bluuebunny/crossref_metadata_2025 huggingface dataset:
Aortic Stiffness Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Hypertensive Patients
Authors: Laurent Stéphane , Boutouyrie Pierre , Asmar Roland , Gautier Isabelle , Laloux Brigitte , Guize Louis , Ducimetiere Pierre , Benetos Athanase
Published: June 2012

Abstract
—Although various studies reported that pulse pressure, an indirect index of arterial stiffening, was an independent risk factor for mortality, a direct relationship between arterial stiffness and all-cause and cardiovascular mortality remained to be established in patients with essential hypertension. A cohort of 1980 essential hypertensive patients who attended the outpatient hypertension clinic of Broussais Hospital between 1980 and 1996 and who had a measurement of arterial stiffness was studied. At entry, aortic stiffness was assessed from the measurement of carotid-femoral pulse-wave velocity (PWV). A logistic regression model was used to estimate the relative risk of all-cause and cardiovascular deaths. Selection of classic risk factors for adjustment of PWV was based on their influence on mortality in this cohort in univariate analysis. Mean age at entry was 50±13 years (mean±SD). During an average follow-up of 112±53 months, 107 fatal events occurred. Among them, 46 were of cardiovascular origin. PWV was significantly associated with all-cause and cardiovascular mortality in a univariate model of logistic regression analysis (odds ratio for 5 m/s PWV was 2.14 [95% confidence interval, 1.71 to 2.67,
P
<0.0001] and 2.35 [95% confidence interval, 1.76 to 3.14,
P
<0.0001], respectively). In multivariate models of logistic regression analysis, PWV was significantly associated with all-cause and cardiovascular mortality, independent of previous cardiovascular diseases, age, and diabetes. By contrast, pulse pressure was not significantly and independently associated to mortality. This study provides the first direct evidence that aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in patients with essential hypertension.
Differential Expression of Voltage-Gated K
+
Channel Genes in Arteries From Spontaneously Hypertensive and Wistar-Kyoto Rats
Authors: Cox Robert H. , Folander Kimberly , Swanson Richard
Published: June 2012

Abstract
—Voltage-gated K
+
currents play an important role in determining membrane potential, intracellular Ca
2+
, and contraction in arterial smooth muscle. In this study, the expression of genes encoding voltage-gated K
+
channels of the Kv1.X family was compared in arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Expression of Kv1.X in thoracic aorta, mesenteric arteries, tail artery, and heart was determined, both qualitatively and quantitatively, by reverse transcription–polymerase chain reaction. Our results demonstrate distinct but overlapping patterns of expression in vascular tissues. In general, Kv1.2 and Kv1.5 were most highly represented, and the levels of Kv1.2 were significantly larger in all tissues from SHR. Levels of Kv1.5 in arteries did not differ significantly between strains but were greater in SHR heart. Moderate levels of Kv1.3 and Kvβ1.1 expression were also found in all tissues and were larger in SHR. Kv1.1 expression was not different between the 2 strains, and no significant expression of Kv1.4 (except in heart and aorta), Kv1.6, or Kvβ2.1 was observed in either strain. Kv1.2 and Kv1.5 transcripts represent ≈1 to 2 parts/10
5
of total mesenteric arterial RNA with ≈2- to 5-fold lower levels in aorta and tail artery. Whole-cell voltage-gated K
+
channel currents, recorded from mesenteric arterial myocytes, were larger in SHR than WKY (eg, at 0 mV: 7.3±0.8 versus 10.9±1.2 pA/pF). The voltage dependence of activation was more negative in SHR (V
0.5
: −20±4 mV versus −32±3 mV) but that of availability was not different. These results indicate that Kv1.X genes are differentially expressed between WKY and SHR (especially Kv1.2 and Kvβ1.1). These differences in gene expression are associated with a greater voltage-gated K
+
channel current density in SHR and shifted voltage-dependent activation compared with WKY. These differences may be a compensatory mechanism related to the membrane potential depolarization in SHR or some manifestation thereof.
Contribution of Bcl-2, but Not Bcl-xL and Bax, to Antiapoptotic Actions of Hepatocyte Growth Factor in Hypoxia-Conditioned Human Endothelial Cells
Authors: Yamamoto Kei , Morishita Ryuichi , Hayashi Shin-ichiro , Matsushita Hidetsugu , Nakagami Hidenori , Moriguchi Atsushi , Matsumoto Kunio , Nakamura Toshikazu , Kaneda Yasufumi , Ogihara Toshio
Published: June 2012

Abstract
—Angiogenic growth factors play important roles in angiogenic responses, such as vasculogenesis and angiogenesis in response to hypoxia. A novel angiogenic growth factor, hepatocyte growth factor (HGF), has been reported to inhibit endothelial cell death. However, its molecular mechanisms are largely unknown. Thus, we studied (1) the effects of HGF on hypoxia-induced endothelial apoptosis and (2) the molecular mechanisms of the antiapoptotic actions of HGF in endothelial cells. Severe hypoxia increased the cell death rate in human aortic endothelial cells, whereas HGF significantly attenuated cell death. In addition, hypoxic treatment resulted in a significant increase in apoptotic cells, whereas HGF could attenuate apoptosis, accompanied by attenuation of the increase in caspase-3–like activity (
P
<0.01). Of importance, HGF significantly increased Bcl-2, an inhibitor of apoptosis, in a dose-dependent manner under normoxic and hypoxic conditions (
P
<0.01), whereas hypoxic conditions resulted in a significant decrease in Bcl-2. In contrast, HGF failed to affect Bcl-xL, which is also well known as an inhibitor of apoptosis under both normoxic and hypoxic conditions, whereas Bcl-xL was significantly decreased in endothelial cells exposed to hypoxia (
P
<0.01). No significant change in Bax, a promoter of apoptosis, was also observed in endothelial cells under hypoxia, whereas HGF did not affect Bax. Overall, this study demonstrated that HGF prevented endothelial cell death induced by hypoxia through its antiapoptotic action. The antiapoptotic mechanisms of HGF in hypoxia-induced endothelial cell death largely depend on Bcl-2, but not Bcl-xL and Bax.
Differential Effect of Chronic Antihypertensive Treatment on Vascular Smooth Muscle Cell Phenotype in Spontaneously Hypertensive Rats
Authors: Bravo Rosario , Somoza Beatriz , Ruiz-Gayo Mariano , González Carmen , Ruilope Luis Miguel , Fernández-Alfonso Maria Soledad
Published: June 2012

