore BP and HR. The enhanced sympathoinhibitory and depressor responses to nifedipine in SHR on high versus regular salt suggest that the sympathetic hyperactivity induced by high salt intake is dependent on neuronal calcium influx via L-type channels.
Antisense Inhibition of AT
1
Receptor in Vascular Smooth Muscle Cells Using Adeno-Associated Virus-Based Vector
Authors: Mohuczy Dagmara , Gelband Craig H. , Phillips M. Ian
Published: June 2012

Abstract
—Vascular smooth muscle cells (VSMCs) are the main peripheral target for vasoconstriction and growth-promoting activity of angiotensin II (Ang II), acting through angiotensin type 1 receptors (AT
1
-R). Current antihypertension treatments include daily reductions in the effects of Ang II. To decrease an effect of Ang II in a prolonged fashion, we have developed an adeno-associated virus (AAV) vector with antisense DNA for AT
1
-R. AAV has many advantages over other viral vectors. AAV is nonpathogenic, does not stimulate inflammation or immune reaction and enters nondividing cells, and provides stable long-term gene expression. To test AAV in VSMCs, we constructed and tested plasmid AAV (pAAV) and recombinant AAV (rAAV) with AT
1
-R antisense DNA. rAAV was constructed with a cassette containing a cytomegalovirus promoter and the cDNA for the AT
1
-R inserted in the antisense direction. The cassette was packaged into the virion. Transfection of VSMCs with the pAAV antisense to AT
1
-R produced a significant reduction in the amount of AT
1
-R (
P
<0.01). Transduction of VSMCs with the rAAV-AT
1
-R-AS at MOI of 5 also showed significant reduction of AT
1
-R and long-lasting expression of the transgene for at least 8 weeks. The reduction of AT
1
-R number in VSMCs was concomitant with a decrease in the Ang II–stimulated increase of intracellular calcium. The results show that AAV vector delivers AT
1
-R antisense to inhibit AT
1
-R in VSMCs. For the purpose of gene therapy for hypertension, it is necessary to demonstrate the effectiveness of a vector system in VSMCs. This study provides support for the potential use of AAV AT
1
-R antisense in VSMCs.
Influence of Heart Rate on Mortality in a French Population
Authors: Benetos Athanase , Rudnichi Annie , Thomas Frédérique , Safar Michel , Guize Louis
Published: June 2012

Abstract
—The aim of the present study was to assess the effects of high heart rate on mortality in different subgroups in a French population according to age, gender, and blood pressure levels. We studied 19 386 subjects (12 123 men, 7263 women), aged 40 to 69 years, who had a routine health examination at the Centre d’Investigations Préventives et Cliniques (IPC) between 1974 and 1977. Heart rate (HR) measured by ECG was classified into 4 groups: HR1, <60; HR2, 60 to 80; HR3, 81 to 100; and HR4, >100 bpm. Mortality data were recorded for the period of 1974 through 1994. In both sexes, HR was a significant predictor of noncardiovascular mortality. In men, the relative risk (95% confidence interval) for cardiovascular death after adjustment for age and other risk factors in the HR2, HR3, and HR4 groups was 1.35 (1.01 to 1.80), 1.44 (1.04 to 2.00), and 2.18 (1.37 to 3.47), respectively, when compared with HR1. In women, HR did not influence cardiovascular mortality. The association of HR with cardiovascular mortality in men was (1) related to a strong association with coronary but not cerebrovascular mortality, (2) independent of age and hypertension, and (3) influenced by the level of pulse pressure; in patients with high pulse pressure (>65 mm Hg), accelerated HR was not associated with increased cardiovascular mortality. In conclusion, in a large French population, accelerated resting HR represents an independent predictor of noncardiovascular mortality in both genders, and of cardiovascular mortality in men, independent of age and the presence of hypertension. Further investigations are needed to explain the complex interactions between HR, pulse pressure, and cardiovascular complications.
CGRP Activates Renal Pelvic Substance P Receptors by Retarding Substance P Metabolism
Authors: Gontijo José R. , Smith Lori A. , Kopp Ulla C.
Published: June 2012

Abstract
—Substance P and calcitonin gene–related peptide (CGRP) are colocalized in renal pelvic sensory nerves. Increasing renal pelvic pressure results in an increase in afferent renal nerve activity that is blocked by a substance P receptor antagonist but not by a CGRP receptor antagonist. CGRP potentiates the effects of substance P by preventing the metabolism of substance P. Therefore, we examined whether CGRP enhanced the afferent renal nerve activity responses to substance P and increased renal pelvic pressure, a stimulus known to increase substance P release. Combined administration of substance P and CGRP into the renal pelvis resulted in an increase in afferent renal nerve activity (1392±217% · s; area under the curve of afferent renal nerve activity versus time) that was greater (
P
<0.01) than that produced by substance P (620±156% · s) or CGRP (297±96% · s) alone. Likewise, CGRP enhanced the afferent renal nerve activity response to increased renal pelvic pressure. During renal pelvic administration of the neutral endopeptidase inhibitor thiorphan, the afferent renal nerve activity response to substance P plus CGRP was similar to that produced by either neuropeptide alone. Because these studies suggested that CGRP potentiated the afferent renal nerve activity responses to substance P, we examined whether the afferent renal nerve activity response to CGRP was blocked by a substance P receptor antagonist, RP67580. RP67580 blocked the afferent renal nerve activity response to CGRP by 85±12% (
P
<0.02). We conclude that CGRP activates renal pelvic sensory nerves by retarding the metabolism of substance P, thereby increasing the amount of substance P available for stimulation of substance P receptors.
Antihypertensive Mechanisms Underlying a Novel Salt-Sensitive Hypertensive Model Induced by Sensory Denervation
Authors: Wang Donna H. , Li Jianping
Published: June 2012

