bluuebunny/crossref_metadata_2025 huggingface dataset:
Antihypertensive Therapy in Dyslipidemic Men
Authors: Mänttäri Matti , Tenkanen Leena , Manninen Vesa , Alikoski Tiina , Frick M. H.
Published: June 2012

Abstract
To investigate the influence of antihypertensive therapy and the success of blood pressure control on coronary heart disease incidence and total mortality, we studied dyslipidemic middle-aged men participating in the placebo arm of the Helsinki Heart Study, a randomized coronary primary prevention trial with gemfibrozil. Based on blood pressure level and the presence of antihypertensive therapy at study entry, the participants were classified into four categories. Relative risks of coronary heart disease (nonfatal myocardial infarction or cardiac death) and total mortality during the 5-year trial period were calculated using Cox proportional hazards models. With subjects who were not using antihypertensive drugs and who had normal blood pressure (category I) as reference, the relative risks of coronary heart disease during the trial period were 2.1 (95% confidence interval [CI], 1.3 to 3.3) in untreated hypertensive subjects (category II), 0.9 (95% CI, 0.2 to 3.8) in subjects with successful antihypertensive therapy (category III), and 2.0 (95% CI, 1.0 to 4.1) in subjects who remained hypertensive despite drug therapy (category IV). The relative risks of death were 1.9 (95% CI, 0.9 to 3.9) in category II and 1.0 (95% CI, 0.1 to 7.3) in category III; in category IV subjects, those with unsuccessful antihypertensive therapy, the relative risk was 4.4 (95% CI, 2.0 to 9.6). The excess mortality in this category was due to cardiovascular causes and was clustered in subjects with multiple drug therapy for hypertension control. We conclude that successful antihypertensive therapy in dyslipidemic men reduced coronary heart disease incidence despite its adverse effects on high-density lipoprotein cholesterol and triglycerides. With regard to total mortality, adequate blood pressure reduction had a positive effect, and unsuccessful hypertension control increased total mortality, especially cardiovascular mortality.
Relation Between Cold Pressor Test and Development of Hypertension Based on 28-Year Follow-up
Authors: Kasagi Fumiyoshi , Akahoshi Masazumi , Shimaoka Katsutaro
Published: June 2012

Abstract
The present study examined the relation between blood pressure reactivity to cold stimulus and the subsequent development of hypertension based on a follow-up study from 1960 through 1988 of 824 normotensive participants (mean age, 35.8±10.8 years) in the Adult Health Study in Nagasaki, Japan. Hypertension developed in 343 individuals during the 28 years of follow-up, with a mean incidence rate of 24.6 per 10
3
person-years. Confounding variables, including attained age, resting systolic and diastolic blood pressures, and body mass index at baseline, were adjusted using a Poisson regression model. Systolic response was found to be an independent and significant predictor. The relative risk of hypertension for systolic hyperreactors was 1.37, with a 95% confidence interval of 1.10 to 1.71. Diastolic response was significant only when resting diastolic blood pressure was also considered. The cold pressor test appears to be useful if performed on middle-aged subjects older than 40 years at the time of examination, when hypertension is more prevalent. The current results support the hypothesis that hyperre- activity is a predictor of the development of hypertension.
Ramipril-Induced Regression of Left Ventricular Hypertrophy in Treated Hypertensive Individuals
Authors: Lièvre Michel , Guéret Pascal , Gayet Christian , Roudaut Raymond , Haugh Margaret C. , Delair Sylvie , Boissel Jean-Pierre
Published: June 2012