Abstract
—The aim of this study was to investigate the effect of chronic losartan or captopril on vascular smooth muscle cell (VSMC) phenotype and vascular function in spontaneously hypertensive rats. Male 12-week-old rats were treated for 16 weeks with losartan (15 mg/kg per day) or captopril (60 mg/kg per day) in their drinking water. Systolic blood pressure, measured by the tail-cuff method, was reduced ≈40 mm Hg in both treatment groups compared with a nontreated control group. Cell structure and proliferation studies were performed in VSMCs obtained from rat carotid arteries. Cells from the losartan-treated group showed a significant reduction in size, total protein content, and nucleus number, as well as proliferation after stimulation with 10% fetal calf serum and an increased percentage of cells in the G
1
phase compared with the control and captopril-treated groups. Functional studies were performed in isolated carotid arteries from these groups. Contractions elicited by 75 mmol/L KCl or 10
−
7
mol/L norepinephrine and relaxations elicited by acetylcholine were similar in all groups. Concentration-response curves to angiotensin I or angiotensin II (10
−
10
to 3×10
−
7
mol/L) were almost abolished in the losartan-treated group and were not modified by preincubation with the angiotensin type 2 receptor antagonist PD 123,319. These results suggest that long-term losartan treatment significantly changes VSMC phenotype and proliferative status, apparently unrelated to blood pressure lowering or to endothelial function improvements.
Peripheral “Oscillatory” Compliance Is Associated With Aortic Augmentation Index
Authors: Segers Patrick , Qasem Ahmad , De Backer Tine , Carlier Stephane , Verdonck Pascal , Avolio Albert
Published: June 2012

Abstract
—The augmentation index (AIx) and “oscillatory” compliance (C
2
) are wave contour analysis parameters for the central aorta (P
ao
) and radial artery pressure wave (P
rad
), respectively. Both are sensitive to cardiovascular risk factors such as aging, hypertension, and diabetes and have been proposed as prognostic markers for cardiovascular disease. In this work, we studied the relation between both. We first calculated P
rad
corresponding to a typical aortic A-type (AIx >0.15) and C-type wave (AIx <0), taken from the literature, by using a generalized aorta-radial pressure transfer function. P
rad
corresponding to C-type waves yielded the highest C
2
value. We further used simultaneously measured aortic and radial artery pressure in 45 human subjects age 34 to 84 years (63±12 [SD]) at baseline and after administration of nitroglycerin to calculate AIx
meas
and C
2
, respectively. Transfer function was used to calculate reconstructed aortic pressure and AIx
rec
. AIx
rec
underestimates AIx
meas
by 0.03±0.16, but both values correlate well (
r
=0.64;
P
<0.001). C
2
and AIx were inversely correlated (
r
=−0.36;
P
<0.001 for AIx
meas
;
r
=−0.30;
P
<0.01 for AIx
rec
). Both AIx
meas
(0.06±0.17 versus 0.20±0.21;
P
<0.01) and AIx
rec
(0.04±0.12 versus 0.16±0.16;
P
<0.001) were lower after nitroglycerin, whereas C
2
increased only nonsignificantly (0.080±0.036 versus 0.071±0.042). C
2
is related to AIx and reflects, at least in part, hemodynamic changes affecting central aortic pressure. Nevertheless, given the model assumptions and computational steps associated with calculating C
2
, AIx could be a more appropriate parameter to use in the clinical setting because it is determined directly from the pressure wave contour.
Angiotensinogen Polymorphism M235T, Carotid Atherosclerosis, and Small-Vessel Disease-Related Cerebral Abnormalities
Authors: Schmidt Reinhold , Schmidt Helena , Fazekas Franz , Launer Lenore J. , Niederkorn Kurt , Kapeller Peter , Lechner Anita , Kostner Gert M.
Published: June 2012

The angiotensinogen M235T polymorphism has been linked to hypertension and cardiovascular disease. We studied the role of this polymorphism as a risk factor for carotid atherosclerosis and small-vessel disease-related brain abnormalities. A total of 431 randomly selected community-dwelling subjects without clinical evidence for strokes underwent angiotensinogen genotyping and carotid Duplex scanning; 1.5-T brain magnetic resonance imaging (MRI) was done in 396 individuals. At 3-year follow-up, we reexamined 343 and 267 study participants by ultrasound and brain MRI, respectively. Carotid atherosclerosis was graded on a 5-point scale. Small-vessel disease-related brain abnormalities were deep or subcortical white matter lesions or lacunes. Progression of carotid atherosclerosis and MRI findings was rated by direct imaging comparison by 3 independent raters. The M/M, M/T, and T/T genotypes were seen in 20.9%, 52.9%, and 18.1% of subjects, respectively. The M235T polymorphism was neither associated with baseline carotid findings nor with progression of carotid atherosclerosis. There was a trend toward more frequent small-vessel disease-related MRI abnormalities in the T/T than in the other genotypes at the baseline examination. Progression of brain lesions occurred significantly more commonly in T/T than in M/M and M/T carriers (
P
<0.001). Logistic regression analysis identified the T/T genotype (odds ratio, 3.19;
P
=0.002) and arterial hypertension (odds ratio, 3.06;
P
=0.03) as significant independent predictors of lesion progression. These data suggest that the angiotensinogen T/T genotype at position 235 is a genetic marker for brain lesions from and progression of small vessel disease but not for extracranial carotid atherosclerosis.
Angiotensin-Converting Enzyme Inhibition Potentiates Angiotensin II Type 1 Receptor Effects on Renal Bradykinin and cGMP
Authors: Siragy Helmy M. , de Gasparo Marc , El-Kersh Mohamed , Carey Robert M.
Published: June 2012