Abstract
—A novel model of hypertension recently developed in our laboratory shows that neonatal degeneration of capsaicin-sensitive sensory nerves renders a rat responsive to a salt load with a significant rise in blood pressure. To determine the role of the renin-angiotensin system and the sympathetic nervous system in the development of hypertension in this model, newborn Wistar rats were given capsaicin 50 mg/kg SC on the first and second days of life. Control rats were treated with vehicle. After they were weaned, male rats were divided into 6 groups and subjected to the following treatments for 2 weeks: control+high sodium diet (4%) (CON-HS), capsaicin+normal sodium diet (0.5%) (CAP-NS), capsaicin+high sodium diet (CAP-HS), capsaicin+high sodium diet+losartan (10 mg/kg per day) (CAP-HS-LO), capsaicin+high sodium diet+prazosin (3 mg/kg per day) (CAP-HS-PR), and capsaicin+high sodium diet+hydralazine (10 mg/kg per day) (CAP-HS-HY). Levels of calcitonin gene–related peptide in dorsal root ganglia were decreased by capsaicin treatment (
P
<0.05). Both tail-cuff systolic blood pressure and mean arterial pressure were higher in CAP-HS and CAP-HS-PR than in CON-HS, CAP-NS, CAP-HS-LO, and CAP-HS-HY (
P
<0.05). The 24-hour urinary volume and sodium excretion were increased when a high sodium diet was given (
P
<0.05), but they were lower in CAP-HS, CAP-HS-LO, CAP-HS-PR, and CAP-HS-HY than in CON-HS (
P
<0.05). Urinary potassium excretion was not different among all 6 groups. We conclude that blockade of the angiotensin type 1 receptor with losartan but not antagonism of the α
1
-adrenoreceptor with prazosin prevents the development of salt-sensitive hypertension induced by sensory denervation. Sensory denervation impairs urinary sodium and water excretion in response to a high sodium intake, regardless of blood pressure, suggesting that sensory innervation plays a direct role in regulating the natriuretic response to sodium loading.
α
1
- and α
2
-Adrenoceptor Control of Sodium Transport Reverses in Developing Hypertension
Authors: Gesek Frank A.
Published: June 2012

Abstract
—α-Adrenergic receptor (AR) activation enhances sodium retention in certain forms of hypertension. The objective of the present study was to understand the role of α-ARs in regulating sodium transport by distal tubules (DT). DT cells were isolated from kidneys of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at 6 weeks, when hypertension is developing, or at 12 weeks, when hypertension is established. The α
1
-AR agonist phenylephrine increased
22
Na uptake by 50% into DT cells of 6-week SHR; no effect was observed with WKY cells. The α
2
-AR agonist B-HT 933 increased uptake by only 10%. At 12 weeks, the pattern of α-AR regulation was reversed: α
1
-AR–induced sodium uptake was only 15%, whereas α
2
-AR activation increased sodium uptake by 35% in SHR and WKY cells. α
1
-AR–induced sodium uptake in 6-week SHR cells was abolished by prazosin; α
2
-AR–stimulated sodium uptake was blocked by yohimbine in 12-week SHR and WKY. Competitive binding studies were performed with [
3
H]prazosin and α
1A
-, α
1B
-, and α
1D
-selective antagonists with DT cell membranes from 6- and 12-week SHR and WKY. α
2
-AR subtypes were determined with [
3
H]rauwolscine and α
2A
- and α
2B
-selective antagonists. Expression of α
1B
-ARs was increased 4-fold in DT cells during the developing phase of hypertension in SHR. No change was detected in α
2
-AR expression. DT cells transiently increase [Ca
2+
]
i
in response to α
1
-AR agonists from 6-week but not 12-week SHR. Conversely, α
2
-AR agonists increase [Ca
2+
]
i
at 12 weeks. In summary, during developing hypertension, α
1
-ARs increase sodium uptake and [Ca
2+
]
i
in SHR cells. Expression of α
1B
-ARs is selectively upregulated during developing hypertension. In established hypertension (and normotension), α
2
-ARs regulate sodium transport and [Ca
2+
]
i
in DT cells. We conclude that a molecular switch of α
1
-AR and α
2
-AR signaling occurs in DT cells during the development of hypertension.
Intracellular Sodium Modulates the Expression of Angiotensin II Subtype 2 Receptor in PC12W Cells
Authors: Tamura Masaaki , Wanaka Yoshio , Landon Erwin J. , Inagami Tadashi
Published: June 2012