Abstract
The objective of this trial was to assess the effects of 6-month daily treatment with two doses of ramipril on left ventricular mass and the dependence of this on blood pressure changes in hypertensive patients with left ventricular hypertrophy. After a selection phase of 4 to 6 weeks with patients under antihypertensive therapy with 20 mg furosemide daily, 115 patients with either controlled or uncontrolled hypertension and left ventricular hypertrophy were randomized in a double-blind manner to receive either placebo (n=40), 1.25 mg (low dose, n=38), or 5 mg (regular dose, n=37) ramipril daily for 6 months. Treatment with furosemide was continued unchanged during this phase. The main outcome measured was left ventricular hypertrophy regression as assessed from central blind reading of echocardiograms recorded at randomization and after 6 months. No significant differences were observed for changes in casual or ambulatory blood pressure between the three groups. Left ventricular mass index was found to be significantly reduced in patients receiving 5 mg ramipril compared with those receiving placebo (−10.8±3.7 versus +4.1±4.0 g/m
2
,
P
=.008); in patients receiving 1.25 mg ramipril, the difference was close to borderline significance compared with placebo (−7.0±4.3 g/m
2
,
P
=.06). Similar results were observed for changes in left ventricular mass (−20.3±6.6 and −13.0±7.8 g in the 5- and 1.25-mg ramipril groups, respectively, versus +9.1±7.2 g in the placebo group;
P
=.004 and .04, respectively). In a multiple regression model testing 10 potential explicative variables, we found that this reduction was correlated with treatment, both 1.25 and 5.0 mg ramipril (
P
=.03 and .01, respectively), and with the baseline value of the left ventricular mass index (
P
=.005). Changes in ambulatory or casual systolic and diastolic blood pressures were not predictive of changes in left ventricular mass (
P
=.15 and .16, respectively). Ramipril at 1.25 and 5 mg daily for 6 months can induce left ventricular hypertrophy regression, independent of changes in blood pressure, in patients under furosemide (20 mg/d) antihypertensive therapy. The implications of this regression for cardiovascular morbidity and mortality in hypertensive patients should now be assessed.
Impaired Endothelium-Dependent Vasodilation of Large Epicardial and Resistance Coronary Arteries in Patients With Essential Hypertension
Authors: Egashira Kensuke , Suzuki Satoshi , Hirooka Yoshitaka , Kai Hisashi , Sugimachi Masaru , Imaizumi Tsutomu , Takeshita Akira
Published: June 2012

Abstract
Hypertensive patients have impaired endothelium-dependent coronary vasodilation evoked with acetylcholine. The aim of this study was to examine whether the impaired endothelium-dependent dilation of coronary arteries is related to a specific abnormality of the muscarinic receptor that mediates the effects of acetylcholine. Responses of the large epicardial and resistance coronary arteries were assessed in seven hypertensive patients (mean arterial pressure, 106±14 mm Hg) and seven control subjects (83±6 mm Hg,
P
<.01) during cardiac catheterization. To assess coronary endothelial function, we infused acetylcholine and substance P (endothelium-dependent agents that act on different receptors) and papaverine and nitrate (direct vascular smooth muscle dilators) into the left anterior descending coronary artery and determined coronary artery diameter by arteriography and coronary blood flow with an intracoronary Doppler catheter technique. In control subjects, 3 μg/min acetylcholine increased (
P
<.05) and 30 μg/min acetylcholine decreased (
P
<.05) arterial diameter, and in hypertensive patients, 1, 3, 10, and 30 μg/min acetylcholine decreased arterial diameter in a dose-dependent manner. Substance P at 3, 10, and 30 ng/min caused comparable increases in diameter in both groups. Increases in coronary blood flow with both acetylcholine and substance P were significantly (
P
<.01) blunted in hypertensive patients compared with control subjects. No significant differences were noted between the groups in the responses of large epicardial coronary artery diameter and coronary blood flow to papaverine and nitrate. Vasodilation of the large coronary artery with acetylcholine was impaired, but the response to substance P was preserved in hypertensive patients, indicating that diminished vasodilation of the large epicardial coronary artery in hypertensive patients may be related to a specific abnormality in the endothelial muscarinic receptor. Blunted coronary blood flow responses to both acetylcholine and substance P in hypertensive patients suggest that endothelial dysfunction in the resistance coronary artery in this condition is related to a more generalized endothelial abnormality but is not confined to the muscarinic receptor.
Prevalence of Hypertension in the US Adult Population
Authors: Burt Vicki L. , Whelton Paul , Roccella Edward J. , Brown Clarice , Cutler Jeffrey A. , Higgins Millicent , Horan Michael J. , Labarthe Darwin
Published: June 2012