Angiotensin (Ang) receptor blockers (ARBs) increase bradykinin (BK) by antagonizing Ang II at its type 1 (AT
1
) receptors and diverting Ang II to its counterregulatory type 2 (AT
2
) receptors. Because the effect of ARBs on BK is constrained by the short half-life of BK and because ACE inhibitors block the degradation of BK, this study was designed to test the hypothesis that an ACE inhibitor can potentiate ARB-induced increases in renal interstitial fluid (RIF) BK levels. We used a microdialysis technique to recover BK and cGMP in vivo from the RIF of sodium-depleted, conscious Sprague-Dawley rats infused for 60 minutes with the AT
1
receptor blocker valsartan (0.17 mg/kg per minute), with the active metabolite of the ACE inhibitor benazepril (benazeprilate, 0.05 mg/kg per minute), or with the specific AT
2
receptor blocker PD 123,319 (50 μg/kg per minute) alone or combined. Each animal served as its own control. RIF BK and cGMP levels increased significantly over 1 hour in response to valsartan, benazeprilate, or both but not to a vehicle control (
P
<0.01). The combined benazeprilate-valsartan effect was greater than the sum of their individual effects, suggesting potentiation rather than addition, and was abolished by PD 123,319. We demonstrate for the first time that an ACE inhibitor (benazepril) and an ARB (valsartan) potentiate each other, and we postulate that such combinations may be beneficial in clinical states marked by Ang II elevation, such as chronic heart failure, postinfarction left ventricular dysfunction, and hypertension.
Human Heme Oxygenase-1 Gene Transfer Lowers Blood Pressure and Promotes Growth in Spontaneously Hypertensive Rats
Authors: Sabaawy Hatem E. , Zhang Fan , Nguyen Xuandai , ElHosseiny Abdelmonem , Nasjletti Alberto , Schwartzman Michal , Dennery Phyllis , Kappas Attallah , Abraham Nader G.
Published: June 2012

Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, with release of free iron and carbon monoxide. Both heme and carbon monoxide have been implicated in the regulation of vascular tone. A retroviral vector containing human HO-1 cDNA (LSN-HHO-1) was constructed and subjected to purification and concentration of the viral particles to achieve 5×10
9
to 1×10
10
colony-forming units per milliliter. The ability of concentrated infectious viral particles to express human HO-1 (HHO-1) in vivo was tested. A single intracardiac injection of the concentrated infectious viral particles (expressing HHO-1) to 5-day-old spontaneously hypertensive rats resulted in functional expression of the HHO-1 gene and attenuation of the development of hypertension. Rats expressing HHO-1 showed a significant decrease in urinary excretion of a vasoconstrictor arachidonic acid metabolite and a reduction in myogenic responses to increased intraluminal pressure in isolated arterioles. Unexpectedly, HHO-1 chimeric rats showed a simultaneous significant proportionate increase in somatic growth. Thus, delivery of HHO-1 gene by retroviral vector attenuates the development of hypertension and promotes body growth in spontaneously hypertensive rats.
Pulse Pressure Compared With Other Blood Pressure Indexes in the Prediction of 25-Year Cardiovascular and All-Cause Mortality Rates
Authors: Miura Katsuyuki , Dyer Alan R. , Greenland Philip , Daviglus Martha L. , Hill MaryAnn , Liu Kiang , Garside Daniel B. , Stamler Jeremiah
Published: June 2012

We compared the relations of 4 blood pressure (BP) indexes (pulse pressure [PP], systolic BP [SBP], diastolic BP [DBP], and mean arterial pressure [MAP]) with 25-year mortality rates for coronary heart disease (CHD), cardiovascular disease (CVD), and all causes in younger, middle-aged, and older men and women by using data from a long-term prospective epidemiological study of employed persons who were screened between 1967 and 1973. A single supine BP measurement was obtained at baseline. Vital status was determined through 1995. We report on 5 groups (total, 28 360 participants) consisting of men age 18 to 39, 40 to 59, and 60 to 74 years and of women age 40 to 59 and 60 to 74 years who were not receiving antihypertensive treatment, had no history of CHD, and did not have diabetes. Cox proportional hazards analyses were used to determine multivariate-adjusted hazard ratios with a 1-SD higher value for each BP index; Wald χ
2
tests were used to compare the strength of relations. Relations of PP were less strong than were those of SBP for all end points in all age/gender groups. SBP or MAP showed the strongest relations to all end points in all age/gender groups (hazard ratio, 1.17 to 1.36). The relations of SBP to death were stronger than were those of DBP, except for middle-aged men and for CVD in women. DBP showed significant positive associations with death, after control for SBP, in middle-aged participants. In conclusion, these data indicate that the long-term risk of high BP should be assessed mainly on the basis of SBP or of SBP and DBP together, not on the basis of PP, in apparently healthy adults.
Increased Expression of Peroxisome Proliferator-Activated Receptor-α and -γ in Blood Vessels of Spontaneously Hypertensive Rats
Authors: Diep Quy N. , Schiffrin Ernesto L.
Published: June 2012