Abstract
—Although the angiotensin II subtype 2 receptor (AT
2
-R) is expressed abundantly in the adrenal medulla, its physiological significance has not yet been determined. To obtain fundamental knowledge of the regulation of AT
2
-R expression in the adrenal medulla, we investigated the effects of modulating several ion channels on AT
2
-R expression in PC12W cells. Experiments were performed after 24 hours of serum depletion under subconfluent conditions. After 48 hours of treatment with various agonists or antagonists, the receptor density and mRNA level of AT
2
-Rs were quantified by
125
I-[Sar
1
,Ile
8
]angiotensin II binding and Northern blot analysis. Ouabain (10 to 100 nmol/L) and insulin (10 to 100 nmol/L) dose-dependently increased receptor density and mRNA level. Analysis of the binding characteristics revealed that the ouabain-dependent increase in AT
2
-R levels was due to an increase in binding capacity without a change in the
K
d
value. These increases were blocked by lowering the Na
+
concentration in the medium. A low concentration of the sodium ionophore monensin (10 nmol/L), the K
+
-channel blocker quinidine (10 μmol/L), and the ATP-sensitive K
+
-channel blockers tolbutamide (100 μmol/L) and glybenclamide (10 μmol/L) also significantly increased receptor density, but the ATP-sensitive K
+
-channel agonist cromakalim (100 μmol/L) decreased receptor density significantly (
P
<0.01). Nifedipine (10 μmol/L) decreased basal receptor density and completely blocked the increase in receptor density caused by these agents. The increase in receptor density caused by an increase in intracellular Na
+
was accompanied by an increase in mRNA level, whereas the ATP-sensitive K
+
-channel blockers did not change mRNA level. Nifedipine slightly decreased mRNA level. These results suggest that AT
2
-R expression is sensitively regulated by intracellular cation levels. The change in intracellular Na
+
level transcriptionally regulates AT
2
-R expression, whereas the K
+
-channel blocker–dependent upregulation appears to be at least in part posttranslational.
Adducin Polymorphism Affects Renal Proximal Tubule Reabsorption in Hypertension
Authors: Manunta Paolo , Burnier Michel , D’Amico Marco , Buzzi Laura , Maillard Marc , Barlassina Cristina , Lanella Giovanna , Cusi Daniele , Bianchi Giuseppe
Published: June 2012

Abstract
—Abnormalities in renal sodium reabsorption may be involved in the development and maintenance of experimental and clinical hypertension. Adducin polymorphism is thought to regulate ion transport in the renal tubule. It has recently been shown that there is a significant linkage of α-adducin locus to essential hypertension and that the 460Trp allele is associated with hypertension. Patients with this allele display larger blood pressure changes with body sodium variation. The aim of this study was to test whether α-adducin polymorphism is involved in abnormalities of renal function. Because proximal tubular reabsorption has been shown to be tightly coupled to renal perfusion pressure, this segmental tubular function was investigated in 54 (29 Gly/Gly and 25 Gly/Trp) untreated hypertensive patients in basal conditions with the use of endogenous lithium concentration and uric acid. Fractional excretions of lithium and uric acid were significantly decreased in the Gly/Trp hypertensive patients compared with the Gly/Gly hypertensives. The contribution of α-adducin to fractional excretion of lithium was investigated by multiple regression analysis. Adducin genotype was significantly (
R
2
=0.11, F=6.5;
P
<0.01) and directly related to fraction excretion of lithium; gender, age, urinary Na
+
, urinary uric acid, mean blood pressure, and plasma renin activity were not related. In conclusion, the adducin gene can be considered to be a ‘renal hypertensive gene’ that modulates the capacity of tubular epithelial cells to transport Na
+
and hence contributes to the level of blood pressure.
Assessment of Arterial Compliance by Carotid Midwall Strain-Stress Relation in Normotensive Adults
Authors: Bella Jonathan N. , Roman Mary J. , Pini Riccardo , Schwartz Joseph E. , Pickering Thomas G. , Devereux Richard B.
Published: June 2012

Abstract
—Examining left ventricular midwall as opposed to endocardial mechanics enhances understanding of left ventricular function in individuals with abnormal cardiac geometry. Accordingly, we used carotid ultrasound and applanation tonometry of arterial pressure to derive carotid midwall strain and its relation to carotid peak-systolic and end-diastolic stresses in 82 apparently normal, employed subjects (56 men, 26 women; median age, 47 years; 70% white; 21% overweight) with no evidence of coronary or valvular heart disease. Regression equations relating carotid luminal and midwall strain to the increment in carotid stress during systole (Δcarotid stress) were used to predict strain for the observed Δstress. Observed/predicted carotid luminal or midwall strain was calculated as a measure of carotid luminal or midwall strain for imposed stress, termed stress-corrected strain. Midwall carotid strain was similar in women and men but was negatively related to older age (
r
=−0.35,
P
=0.001) and higher body mass index (
r
=−0.31,
P
=0.005) and brachial and carotid blood pressure (
r
=−0.30 to −0.45, all
P
<0.01). The pulsatile change in arterial load, measured by Δcarotid stress, was positively related to midwall strain (
r
=0.44,
P
<0.001) more closely than was carotid luminal strain. Regression analyses revealed that carotid midwall strain was positively related to Δstress, with additional negative relations to age and carotid diastolic diameter (all
P
<0.001). Stress-corrected carotid midwall strain was strongly and negatively correlated with midwall elastic modulus and Young’s modulus (both
r
=−0.77,
P
<0.001), followed by elastic modulus (
r
=−0.74,
P
<0.001), midwall Young’s modulus (
r
=−0.73,
P
<0.001), midwall stiffness index (
r
=−0.70,
P
<0.001), and stiffness index (
r
=−0.66,
P
<0.001). Thus, in normal adults, carotid midwall strain is unrelated to gender, is positively related to pulsatile carotid load as measured by Δcarotid stress, and is negatively related to age, overweight, and standard measures of arterial stiffness.
Chronic Bradykinin Infusion and Receptor Blockade in Angiotensin II Hypertension in Rats
Authors: Pasquié Jean Luc , Herizi Abderraouf , Jover Bernard , Mimran Albert
Published: June 2012