Abstract
The purpose of this study was to estimate the current prevalence and distribution of hypertension and to determine the status of hypertension awareness, treatment, and control in the US adult population. The study used a cross-sectional survey of the civilian, noninstitutionalized population of the United States, including an in-home interview and a clinic examination, each of which included measurement of blood pressure. Data for 9901 participants 18 years of age and older from phase 1 of the third National Health and Nutrition Examination Survey, collected from 1988 through 1991, were used. Twenty-four percent of the US adult population representing 43 186 000 persons had hypertension. The age-adjusted prevalence in the non-Hispanic black, non-Hispanic white, and Mexican American populations was 32.4%, 23.3%, and 22.6%, respectively. Overall, two thirds of the population with hypertension were aware of their diagnosis (69%), and a majority were taking prescribed medication (53%). Only one third of Mexican Americans with hypertension were being treated (35%), and only 14% achieved control in contrast to 25% and 24% of the non-Hispanic black and non-Hispanic white populations with hypertension, respectively. Almost 13 million adults classified as being normotensive reported being told on one or more occasions that they had hypertension; 51% of this group reported current adherence to lifestyle changes to control their hypertension. Hypertension continues to be a common finding in the general population. Awareness, treatment, and control of hypertension have improved substantially since the 1976-1980 National Health and Nutrition Examination Survey but continue to be suboptimal, especially in Mexican Americans. Consideration should be given to revision of the criteria for classification of hypertension to reflect the widespread use of lifestyle modification for treatment of hypertension.
Role of Nitric Oxide on Papillary Blood Flow and Pressure Natriuresis
Authors: Fenoy Francisco J. , Ferrer Paloma , Carbonell Luis , García-Salom Miguel
Published: June 2012

Abstract
This study examined whether nitric oxide synthesis blockade or potentiation (with
N
ω
-nitro-
l-
arginine methyl ester [L-NAME] or
N
-acetylcysteine, respectively) can shift the relations between sodium excretion, papillary blood flow, and renal perfusion pressure. Papillary blood flow was measured by laser Doppler flowmetry. A low dose of L-NAME (3.7 nmol/kg per minute) reduced papillary blood flow only at high arterial pressure (140 mm Hg), but it had no effect on pressure natriuresis. Infusion of 37 nmol/kg per minute L-NAME reduced cortical blood flow by 9% at all perfusion pressures studied, lowered papillary blood flow by 8% and 19% at 120 and 140 mm Hg, respectively, and blunted the pressure-natriuresis response. The administration of 185 nmol/kg per minute L-NAME reduced cortical blood flow by 30% and decreased papillary blood flow by 25% in the range of 100 to 140 mm Hg of arterial pressure. Blockade of nitric oxide synthesis with L-NAME at all doses studied reduced papillary blood flow only at high renal perfusion pressures, but papillary blood flow remained essentially unchanged at low perfusion pressures, thus restoring papillary blood flow autoregulation.
N
-Acetylcysteine (1.8 mmol/kg) increased papillary blood flow by 9% and shifted the relations between papillary blood flow, sodium excretion, and renal perfusion pressure toward lower pressures. This effect of
N
-acetylcysteine on papillary blood flow was blocked by subsequent L-NAME administration. The results indicate that increases in renal medullary levels of nitric oxide as renal perfusion pressure rises may be responsible for the lack of renal medullary blood flow autoregulation and the pressure-natriuretic response in volume-expanded rats.
Effects of Interleukin-1β and Nitric Oxide on Cardiac Myocytes
Authors: Harding Pamela , Carretero Oscar A. , LaPointe Margot C.
Published: June 2012