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors that include PPAR-α, PPAR-γ, and PPAR-δ. We hypothesized that PPAR expression in blood vessels could be reduced in hypertension to result in increased vascular growth and reduced apoptosis. We investigated the abundance of PPAR-α and PPAR-γ in aorta and mesenteric arteries from young (6-week-old) and adult (16-week-old) spontaneously hypertensive rats (SHR) compared with age-matched control Wistar-Kyoto rats (WKY). mRNA levels of PPAR-α and PPAR-γ were determined by reverse transcription-polymerase chain reaction. Protein expression was evaluated by Western blot and by immunohistochemistry. PPAR-γ was expressed in aortic and mesenteric vascular smooth muscle cells (VSMCs) from intact tissue and cultured cells. PPAR-α was expressed in intact vascular tissue but was almost undetectable in cultured VSMCs. In mesenteric arteries from adult SHR, PPAR-α and PPAR-γ mRNA levels were significantly greater than in WKY (
P
<0.05). In aorta, PPAR-α mRNA was significantly (
P
<0.05) more abundant in adult (but not in young) SHR than in WKY, whereas there was no difference in PPAR-γ mRNA between WKY and SHR. PPAR-α and PPAR-γ mRNA were greater in mesenteric arteries (
P
<0.05) in young and adult SHR than in WKY. Expression of PPAR-α and PPAR-γ was similar in SHR and WKY in other tissues. In cultured mesenteric VSMCs, PPAR-γ mRNA was 3-fold higher in SHR than in WKY. Immunohistochemistry demonstrated that PPAR-γ resided constitutively in the cytoplasm in primary and low-passaged aortic and mesenteric VSMCs, whereas PPAR-α was almost undetectable. Thus, aorta and mesenteric resistance arteries from SHR in the prehypertensive and the established phase of hypertension exhibit increased expression of both PPAR isoforms, whereas other tissues do not. Changes (increases) in PPAR expression may play a compensatory role in the remodeling of blood vessels in SHR.
Importance of the Renin System for Determining Blood Pressure Fall With Acute Salt Restriction in Hypertensive and Normotensive Whites
Authors: He Feng J. , Markandu Nirmala D. , MacGregor Graham A.
Published: June 2012

Hypertensive (n=93) and normotensive (n=39) white individuals were given a high sodium intake of ≈350 mmol/d for 5 days followed by a low sodium intake of 10 to 20 mmol/d for 5 days. With this acute and large reduction in salt intake, no significant change was seen in blood pressure in the normotensive individuals, but blood pressure decreased in the hypertensive individuals. Compared with normotensive subjects, hypertensive patients had a 7/7-mm Hg greater fall in blood pressure (
P
<0.05 for systolic and
P
<0.01 for diastolic, adjusted for age), with similar changes in urinary sodium excretion. From the high-salt to low-salt diet, plasma renin activity rose from 0.90 to 5.99 ng · mL
−1
· h
−1
in normotensives, whereas in hypertensives it rose from 0.73 to only 3.14 ng · mL
−1
· h
−1
(
P
<0.05 between hypertensives and normotensives). Plasma aldosterone rose by 1396 pmol/L in normotensive subjects and by 511 pmol/L in hypertensive patients (
P
<0.05). Significant inverse correlations were obtained for all subjects between the fall in blood pressure from the high-salt to low-salt diet and the rise in plasma renin activity and aldosterone that occurred in addition to the absolute level on the low-salt diet. These results demonstrate that the larger fall in blood pressure with an acute reduction in salt intake in hypertensives compared with normotensives is, at least in part, due to a less-responsive renin-angiotensin-aldosterone system in the hypertensive patients.
Splenorenal Reflex Regulation of Arterial Pressure
Authors: Deng Yiming , Kaufman Susan
Published: June 2012

During the course of our studies into the control of fluid extravasation from the splenic vasculature, we found that intrasplenic inhibition of NO biosynthesis caused an increase in systemic blood pressure. The present experiments were designed to investigate the mechanisms underlying this novel observation. There was an increase in mean arterial pressure when the nonspecific NO inhibitor
N
G
-monomethyl-
l
-arginine (L-NMMA) was infused via the splenic artery but not when the same dose was administered systemically. Conversely, blood pressure decreased after intrasplenic but not systemic administration of the NO donor S-nitroso-
N
-acetyl-D,
l
-penicillamine. There was no pressor response to intrasplenic administration of either the inducible or neuronal NO synthase inhibitors
N
-[3-(aminomethyl)-benzyl] aceramidine and
l
-
N
5
-(1-imino-3-butenyl)-ornithine. The pressor response to L-NMMA was abolished by denervation of either the spleen or the kidney and by pretreatment with the ACE inhibitor enalapril. We propose that the spleen influences systemic blood pressure through a reflex pathway comprising splenic afferent nerves and renal sympathetic control of renin release.
Enhanced Interaction Between Renovascular α
2
-Adrenoceptors and Angiotensin II Receptors in Genetic Hypertension
Authors: Jackson Edwin K. , Herzer William A. , Kost Curtis K. , Vyas Subhash J.
Published: June 2012