Abstract
—The influence of endogenous bradykinin(BK) on the control of arterial pressure and the development of cardiac hypertrophy was assessed in chronically angiotensin II(Ang II)–infused rats (200 ng · kg
−1
· min
−1
) through the effects of concomitant infusion of 3 doses of BK (15 ng · kg
−1
· d
−1
, 100 ng · kg
−1
· d
−1
and 100 ng · kg
−1
· min
−1
ie, 144 000 ng · kg
−1
· d
−1
) or BK-blockade by Hoe140 (300 μg · kg
−1
· d
−1
) for 10 days. In Ang II–infused rats, tail-cuff pressure increased from 124±3 to 174±6 mm Hg (
P
<0.001). The pressor effect of Ang II was not affected by simultaneous infusion of BK or Hoe140. At the end of the experiments, cardiac mass was higher in rats infused with Ang II alone (3.56±0.10 versus 2.89±0.05 mg/g in untreated controls,
P
<0.01) and the development of cardiac hypertrophy was not modified by administration of the 3 doses of BK or Hoe140. In addition, the fall in cardiac output associated with Ang II was prevented only by the moderate and high doses of BK, mainly through an increase in stroke volume and a decrease in total peripheral resistance. In the same way, the renal vasoconstrictor effect of Ang II was abolished by the medium and high dose of BK. Hoe140 did not affect cardiac output or renal blood flow in this model. No influence of BK or Hoe140 on the increase in albuminuria induced by Ang II was detected. In conclusion, exogenous BK may oppose the effect of Ang II on vascular tone, but it cannot prevent hypertension and target-organ damage associated with this experimental model of hypertension, even at a very high dose.
Effects of Candesartan and Cilazapril on Rats With Myocardial Infarction Assessed by Echocardiography
Authors: Yoshiyama Minoru , Takeuchi Kazuhide , Omura Takashi , Kim Shokei , Yamagishi Hiroyuki , Toda Iku , Teragaki Masakazu , Akioka Kaname , Iwao Hiroshi , Yoshikawa Junichi
Published: June 2012

Abstract
—The purpose of this study was to compare the angiotensin II type 1 receptor antagonist candesartan cilexitil (candesartan) and the angiotensin-converting enzyme inhibitor cilazapril on cardiac function, assessed by Doppler echocardiography and cardiac gene expression associated with cardiac remodeling, in rats with myocardial infarction. Candesartan or cilazapril was administered after myocardial infarction. At 1 and 4 weeks after myocardial infarction, cardiac function and mRNA expression in noninfarcted myocardium were analyzed. Candesartan and cilazapril equally prevented increases in hypertrophy in noninfarcted myocardium, left ventricular dilatation, and ejection fraction at 4 weeks. The E-wave/A-wave velocity ratio and the rate of E-wave deceleration, measures of diastolic function, increased to 9.2±0.6 and 26.3±2.6 m/s
2
at 1 week after myocardial infarction. Candesartan and cilazapril, administered at a dose of 1 mg/kg per day, prevented increases in E-wave/A-wave velocity ratio and E-wave deceleration at 1 and 4 weeks. Candesartan and cilazapril significantly suppressed increased mRNA expression of β-myosin heavy chain, α-skeletal actin, and atrial natriuretic peptide in noninfarcted ventricle at 1 and 4 weeks and expression of collagen I and III at 4 weeks to a similar extent. When given at a dose of 10 mg/kg per day, both candesartan and cilazapril prevented cardiac dysfunction and gene expression to the same extent as when given at 1 mg/kg per day. In conclusion, Doppler echocardiography showed that candesartan and cilazapril equally improved systolic and diastolic function and that ventricular remodeling accompanied modulation of cardiac gene expression.
Structural Skin Capillary Rarefaction in Essential Hypertension
Authors: Antonios Tarek F. T. , Singer Donald R. J. , Markandu Nirmala D. , Mortimer Peter S. , MacGregor Graham A.
Published: June 2012

Abstract
—A reduction in the density of capillaries (rarefaction) is known to occur in many tissues in patients with essential hypertension. This rarefaction may play a role in increasing peripheral resistance. However, the mechanism underlying this capillary rarefaction is not understood. The aim of this study was to assess the extent of structural versus functional capillary rarefaction in the skin of dorsum of fingers in essential hypertension. The capillary microcirculation was examined with video microscopy before and after maximizing the number of perfused capillaries by venous congestion. The study group comprised 17 patients with essential hypertension (mean supine blood pressure, 155/96 mm Hg) and 17 closely matched normotensive controls (mean blood pressure, 127/77 mm Hg). We used intravital video microscopy with an epi-illuminated microscope to examine the skin of the dorsum of left middle phalanx before and after venous congestion at 60 mm Hg for 2 minutes. A significantly lower mean capillary density occurred at baseline in hypertensive subjects versus normotensive subjects. With venous occlusion, capillary density increased significantly in both groups; however, maximal capillary density remained significantly lower in the hypertensive subjects than in the normotensive subjects. The study strongly suggests that much of the reduction in capillary density in the hypertensive subjects is caused by structural (anatomic) absence of capillaries rather than functional nonperfusion.
Race and Diurnal Blood Pressure Patterns
Authors: Profant Judi , Dimsdale Joel E.
Published: June 2012