Abstract
Using cultured neonatal ventricular myocytes, we investigated whether nitric oxide (NO) directly influences myocyte growth. Treatment of myocytes with phenylephrine stimulated growth, as indicated by increases in atrial natriuretic factor, brain natriuretic peptide (BNP) mRNA and BNP secretion, activator protein 1 activity (activation of early-response genes), and total cellular protein content. NO was stimulated by treatment of myocytes with interleukin-1β (IL-1β) or was generated by the NO donor nitroglycerin, and its effects on total protein content and BNP secretion were measured. Treatment of cardiocytes with 3.4 nmol/L IL-1β for 24 hours stimulated NO (nitrite) production by threefold, which resulted from an increase in the inducible isoform of NO synthase mRNA. Dexamethasone inhibited IL-1β induction of nitrite production, whereas the protein kinase C inhibitor staurosporine had no effect. IL-1β had no effect on either basal or phenylephrine-stimulated protein content but inhibited phenylephrine-stimulated BNP secretion. Nitroglycerin (10
−7
to 10
−3
mol/L) dose-dependently increased NO production; however, only the highest dose (10
−3
mol/L) reduced basal and phenylephrine-stimulated total protein content and BNP secretion. cGMP, a second messenger of NO, had no effect on either basal or phenylephrine-stimulated BNP secretion or total protein content. In conclusion, our data indicate that BNP mRNA is stimulated by phenylephrine as shown previously for atrial natriuretic factor. Although both BNP and total protein content are increased by phenylephrine, these effects are not inhibited by NO. However, IL-1β inhibits phenylephrine-stimulated BNP secretion but not total protein content, suggesting that regulation of BNP secretion can be dissociated from total protein synthesis during myocyte growth.
Early Blockade of Bradykinin B
2
-Receptors Alters the Adult Cardiovascular Phenotype in Rats
Authors: Madeddu Paolo , Parpaglia Paolo Pinna , Demontis Maria Piera , Varoni Maria Vittoria , Fattaccio Maria Caterina , Anania Vittorio , Glorioso Nicola
Published: June 2012

Abstract
We evaluated whether long-term inhibition of bradykinin B
2
-receptors by the long-acting antagonist Hoe 140 (
d
-Arg,[Hyp
3
,Thi
5
,
d
-Tic
7
,Oic
8
]-bradykinin) affects the blood pressure of normotensive rats. Neither Hoe 140 (at 75 nmol/d for 8 weeks) nor its vehicle altered systolic pressure of adult rats on a normal or high sodium intake. In further experiments, pairs of Hoe 140–treated rats were mated and their offspring maintained on Hoe 140 and a normal sodium diet. Controls were given vehicle instead of Hoe 140. At 9 weeks of age, rats given Hoe 140 during prenatal and postnatal phases of life showed greater systolic pressures, heart rates, and body weights than controls (122±1 versus 113±1 mm Hg, 444±6 versus 395±8 beats per minute, 258±7 versus 213±3 g, respectively,
P
<.01), whereas urinary creatinine excretion was reduced (1.13±0.05 versus 1.36±0.04 μmol/100 g body wt in controls,
P
<.05). The difference in blood pressure (confirmed by direct intra-arterial measurement) persisted after 20 days of dietary sodium loading, whereas it was nullified by sodium restriction. In additional experiments, the offspring of untreated rats received Hoe 140 or vehicle from 2 days to 11 weeks of age. At this stage, systolic pressure and body weight were significantly greater in Hoe 140–treated rats compared with controls, and heart rate was similar. In addition, Hoe 140–treated rats showed higher sodium levels in serum and erythrocytes and a greater ratio of heart weight to body weight compared with controls; hematocrit and the ratio of kidney weight to body weight were lower. In conclusion, long-term blockade of bradykinin receptors by Hoe 140 alters the adult cardiovascular phenotype, provided that the antagonist is given since the early phases of life. Our data suggest that endogenous kinins may play a role in the regulation of cardiovascular function by influencing renal function and the activity of the sympathetic nervous system during development.
Gender Difference in Endothelial Dysfunction in the Aorta of Spontaneously Hypertensive Rats
Authors: Kauser Katalin , Rubanyi Gabor M.
Published: June 2012