In spontaneously hypertensive rats (SHR), hypertension is mediated in part by an enhanced renovascular response to angiotensin (Ang) II. Pertussis toxin normalizes renovascular responses to Ang II and lowers blood pressure in SHR, suggesting a role for altered G
i
signaling in the enhanced renovascular response to Ang II in SHR. To further investigate this hypothesis, we measured reductions in renal blood flow and increases in renovascular resistance in response to intrarenal infusions of Ang II in the presence and absence of coactivation of α
2
-adrenoceptors (ie, receptors selectively coupled to G
i
) with UK 14,304 in adrenalectomized, renal-denervated, captopril-pretreated SHR and normotensive Wistar-Kyoto rats. In SHR, but not Wistar-Kyoto rats, UK 14,304 markedly enhanced renovascular responses to Ang II and vasopressin. However, UK 14,304 did not enhance renovascular responses to methoxamine (α
1
-adrenoceptor agonist) in either strain. In uninephrectomized, normotensive Sprague-Dawley animals and in Sprague-Dawley rats with nongenetic hypertension induced by uninephrectomy, chronic administration of deoxycorticosterone acetate, and 1% saline as drinking water, UK 14,304 had little or no effect on renovascular responses to Ang II. In SHR, intrarenal infusions of U73122, a phospholipase C/D inhibitor, blocked the enhancement of renovascular responses to Ang II by UK 14,304. We conclude that activation of α
2
-adrenoceptors selectively enhances renovascular responses to Ang II and vasopressin in vivo in animals with genetic hypertensive but not in normotensive animals or animals with acquired hypertension. These results suggest that in SHR, there is a genetically mediated enhanced cross talk between the G
i
signal transduction pathway and signal transduction pathways activated by Ang II and vasopressin, but not methoxamine, and involving phospholipase C and/or D.
Arterial Wave Reflections and Survival in End-Stage Renal Failure
Authors: London Gérard M. , Blacher Jacques , Pannier Bruno , Guérin Alain P. , Marchais Sylvain J. , Safar Michel E.
Published: June 2012

The increased effect of arterial wave reflections on central arteries like the common carotid artery seen in end-stage renal failure (ESRF) patients favors myocardial hypertrophy and oxygen consumption and alters coronary blood flow distribution. Nevertheless, the impact of wave reflection on the outcome and end points such as mortality remains to be demonstrated. One hundred eighty ESRF patients (age, 54±16 years) were monitored for 52±36 months (mean±SD). Seventy deaths, including 40 cardiovascular (CV) and 30 non-CV events, occurred. At entry, patients, in addition to standard clinical and biochemical analyses, underwent aortic pulse wave velocity measurement and determination of arterial wave reflexion by applanation tonometry on the common carotid artery that was expressed as augmentation index. Cox analyses demonstrated that predictors of all-cause and CV mortality were age, aortic pulse wave velocity, low diastolic blood pressure, preexisting CV disease, and increased augmentation index, whereas the prescription of an ACE inhibitor had a favorable effect on survival. After adjustment for all confounding factors, the risk ratio for each 10% increase in augmentation index was 1.51 (95% confidence interval, 1.23 to 1.86;
P
<0.0001) for all-cause mortality and 1.48 (95% confidence interval, 1.16 to 1.90;
P
<0.0001) for CV mortality. These results provide the first direct evidence that in ESRF patients increased effect of arterial wave reflections is an independent predictor of all-cause and CV mortality.
Effect of a
COL1A1
Sp1 Binding Site Polymorphism on Arterial Pulse Wave Velocity
Authors: Brull David J. , Murray Liam J. , Boreham Colin A. , Ralston Stuart H. , Montgomery Hugh E. , Gallagher Alison M. , McGuigan Fiona E.A. , Davey Smith George , Savage Maurice , Humphries Steve E. , Young Ian S.
Published: June 2012

—Reduced arterial compliance precedes changes in blood pressure, which may be mediated through alterations in vessel wall matrix composition. We investigated the effect of the collagen type I-α1 gene (
COL1A1
) +2046G>T polymorphism on arterial compliance in healthy individuals. We recruited 489 subjects (251 men and 238 women; mean age, 22.6±1.6 years).
COL1A1
genotypes were determined using polymerase chain reaction and digestion by restriction enzyme
Bal
1. Arterial pulse wave velocities were measured in 3 segments, aortoiliac (PWVA), aortoradial (PWVB), and aorto-dorsalis-pedis (PWVF), as an index of compliance using a noninvasive optical method. Data were available for 455 subjects. The sample was in Hardy-Weinberg equilibrium with genotype distributions and allele frequencies that were not significantly different from those reported previously. The
T
allele frequency was 0.22 (95% confidence interval, 0.19 to 0.24). Two hundred eighty-three (62.2%) subjects were genotype
GG
, 148 (35.5%) subjects were genotype
GT
, and 24 (5.3%) subjects were genotype
TT
. A comparison of
GG
homozygotes with
GT
and
TT
individuals demonstrated a statistically significant association with arterial compliance: PWVF 4.92±0.03 versus 5.06±0.05 m/s (ANOVA,
P
=0.009), PWVB 4.20±0.03 versus 4.32±0.04 m/s (ANOVA,
P
=0.036), and PWVA 3.07±0.03 versus 3.15±0.03 m/s (ANOVA,
P
=0.045). The effects of genotype were independent of age, gender, smoking, mean arterial pressure, body mass index, family history of hypertension, and activity scores. We report an association between the
COL1A1
gene polymorphism and arterial compliance. Alterations in arterial collagen type 1A deposition may play a role in the regulation of arterial compliance.
Cardiovascular Neural Reflexes in L-NAME–Induced Hypertension in Mice
Authors: Peotta Veronica A. , Vasquez Elisardo C. , Meyrelles Silvana S.
Published: June 2012