Abstract
—Investigators have reported variable findings regarding the role of race in diurnal blood pressure patterns. We performed a review and meta-analysis of this literature to identify the overall effect of race on circadian blood pressure patterns. Eighteen studies involving 2852 participants were reviewed. Meta-analyses were conducted using effect sizes calculated from the data provided directly in the study reports. Separate meta-analyses were conducted on effect sizes for differences between blacks and whites in daytime and nighttime systolic and diastolic blood pressure and nocturnal dip in systolic and diastolic blood pressure. To evaluate discrepancies in findings from studies involving American versus non-American blacks, overall meta-analyses as well as within-subset meta-analyses of black/white differences were conducted for comparisons involving American and non-American blacks. Results of overall meta-analyses indicate that blacks experience higher levels of systolic and diastolic blood pressure, both at night and during the day. These differences were significantly greater at night than during the day (
P
<0.05). Results of within-subset analyses involving American blacks mirrored those for all black/white comparisons, except that the effect of race on nocturnal dip, ie, that American blacks experienced less of a dip in both systolic and diastolic blood pressure at night, was significant (
P
<0.05). In contrast, the effect of race on nocturnal dip was not significant for comparisons involving non-American blacks. These results suggest a consistent difference in the chronobiology of blood pressure, particularly in American blacks.
Diastolic Dysfunction and Baroreflex Sensitivity in Hypertension
Authors: Pitzalis Maria Vittoria , Passantino Andrea , Massari Francesco , Forleo Cinzia , Balducci Cataldo , Santoro Giuseppe , Mastropasqua Filippo , Antonelli Gianfranco , Rizzon Paolo
Published: June 2012

Abstract
—The determinants of diastolic dysfunction in patients with systemic hypertension are not completely known. To evaluate the possible role of age, arterial blood pressure, and baroreflex heart rate response impairment in causing diastolic dysfunction, we studied 61 patients (42 male; mean±SD age, 43.9±12 years) with newly recognized and therefore previously untreated systemic hypertension. Diastolic dysfunction was evaluated by means of Doppler echocardiography (and diagnosed as such when the early to atrial peak velocity ratio corrected to heart rate was <1), arterial blood pressure by 24-hour ambulatory monitoring, and baroreflex heart rate response by means of the spectral technique (α index) during paced (0.27 Hz) and spontaneous breathing (in a supine position and during tilt). Nineteen patients had diastolic dysfunction, the most powerful predictor of which was age (
r
=−0.63,
P
<0.001). The patients with diastolic dysfunction had significantly lower values for spectral baroreflex gain in the high-frequency band than those without (5.2±3 versus 8.4±5 ms/mm Hg during paced breathing,
P
<0.05; 7.4±4 versus 13.3±7 ms/mm Hg in a supine position,
P
<0.05; 4.3±4 versus 5±2 ms/mm Hg during tilt,
P
<NS). Ambulatory blood pressure values were not significantly different in the patients with (137±14 and 89±9 mm Hg) and without (144±11 and 82±24 mm Hg) diastolic dysfunction. In conclusion, age and impaired baroreflex heart rate response (but not pressure overload) are determinants of left ventricular diastolic dysfunction in patients with newly recognized and untreated systemic hypertension.
DD
Angiotensin-Converting Enzyme Gene Polymorphism Is Associated With Endothelial Dysfunction in Normal Humans
Authors: Butler Robert , Morris Andrew D. , Burchell Brian , Struthers Allan D.
Published: June 2012

Abstract
—A polymorphism within the angiotensin-converting enzyme (ACE) gene may increase the risk of myocardial infarction in individuals previously thought to be at low cardiovascular risk. The mechanism through which it exerts this effect is unknown but may be due to increased angiotensin II–induced nitric oxide (NO) breakdown and/or reduced bradykinin-mediated NO release. We investigated whether endothelial function was different between different ACE genotypes. We performed a cross-sectional study comparing the endothelial function of the 3 genotypes (
II
: n=25;
ID
: n=31;
DD
: n=12). Mean±SD ages of the subjects were 24±4 (
II
), 25±6 (
ID
), and 25±6 (
DD
) years. We assessed the impact of the genotypes on endothelial function and found that the
DD
genotype was associated with a significant blunting in endothelial-dependent vasodilatation (forearm blood flow data are presented as mean±SD ratio of blood flow in response to 3 incrementally increasing doses of each vasoactive agent in the test arm to blood flow in the control arm; the comparison is between
DD
versus
ID
versus
II
; the
P
value is an expression of an overall difference by ANOVA, and the 95% CIs are of a pairwise comparison between genotypes): acetylcholine, 2.88±1.45 versus 3.81±1.93 versus 4.23±2.37 (
P
=0.002; 95% CI [
II
versus
ID
], −0.19 to 0.91; 95% CI [
II
versus
DD
], 0.36 to 1.80; 95% CI [
ID
versus
DD
], 0.02 to 1.42). There was also a significant difference with the endothelial-independent vasodilator sodium nitroprusside, with values of 2.11±1.00 versus 2.55±1.36 versus 2.75±1.18 (
P
<0.05; 95% CI [
II
versus
ID
], −0.15 to 0.51; 95% CI [
II
versus
DD
], 0.03 to 0.89; 95% CI [
ID
versus
DD
], −0.13 to 0.71), but not with verapamil. There was no effect of the ACE genotype on endothelial-dependent or -independent vasoconstrictors
N
G
-monomethyl-
l
-arginine or norepinephrine. Investigating the effects of cigarette smoking on each genotype demonstrated that for
II
and
DD
genotypes, acetylcholine responses were further blunted if subjects smoked. These data demonstrate that the
DD
ACE genotype in a young population is associated with a blunting of stimulated endothelial NO and donated NO responses but not to non-NO vasodilators or vasoconstrictors.
Effects of Age and Gender on Autonomic Control of Blood Pressure Dynamics
Authors: Barnett Sheila R. , Morin Raymond J. , Kiely Dan K. , Gagnon Margaret , Azhar Gohar , Knight Eric L. , Nelson Jerald C. , Lipsitz Lewis A.
Published: June 2012