Abstract
We investigated endothelium-dependent responses of thoracic aorta isolated from age-matched male and female spontaneously hypertensive rats (SHR) to explore gender differences in endothelial dysfunction that may contribute to the sexual dimorphism observed in the development of hypertension in this strain. Endothelium-dependent relaxation in response to acetylcholine (10
−9
to 10
−4
mol/L) was significantly greater in female rats than in male rats, although impaired responses were seen in both sexes compared with normotensive controls. Inhibition of cyclooxygenase by indomethacin (10
−5
mol/L) improved endothelium-dependent relaxation, but it did not abolish the gender difference. Relaxations in response to sodium nitroprusside were identical in denuded aortic rings from male and female SHR. Acetylcholine at higher concentrations (10
−6
to 10
−4
mol/L) induced endothelium-dependent contraction in intact, quiescent aortic rings from male SHR but not in those from female SHR. After incubation with
N
G
-nitro-
l
-arginine (10
−4
mol/L), contraction in response to acetylcholine became apparent in rings from female SHR, but it was still significantly less pronounced than in similarly treated rings from male SHR. Endothelium-dependent contraction was prevented by indomethacin in both sexes, suggesting that a cyclooxygenase product such as endoperoxide may be mediating this effect. Because responses evoked by the thromboxane/endoperoxide receptor agonist U46619 (10
−10
to 10
−6
mol/L) were not greater in rings from male SHR than those from female SHR, increased smooth muscle responsiveness or higher thromboxane/endoperoxide receptor density in the males could not account for the differences in endothelium-dependent contraction. These results suggest that sex steroid hormones may control endothelium-dependent vascular reactivity. The less severe endothelial dysfunction in the female SHR can contribute to the gender differences observed in the extent and rate of progression of hypertension in the SHR.
Blood Pressure and Heat Shock Protein Expression in Response to Acute and Chronic Stress
Authors: Blake Michael J. , Klevay Leslie M. , Halas Edward S. , Bode Ann M.
Published: June 2012

Abstract
We previously demonstrated that restraint and pharmacological agents that activate sympathetic nervous system activity induce expression of the 70-kD heat shock protein (HSP70) in major blood vessels. The magnitude and rapidity in which HSP70 is induced in the aorta suggest that it may play a salient role in the mechanical properties of vascular smooth muscle. Other investigators have reported that HSP70 inducibility is increased in genetically hypertensive animals. In this report, we have investigated the effects of acute and chronic (8-week) exposure to restraint and restraint in the presence of a randomized intermittent air jet on the development of hypertension and the induction of HSP70 in the aorta and adrenal glands of normotensive adult male Sprague-Dawley rats. Acute restraint or air jet resulted in a fivefold to sixfold increase in aortic HSP70 mRNA expression. Chronic exposure to restraint reduced the HSP70 response to acute restraint. In contrast, no adaptation of the HSP70 response to acute air jet was observed in aortas of chronically air jet–treated rats. In adrenal glands, HSP70 expression was reduced after chronic restraint and air jet, indicating that in this tissue, adaptation occurs to both stressors. There was no difference in HSP70 expression in unstressed rats that had been chronically exposed to restraint or air jet in either adrenal gland or aorta. A significant increase (
P
<.05) in systolic blood pressure developed in air jet–treated animals (120±3 mm Hg) but not in restrained rats (107±2 mm Hg) compared with unstressed controls (106±3 mm Hg). Plasma catecholamine concentrations were not indicative of HSP70 expression in the aorta. From these results, we conclude that adaptation to a stressor influences both resting blood pressure and the magnitude of the HSP70 response in aorta to an acute stress. Thus, the ability to induce HSP70 in vascular tissue may contribute to the development of hypertension in chronically stressed animals.
Differential Gene Expression of Renin and Angiotensinogen in the TGR(mREN-2)27 Transgenic Rat
Authors: Lee Min Ae , Böhm Manfred , Kim Shokei , Bachmann Sebastian , Bachmann Jürgen , Bader Michael , Ganten Detlev
Published: June 2012

Abstract
Transgenic rats carrying the murine
Ren-2
gene represent a monogenetic model of hypertension characterized by low plasma renin and high extrarenal expression of the transgene. The hypothesis has been raised that stimulated local renin-angiotensin systems may be responsible for the development of hypertension in this model. This study analyzes the effects of the converting enzyme inhibitor lisinopril, which specifically interferes with the renin-angiotensin system, and the direct vasodilator dihydralazine on the renal and extrarenal expression of renin and angiotensinogen. A comparison of gene expression between heterozygous and homozygous transgenic and normal Sprague-Dawley rats was also performed. We demonstrate high sensitivity of blood pressure toward converting enzyme inhibition in transgenic TGR(mREN-2)27 rats. In the kidney, expression of the transgene and the endogenous renin gene increased, suggesting that both are modulated by lisinopril in a similar manner. On the other hand, blood pressure reduction by dihydralazine did not abolish renal renin suppression in transgenic rats, indicating that mechanisms different from direct effects of blood pressure account for renin suppression. Homozygosity for the transgene led to increased
Ren-2
expression and higher blood pressure and had opposite effects on angiotensinogen expression compared with heterozygous rats. Cardiac hypertrophy was reduced by lisinopril but not dihydralazine and was positively correlated with cardiac angiotensinogen expression. Increased angiotensin II in the adrenal gland of TGR(mREN-2)27 rats, which overexpresses the transgene, provides evidence that this leads to enhanced generation of tissue angiotensin II. We conclude that expression of the mouse transgene, the endogenous rat renin gene, and the angiotensinogen gene is subject to differential tissue-specific regulation. Reversal of cardiovascular damage with the converting enzyme inhibitor but not dihydralazine suggests that angiotensin II generated locally may be involved in the pathogenesis of hypertension and structural changes in TGR(mREN-2)27 rats.
Early Predictors of 15-Year End-Stage Renal Disease in Hypertensive Patients
Authors: Perry H. Mitchell , Miller J. Philip , Fornoff Jane Rossiter , Baty Jack D. , Sambhi Mohinder P. , Rutan Gale , Moskowitz David W. , Carmody Sharon E.
Published: June 2012