Abstract
—

— The mouse is the most used animal for studying the genetic basis of cardiovascular diseases. However, the mechanisms of regulation of cardiovascular function in this animal are not yet well understood. The goal of this study was to evaluate the baroreflex, the Bezold-Jarisch cardiopulmonary reflex (BJR), and the chemoreflex in mice with hypertension induced by inhibition of NO using
Nω
-nitro-
l
-arginine-methyl ester (L-NAME). Basal mean arterial pressure (MAP) measured under anesthesia (urethane, 1 mg/g IP) was significantly higher in L-NAME (400 μg/g IP for 7 days)–treated (HT) mice (n=7) compared with vehicle-treated (NT; n=10) animals (126±9 versus 79±2 mm Hg) without differences in heart rate (HR). Baroreflex sensitivity, evaluated using phenylephrine (1 μg/g IV) was enhanced in HT mice compared with NT mice (−9.8±1.4 versus −4.9±0.5 bpm/mm Hg). The BJR, induced by phenylbiguanide (40 ng/g IV), was significantly attenuated in HT animals (MAP, −13±5%; HR, −39±6%) compared with NT animals (MAP, −38±5%; HR, −66±2%). The chemoreflex, induced by potassium cyanide (0.26 μg/g IV), was significantly attenuated in HT animals (MAP, +14±4%; HR, −8±2%) compared with NT animals (MAP, +29±4%; HR, −15±4%). As has been observed in rats, chronic inhibition of NO synthase in mice results in arterial hypertension. Enhancement of baroreflex sensitivity and attenuation of BJR and chemoreflex seem to be mainly caused by inhibition of NO synthesis because individual analyses did not show positive correlation between changes in these reflexes and MAP levels in the HT group.
Antioxidants Block Angiotensin II-Induced Increases in Blood Pressure and Endothelin
Authors: Ortiz Maria Clara , Manriquez Melissa C. , Romero Juan C. , Juncos Luis A.
Published: June 2012

Abstract
—

— Chronically infusing a subpressor dose of angiotensin (Ang) II increases blood pressure via poorly defined mechanisms. We found that this hypertensive response is accompanied by increased oxidant stress and is prevented by blocking endothelin (ET) receptors. Thus, we now tested whether blocking oxidant stress decreases both blood pressure and ET levels. We infused Sprague-Dawley rats (via osmotic pumps) with either vehicle (group 1) or Ang II (5 ng · kg
−1
· min
−1
; groups 2 to 4) for 15 days. Groups 3 and 4 also received either tempol in the drinking water (1 mmol/L) or vitamin E (5000 IU/kg diet), respectively, for 15 days. We measured systolic blood pressure (SBP) and urinary nitrite excretion every 3 days, and on day 15 we measured systemic and renal venous plasma levels of ET, isoprostanes, and thiobarbituric acid reactive substances (TBARS). SBP in Group 1 did not change throughout the study, whereas Ang II increased SBP (from 132±5 to 151±7 mm Hg). In addition, Ang II increased the systemic and renal venous levels of isoprostanes, TBARS, and ET and caused a transient decrease in urinary nitrites (that returned to control levels by day 9). Both tempol and vitamin E prevented Ang II-induced hypertension and either prevented or tended to blunt the increase in systemic and renal isoprostanes, TBARS, and ET. Finally, both antioxidants abolished the transient decrease in urinary nitrites. These results together with our previous study suggest that subpressor-dose Ang II increases oxidant stress (and isoprostanes). This in turn increases ET levels, which participate in the hypertensive response to Ang II.
Ovarian Hormones Modulate Endothelin-1 Vascular Reactivity and mRNA Expression in DOCA-Salt Hypertensive Rats
Authors: David Flavia L. , Carvalho Maria Helena C. , Cobra Ana L.N. , Nigro Dorothy , Fortes Zuleica B. , Rebouças Nancy A. , Tostes Rita C.A.
Published: June 2012

Abstract
—

— We previously demonstrated a differential activation of the endothelin-1 (ET-1) pathway in male and female deoxycorticosterone (DOCA)-salt hypertensive rats, with the male rats exhibiting marked alterations in vascular and pressor responses to ET-1 and Suc-[Glu,
9
Ala
11,15
]-ET-1(8-21) (IRL-1620), an ET
B
agonist. Mechanisms underlying these gender differences are unclear, and we hypothesized that the ovarian hormones attenuate vascular ET
B
responses in female DOCA-salt rats. Female Wistar rats were randomized in 3 groups: sham-operated, ovariectomized (OVX), and OVX plus hormone replacement with estradiol (E) or estradiol/progesterone (EP). Two weeks later, rats were uninephrectomized and further randomized in DOCA-salt (subcutaneous injections of desoxycorticosterone and drinking water containing NaCl/KCl) and control normotensive (subcutaneous injections of vehicle and tap water). Blood pressure was evaluated both by direct and standard tail-cuff methods. Responses to IRL-1620 were evaluated in vivo/in situ in the mesenteric microcirculation. mRNA expression of ET-1 and ET
A/B
receptors was evaluated in mesenteric arteries by reverse transcription–polymerase chain reaction and expressed relative to GAPDH. OVX-DOCA rats developed a more severe form of hypertension than did DOCA rats. Treatment with E or EP restored blood pressure to levels observed in DOCA rats. In the mesentery, IRL-1620 induced vasodilatation in control rats, a mild vasoconstriction in DOCA rats, and marked vasoconstriction in OVX-DOCA rats. Both E and EP decreased IRL-1620–induced vasoconstriction in the DOCA group. In the normotensive group, OVX did not change blood pressure or IRL-1620–induced vasodilation. Removal of the ovaries increased ET-1 mRNA in arteries from DOCA and control rats, although treatment with E or EP reversed these changes. Vascular ET
B
receptor mRNA levels were greatly enhanced in OVX-DOCA but not OVX-control rats. Hormone replacement with E or EP restored ET
B
receptor expression in the DOCA group. A greater blood pressure–lowering effect of bosentan (ET
A
/ET
B
blocker) was observed in OVX-DOCA rats. The observation that OVX worsens hypertension as well as the altered ET
B
receptor–mediated responses and the effects of bosentan in female DOCA rats supports our suggestion that the ovarian hormones modulate ET-1/ET
B
receptor vascular responses/expression in DOCA-salt hypertension.
Ultrasonography for the Evaluation of Visceral Fat and Cardiovascular Risk
Authors: Ribeiro-Filho Fernando F. , Faria Alessandra N. , Kohlmann Oswaldo , Ajzen Sérgio , Ribeiro Artur B. , Zanella Maria Teresa , Ferreira Sandra R.G.
Published: June 2012