Abstract
—Both age and gender influence cardiovascular autonomic control, which in turn may influence the ability to withstand adverse cardiac events and respond to orthostatic stress. The purpose of this study was (1) to quantify age- and gender- related alterations in autonomic control of blood pressure (BP) and (2) to examine the impact of these autonomic alterations on BP response to orthostatic stress. We measured continuous BP and R-R intervals and vasoactive peptide levels in the supine and 60° head-up tilt positions during paced respiration (0.25 Hz) in 89 carefully screened healthy subjects (41 men, 48 women, aged 20 to 83 years). Data were analyzed by gender (age adjusted) and by age group (gender adjusted). During tilt, women had greater decreases in systolic BP than men (−10.2±2 versus −1.2±3 mm Hg;
P
=0.02) and smaller increases in low-frequency (sympathetically mediated) BP power (
P
=0.02). Upright plasma norepinephrine was lower in women (
P
=0.02). Women had greater supine high-frequency R-R interval power than men (
P
=0.0001). In elderly subjects, the tilt-induced increase in low-frequency BP power was also diminished (
P
=0.01), despite higher supine (
P
=0.02) and similar upright norepinephrine levels compared with younger subjects. Thus, healthy women have less sympathetic influence on BP and greater parasympathetic influence on R-R interval than men. Elderly subjects also have reduced sympathetic influence on BP, but this appears to be more consistent with a reduction in vasomotor sympathetic responsiveness.
Protective Role of the Angiotensin AT
2
Receptor in a Renal Wrap Hypertension Model
Authors: Siragy Helmy M. , Carey Robert M.
Published: June 2012

Abstract
—We evaluated the role of the renal angiotensin II type 2 (AT
2
) receptor in blood pressure regulation in rats with 2-kidney, 1 figure-8 wrap (Grollman) hypertension. Renal wrapping increased systolic blood pressure (SBP). Renal interstitial fluid (RIF) bradykinin (BK), nitric oxide end-products (NOX), and cGMP were higher in the contralateral intact kidney than in the wrapped kidney. In rats with Grollman hypertension, losartan normalized SBP and increased renal function, RIF BK, NOX, and cGMP only in contralateral kidneys. In contrast, PD 123319, a specific AT
2
-receptor antagonist, significantly increased SBP and decreased RIF BK, NOX, and cGMP in both kidneys. Combined administration of losartan and PD 123319 prevented the decrease in SBP and the increase in RIF BK, NOX, and cGMP levels observed with losartan alone. BK-receptor blockade caused a significant increase in RIF BK and a decrease in RIF NOX and cGMP in both kidneys similar to that observed during administration of PD 123319. In rats that underwent sham operation, RIF BK increased in response to angiotensin II, an effect that was blocked by PD 123319. These data demonstrate that angiotensin II mediates renal production of BK, which, in turn, releases nitric oxide and cGMP via stimulation of AT
2
receptors. The increase in blood pressure and the decrease in renal BK, nitric oxide, and cGMP during AT
2
-receptor blockade suggests that the AT
2
receptor mediates counterregulatory vasodilation in Grollman hypertension and prevents a further increase in blood pressure.
Linkage Analysis of Candidate Genes and Gene-Gene Interactions in Chinese Hypertensive Sib Pairs
Authors: Niu Tianhua , Xu Xiping , Cordell Heather J. , Rogus John , Zhou Yusheng , Fang Zhian , Lindpaintner Klaus
Published: June 2012

Abstract
—Previous studies of hypertension in humans and experimental animal models have identified a number of candidate genes that have since been implicated as possibly contributing to essential hypertension. Among them are the genes encoding angiotensinogen, renin, the β- and γ-subunits of the epithelial sodium channel (
β/γ-ENaC
), α-adducin, and kallikrein (
KLK
). To examine the role of possible contribution of these genes in ethnic Chinese, as well as the epistatic interaction among them, we studied a large cohort of hypertensive sib pairs from China. DNA samples from 310 concordant affected sibling pairs with hypertension were tested for linkage with the use of excess allele–sharing algorithms based on genotyping with highly informative
GT
-repeat microsatellite markers localized in the immediate vicinity of the genes encoding angiotensinogen, renin,
β-
and
γ-ENaC
, α-adducin, and
KLK
. Affected sib pair analysis conducted according to 3 different methods (Statistical Analysis for Genetic Epidemiology [S.A.G.E.]/SIBPAL, MAPMAKER/SIBS, and affected pedigree member [APM] methods) revealed no evidence for linkage of any of these genes to primary hypertension in the population studied. Moreover, 2-locus sib pair linkage analyses to test for gene-gene interactions among each possible pair of candidate genes failed to yield any statistically significant results. Our findings provide no support for a significant contribution of the angiotensinogen, renin,
β/γ-ENaC
, α-adducin, or
KLK
genes, alone or in concert, to the pathogenesis of essential hypertension among Chinese. Our results emphasize the possible role of ethnic differences for complex disease genetics, as well as the need for large, well-characterized investigations.
Serum Uric Acid and Cardiovascular Events in Successfully Treated Hypertensive Patients
Authors: Alderman Michael H. , Cohen Hillel , Madhavan Shantha , Kivlighn Salah
Published: June 2012

Abstract
—To determine whether pretreatment and/or in-treatment serum uric acid (SUA) is independently and specifically associated with cardiovascular events in hypertensive patients, we examined the 20-year experience of 7978 mild-to-moderate hypertensive participants in a systematic worksite treatment program. Clinical evaluation and treatment were protocol-directed. SUA was measured at entry and annually thereafter. Subjects were stratified according to gender-specific quartile of baseline SUA. Blood pressures at entry and in-treatment were, respectively, 152.5/95.6 and 138.9/85.4 mm Hg. SUA was normally distributed with a mean of 0.399±0.0893 and 0.321±0.0833 mmol/L for men and women, respectively. Subjects with highest SUA were heavier, had greater evidence of cardiovascular disease (CVD), higher systolic blood pressure, higher creatinine, more frequent diuretic use, and lower prevalence of diabetes. During an average follow-up of 6.6 years (52 751 patient-years), 548 CVD events (183 mortal) and 116 non-CVD events occurred. In bivariate analysis, the association of SUA to CVD was more robust in nonwhites than whites and in patients at low versus high CVD risk. In multivariate analysis, CVD incidence was significantly associated with SUA with a hazard ratio of 1.22 (95% confidence interval 1.11 to 1.35), controlling for other known cardiovascular risk factors, including serum creatinine, body mass index, and diuretic use. Despite blood pressure control, SUA levels increased during treatment and were significantly and directly associated with CVD events, independently of diuretic use and other cardiovascular risk factors.
Effects of
l
-Arginine on Atherogenesis and Endothelial Dysfunction due to Secondhand Smoke
Authors: Hutchison Stuart J. , Sudhir Krishnankutty , Sievers Richard E. , Zhu Bo-Qing , Sun Yi-Ping , Chou Tony M. , Chatterjee Kanu , Deedwania Prakash C. , Cooke John P. , Glantz Stanton A. , Parmley William W.
Published: June 2012

Abstract
—Secondhand smoke (SHS) and hypercholesterolemia increase cardiovascular risk. We hypothesized that
l
-arginine, the precursor of nitric oxide (NO), might protect against atherogenesis and endothelial dysfunction caused by SHS. The effects of
l
-arginine supplementation (2.25% solution ad libitum) and SHS (smoking chambers for 10 weeks) were examined in 32 hypercholesterolemic rabbits. Eight normal rabbits served as controls. Acetylcholine- and nitroglycerin-induced vasorelaxation was assessed in aortic rings precontracted with norepinephrine. Hypercholesterolemia increased intimal lesion area (
P
=0.012), reduced endothelium-dependent relaxation (
P
=0.009), and reduced basal (
P
=0.005) and stimulated (
P
<0.0005) production of NOs. SHS increased intimal lesion area (
P
=0.01) norepinephrine-induced contraction (
P
=0.001) and reduced endothelium-dependent relaxation (
P
=0.02). SHS-induced increase in norepinephrine contraction was abolished by the inhibition of NO synthase and removal of endothelium.
l
-Arginine improved endothelium-dependent relaxation (
P
=0.001) and attenuated SHS-induced endothelial dysfunction (
P
=0.007) and atherogenesis (
P
=0.001). Basal production of nitrogen oxides correlated inversely with intimal lesion area (
r
=−0.66;
P
<0.0005) and stimulated production of NOs correlated with endothelium-dependent relaxation (
r
=−0.66;
P
<0.001). SHS causes endothelial dysfunction and increased adrenergic responsiveness and atherogenesis in hypercholesterolemic rabbits. Chronic dietary supplementation with the NO precursor
l
-arginine mitigates these effects. The adverse vascular consequences of SHS appear to be mediated via deleterious effects on endothelial function.
Vasodilatory Effects of Troglitazone Improve Blood Pressure at Rest and During Mental Stress in Type 2 Diabetes Mellitus
Authors: Sung Bong Hee , Izzo Joseph L. , Dandona Paresh , Wilson Michael F.
Published: June 2012

Abstract
—The present study examined the hemodynamic mechanisms of blood pressure (BP) lowering by troglitazone in patients with type 2 diabetes mellitus (DM) at rest and during a mental arithmetic test (MAT). Twenty-two patients with DM with normal to high-normal BP and 12 controls matched for age, gender, glucose tolerance, and BP were studied. DM subjects showed significantly higher systolic BP response during MAT than controls (157 versus 139 mm Hg;
P
<0.01). All 22 DM patients and 5 of 12 controls had systolic BP >140 mm Hg during MAT. Heart rate and diastolic BP were not significantly different between the 2 groups. The DM group was then randomized to receive troglitazone (n=10; 400 mg/d) or glyburide (n=12; 20 mg/d). MAT was repeated after 6 months of treatment. Both treatments reduced glucose equally (−1.7 mmol/L for troglitazone and −1.5 mmol/L for glyburide), but only troglitazone reduced insulin (−15 μU/mL;
P
<0.001) and C-peptide (−0.9 ng/mL;
P
<0.02) levels. Troglitazone significantly reduced BP at baseline (
P
<0.05) and systolic BP response to MAT (
P
<0.01), whereas glyburide did not affect BP at baseline or during MAT. Stroke volume and cardiac output did not change with either drug, but troglitazone decreased peripheral vascular resistance (−112 dyne · s · cm
−5
;
P
<0.05). Improved insulin resistance rather than an improved glycemic control is associated with lower resting and stress BP values in patients with DM. A reduction in vascular resistance may be a primary hemodynamic mechanism of the manner in which troglitazone lowers BP. Insulin sensitizers may offer potential therapeutic advantage in subjects with DM with elevated BP.
Evaluation of Common Carotid Hemodynamic Forces
Authors: Carallo Claudio , Irace Concetta , Pujia Arturo , Serena De Franceschi Maria , Crescenzo Anna , Motti Corradino , Cortese Claudio , Mattioli Pier Luigi , Gnasso Agostino
Published: June 2012