Abstract

— —Visceral fat accumulation is associated with increased cardiovascular risk. Clinical evaluation of visceral fat is limited because of the lack of reliable and low-cost methods. To assess the correlation between ultrasonography and computed tomography (CT) for the evaluation of visceral fat, 101 obese women, age 50.5±7.7 years with a body mass index of 39.2±5.4 kg/m
2
, were submitted to ultrasonograph and CT scans. Visceral fat measured by ultrasonography, 1 cm above the umbilical knot, showed a high correlation with CT-determined visceral fat (
r
=0.67,
P
<0.0001). The ultrasonograph method showed good reproducibility with an intra-observer variation coefficient of <2%. Both ultrasonograph and CT visceral fat values were correlated with fasting insulin (
r
=0.29 and
r
=0.27,
P
<0.01) and plasma glucose 2 hours after oral glucose load (
r
=0.22 and
r
=0.34,
P
<0.05), indicating that ultrasonography is a useful method to evaluate cardiovascular risk. A significant correlation was also found between visceral fat by CT and serum sodium (
r
=0.18,
P
<0.05). A ultrasonograph-determined visceral-to-subcutaneous fat ratio of 2.50 was established as a cutoff value to define patients with abdominal visceral obesity. This value also identified patients with higher levels of plasma glucose, serum insulin and triglycerides and lower levels of HDL-cholesterol, which are metabolic abnormalities characteristic of the metabolic syndrome. Our data demonstrate that ultrasonography is a precise and reliable method for evaluation of visceral fat and identification of patients with adverse metabolic profile.
Neurohypophyseal response to dehydration in the spontaneously hypertensive rat.
Authors: Morris M
Published: June 2012

Experiments were performed to evaluate the effect of dehydration on neurohypophyseal hormone secretion, both vasopressin and oxytocin, fluid balance, and blood pressure in male spontaneously hypertensive rats (SHR) and their normotensive controls, Wistar Kyoto (WKY). Metabolic studies showed that the antidiuretic response to dehydration (24 and 48 hours of water deprivation) was significantly depressed (p less than 0.01) in the hypertensive animals. They responded inappropriately to dehydration with a greater loss of water and sodium and a larger increase in hematocrit. In contrast, the vasopressin response (both urinary excretion and plasma levels) was increased. The peak plasma levels were 25.3 pg/ml (SHR) compared to 16.6 pg/ml (WKY), while the urinary excretion was 22.5 ng/24 hrs (SHR) vs 9.0 ng/24 hrs (WKY). Dehydration also elicited a stimulation of oxytocin secretion, with no differences observed in the responses of the groups. Blood pressure was significantly greater in the SHR and it did not change during dehydration. These results provide further support for the idea that hypertension is associated with abnormalities in the control of fluid/electrolyte balance.
Vasopressin and vascular reactivity in the development of DOCA hypertension in rats with hereditary diabetes insipidus.
Authors: Berecek K H , Murray R D , Gross F , Brody M J
Published: June 2012

To examine the role of vasopressin (VP) in DOCA-salt hypertension, arterial pressure and renal vascular reactivity were studied in control Long-Evans (LE) rats and in Brattleboro rats homozygous for diabetes insipidus (DI rats). Vascular reactivity to norepinephrine, VP and angiotensin II was assessed in isolated kidneys perfused at constant flow. LE rats showed an increase in arterial pressure (AP) which was significant at 2 weeks post DOCA and averaged 180 mm Hg at 4 weeks. DI rats lacking VP showed no rise in AP after DOCA; however, DI rats given VP and DOCA developed hypertension with a course and magnitude similar to that observed in LE rats. At 6 to 10 weeks post DOCA, renal vascular reactivity to all agents was increased in LE rats and DI rats replaced with VP. Normotensive DI rats lacking VP showed depressed reactivity. Assessment of changes in reactivity at 3 days post DOCA showed that changes preceded the rise in AP. These data suggest that VP may play a primary role in the pathogenesis of DOCA hypertension and that its mechanism may involve an induction of increased vascular reactivity.
Biological and social correlates of blood pressure among Japanese men in Hawaii.
Authors: Reed D , McGee D , Yano K
Published: June 2012

A cohort of more than 8,000 Japanese men living in Hawaii was studied for factors associated with blood pressure levels, with an emphasis on biological and sociocultural variables. Bivariate and multivariate analyses of more than 50 variables indicated that obesity, age, hematocrit, heart rate, forced vital capacity, serum triglyceride, serum uric acid, cigarette consumption, and family history of hypertension were independently associated with both cross-sectional levels and longitudinal changes in blood pressure. Serum glucose and alcohol consumption were associated with cross-sectional levels only. There was little evidence of association for specific dietary items, type of diet, diet changes, or use of salt. Furthermore, there was no support for the psychosocial hypotheses of elevated blood pressure from the stress of migration, acculturation, or status incongruity.
Overnight urine collections to estimate sodium intake.
Authors: Luft F C , Fineberg N S , Sloan R S
Published: June 2012

This study was undertaken to formulate reliable confidence limits for the relationship between nocturnal and 24-hour urine sodium (Na) excretion for use in population compliance studies. Urine excretions were measured in 12 white and 12 black men at three levels of sodium (Na) intake (10, 200, and 400 mEq/day) for 7 days. Nocturnal Na, chloride (Cl), and Cl determined by titrator stick were all highly correlated (r greater than or equal to 0.86, p less than 0.001) with 24-hour UNaV. No significant difference could be attributed to race. Discriminate analysis revealed that the subjects could be categorized with respect to Na intake with accuracies of 95%, 90%, and 85% (low, middle, and high Na intake respectively) by means of two nocturnal urine Cl titrator stick measurements. In addition, two such measurements showing nocturnal UClV less than 10 mEq indicated with 95% accuracy that 24-hour UNaV was less than 60 mEq. According to these data, measurement of nocturnal Na or Cl excretion is a useful means of assessing compliance to a low sodium intake, and the titrator sticks are a convenient and inexpensive tool.
Streptozotocin diabetic rats are hypertensive despite reduced hypothalamic responsiveness.
Authors: Buñag R D , Tomita T , Sasaki S
Published: June 2012