Abstract
—The localization of atherosclerotic lesions is influenced by hemodynamic factors, namely, shear stress and tensive forces. The present study investigated the relationships between shear stress and circumferential wall tension and between these hemodynamic factors and the intima-media thickness (IMT) of the common carotid artery in healthy men. Fifty-eight subjects were studied. Shear stress was calculated as blood viscosity×blood velocity/internal diameter. Circumferential wall tension was calculated as blood pressure×internal radius. Blood velocity, internal diameter, and IMT were measured by high-resolution echo-Doppler. Mean shear stress was 12.6±3.3 dynes/cm
2
(mean±SD; range, 4.8 to 20.4) and was inversely related with age, blood pressure, and body mass index (BMI). Mean circumferential wall tension was 3.4±0.6×10
4
dynes/cm (range 2.4 to 5.6) and was directly associated with age and BMI. IMT was inversely associated with shear stress (
r
=0.55,
P
<0.0001) and directly associated with circumferential wall tension (
r
=0.43,
P
<0.0001). Shear stress and circumferential wall tension were inversely correlated (
r
=0.66,
P
<0.0001). In multiple regression analysis, shear stress and (marginally) cholesterol were independently associated with IMT, whereas circumferential wall tension, age, and BMI were not. These findings confirm that common carotid shear stress varies among healthy individuals and decreases as age, blood pressure, and BMI increase. Our findings also demonstrate that circumferential wall tension is directly associated with wall thickness, age, and BMI and that shear stress is associated with common carotid IMT independent of other hemodynamic, clinical, or biochemical factors.
Long-Term Inhibition of Renin-Angiotensin System Sustains Memory Function in Aged Dahl Rats
Authors: Hirawa Nobuhito , Uehara Yoshio , Kawabata Yukari , Numabe Atsushi , Gomi Tomoko , Ikeda Toshio , Suzuki Tsutomu , Goto Atsuo , Toyo-oka Teruhiko , Omata Masao
Published: June 2012

Abstract
—The Dahl salt-sensitive (DS) rat, a genetic model of salt-induced hypertension in humans, is more likely to develop severe vascular injuries than a rat with spontaneous hypertension. We designed an experiment to scrutinize the effects of renin-angiotensin inhibition on cognitive dysfunction in the aged, normotensive DS with a passive avoidance test. Eighteen months of treatment with a very low dose of the angiotensin-converting enzyme (ACE) inhibitor cilazapril (2.5 μg/mL in drinking water) or the angiotensin II type 1 receptor antagonist E4177 did not reduce blood pressure throughout the experiment, although in the low dose cilazapril group (12.5 μg/mL in drinking water), blood pressure dropped within 6 months after treatment began. The cilazapril treatments dose-dependently improved memory function in the aged, normotensive DS fed a low-salt diet compared with the untreated, control rats. This improvement was associated with significant increases in hippocampal CA1 cells and capillary densities in the CA1 regions compared with those in the untreated DS. Similarly, E4177 slightly improved the memory dysfunction observed in the aged DS. The cells in the hippocampal CA1 region were restored slightly, but the capillary densities were not influenced by the receptor antagonist. On the other hand, the ACE inhibitor and receptor antagonist both attenuated urinary protein excretions with an improvement of glomerular sclerosis. These data suggest that long-term treatment with an ACE inhibitor improves memory dysfunction probably through restoration of capillary and hippocampal cells. The effects are due to the inhibition of the angiotensin II type 1 receptor and probably to the enhancement of the kallikrein-kinin system.
Effects of Sympathectomy and Nitric Oxide Synthase Inhibition on Vascular Actions of Insulin in Humans
Authors: Sartori Claudio , Trueb Lionel , Nicod Pascal , Scherrer Urs
Published: June 2012

Abstract
—Insulin exerts cardiovascular actions by stimulating nitric oxide (NO) release and sympathetic neural outflow. It is unclear, however, whether insulin stimulates muscle blood flow (and NO release) by a direct action at the vasculature and/or by stimulating neural vasodilator mechanisms. In these studies we used patients with regional sympathectomy to examine the vascular actions of insulin in the presence and absence of sympathetic vasoconstrictor and vasodilator innervation. A 2-hour insulin (6 pmol/kg per minute)/glucose clamp increased muscle blood flow in both innervated and denervated limbs by roughly 40% (
P
<0.01 versus baseline for both limbs). The vasodilation reached its maximum within the first 30 to 45 minutes of insulin/glucose infusion in sympathetically denervated limbs, but only at the end of the infusion in innervated limbs (
P
<0.01, denervated versus innervated limb). Infusion of a NO synthase inhibitor (
N
G
-monomethyl-
l
-arginine [L-NMMA]) increased baseline arterial pressure, abolished the vasodilation in the denervated limb, and led to a significant additional increase in arterial pressure during the clamp, but did not alter whole body glucose uptake. Our data indicate that insulin stimulates blood flow in sympathectomized limbs by a direct action at the vasculature. This effect is mediated by stimulation of NO release and appears to be masked by the sympathetic vasoconstrictor tone in innervated limbs.