To determine whether diabetes predisposes rats to hypertension, tail-cuff systolic pressures were measured in male rats made diabetic by pretreatment with streptozotocin. From Weeks 2 through 7, diabetic rats weighed less but had higher systolic pressures than nondiabetic ones. Further comparisons made while the rats were anesthetized with urethane showed that pressor and sympathetic nerve responses to ventromedial hypothalamic stimulation, as well as pressor responses to injected vasopressin, were significantly reduced in the diabetic group. A generalized reduction of cardiovascular reactivity was considered unlikely because systemic pressor responses to norepinephrine and tyramine were unimpaired. Yet reflex bradycardia elicited by norepinephrine was enhanced indicating that baroreceptor resetting had not occurred. Thus, diabetic rats were characterized by hypertension, narrowed pulse pressure, bradycardia with increased reflex responses to norepinephrine, and reduced pressor responses to hypothalamic stimulation and to vasopressin. The successful induction of diabetes was confirmed not only by the presence of hyperglycemia, hypoinsulinemia, glycosuria, and abnormal glucose tolerance, but also by reductions in pancreatic weight, insulin, and beta-cell content. Although our results suggest that diabetic rats are predisposed to become hypertensive, other mechanisms such as hypothalamic depression may be activated to restrict further elevations in blood pressure.
High molecular weight angiotensinogen levels in hypertensive pregnant women.
Authors: Tewksbury D A , Dart R A
Published: June 2012

An apparent high molecular weight angiotensinogen (H-Aogen) can be separated from the usually predominant low molecular weight angiotensinogen (L-Aogen) by gel filtration of plasma. H-Aogen has been quantitated in plasma from normotensive menstruating women, estrogen treated women, normotensive pregnant women, women with pregnancy-induced hypertension (PIH), and women whose preexisting hypertension was exacerbated during pregnancy. When expressed as a percent of the total angiotensinogen, the H-Aogen levels were: menstruating women 4%, estrogen-treated women 10%, normotensive pregnant women 16%, women with PIH 25%, and pregnant women with exacerbated hypertension 28%. A significant difference (p less than 0.01) was found between H-Aogen concentration in normotensive pregnant women and women with PIH (1.10 +/- 0.12 and 1.73 +/- 0.16 micrograms angiotensin I/ml plasma respectively). In some hypertensive pregnant women, H-Aogen is the predominant form of angiotensinogen. Thus, H-Aogen should be recognized as a component of the renin-angiotensin system.
Central effects of prostaglandin E2 on blood pressure and plasma renin activity in rats. Role of the sympathoadrenal system and vasopressin.
Authors: Okuno T , Lindheimer M D , Oparil S
Published: June 2012

This study was designed to determine the roles of the sympathetic nervous system, adrenal medulla, and arginine vasopressin (AVP) in mediating pressor and plasma activity (PRA) responses to intraventricularly (ICV) administered prostaglandin E2 (PGE2) in conscious rats. The ICV PGE2 elevated blood pressure and caused increases in PRA, plasma AVP, and plasma norepinephrine and epinephrine. The pressor effect of ICV PGE2 was not influenced by pretreatment with captopril, but was attenuated by the AVP antagonist, d(CH2)5Tyr(Me)AVP, and by phenoxybenzamine, and was completely abolished by the combination of the AVP antagonist and phenoxybenzamine. The PRA response to ICV PGE2 was not affected by bilateral renal denervation or by phenoxybenzamine alone, but was attenuated by propranolol alone and was completely abolished by the combination of propranolol and phenoxybenzamine. Bilateral adrenomedullectomy did not affect the pressor response to ICV PGE2, whereas it attenuated the increase in PRA and completely abolished the increase in plasma epinephrine. These results suggest that the pressor effect of ICV PGE2 is the result of increased sympathetic nervous system activity and is dependent on the stimulation of alpha-adrenergic receptors and on AVP release. The pressor response to ICV PGE2 is accompanied by but not dependent on an increase in PRA. The renin-stimulating effect of centrally administered PGE2 is, at least in part, dependent on beta-adrenergic receptor stimulation by increased circulating catecholamines.
Regional changes in rat brain angiotensinogen following bilateral nephrectomy.
Authors: Gregory T J , Wallis C J , Printz M P
Published: June 2012

One approach to establish the existence and functionality of a brain angiotensin system is to demonstrate selective alterations in that system following perturbation of peripheral cardiovascular functions. The present study utilized this approach to quantify regional angiotensinogen levels in the rat brain following bilateral nephrectomy, a perturbation that severely disrupts salt and water homeostasis. Angiotensinogen, the precursor of any centrally-derived angiotensin, was analyzed since it should provide a marker for a putative angiotensin peptidergic system. Net brain angiotensinogen was determined by correcting total tissue concentrations of angiotensinogen with accurate values of contaminating plasma angiotensinogen. The latter was determined by quantifying regional plasma space utilizing tritiated inulin as a marker of cerebral vascular space. It was found that there were no detectable alterations in regional net brain angiotensinogen in the first 24 hours following nephrectomy despite over a twofold increase in plasma angiotensinogen and the absence of significant plasma renin. By 32 hours postnephrectomy, certain areas of the rat hypothalamus and midbrain exhibited significant elevations in net angiotensinogen content. These areas coincided with regions traversed by neural pathways shown to mediate angiotensin-induced drinking or blood pressure elevations. The results lend further support to the concept of an independent brain angiotensin system.