Abstract
There has been a continuing increase in the incidence of end-stage renal disease (ESRD) in the United States, including the fraction that has been attributed to hypertension. This study was done to seek relationships between ESRD and pretreatment clinical data and between ESRD and early treated blood pressure data in a population of hypertensive veterans. We identified a total of 5730 black and 6182 nonblack male veterans as hypertensive from 1974 through 1976 in 32 Veterans Administration Hypertension Screening and Treatment Program clinics. Their mean age was 52.5±10.2 years, and their mean pretreatment blood pressure was 154.3±19.0/100.8±9.8 mm Hg. During a minimum of 13.9 years of follow-up, 5337 (44.8%) of these patients died and 245 developed ESRD. For 1055 of these subjects, pretreatment systolic blood pressure (SBP) was greater than 180 mm Hg; 901 were diabetic; 1471 had a history of urinary tract problems; and 2358 of the 9644 who were treated had an early fall in SBP of more than 20 mm Hg. We used proportional hazards modeling to fit multivariate survival models to determine the effect of the available pretreatment data and early treated blood pressure levels on ESRD. This model demonstrated the independent increased risk of ESRD associated with being black or diabetic (risk ratio, 2.2 or 1.8), having a history of urinary tract problems (risk ratio, 2.2), or having high pretreatment SBP (for SBP 165 to 180 mm Hg, risk ratio was 2.8; for SBP >180 mm Hg, risk ratio was 7.6). In addition, myocardial infarction during follow-up increased the risk of subsequent ESRD almost twofold, and congestive heart failure increased it more than fivefold. The rate of ESRD in those whose SBP fell more than 20 mm Hg decreased by two thirds.
Common Carotid Artery Stiffness and Patterns of Left Ventricular Hypertrophy in Hypertensive Patients
Authors: Boutouyrie Pierre , Laurent Stéphane , Girerd Xavier , Benetos Athanase , Lacolley Patrick , Abergel Eric , Safar Michel
Published: June 2012

Abstract
The aim of this study was to determine the relationship between the lumen diameter and function of the common carotid artery, a vessel representative of the capacitance portion of the circulation, and the different patterns of left ventricular hypertrophy in uncomplicated essential hypertensive patients. Carotid luminal diastolic cross-sectional area, distensibility, and compliance were derived from measurements by a high-definition echotracking system. Left ventricular dimensions were from echocardiography. The 86 hypertensive patients included 31 who had never been treated (group 1), 31 in whom treatment had been stopped for at least 2 weeks (group 2), and 24 treated patients (group 3). In multivariate analysis of the population as a whole, the following relations were statistically independent of age, blood pressure, gender, and group: Left ventricular end-diastolic volume index was positively correlated to carotid luminal cross-sectional area (
r
=.46,
P
<.0001) and compliance (
r
=.47,
P
<.0001); left ventricular mean wall thickness and mass-volume ratio were negatively correlated to distensibility (
r
=−.68,
P
<.0001;
r
=−.46,
P
<.0001, respectively) and compliance (
r
=−.40,
P
<.0001;
r
=−.37;
P
<.001, respectively); and left ventricular mass index was positively correlated to luminal cross-sectional area (
r
=.23,
P
<.02) and negatively to distensibility (
r
=−.26,
P
<.01). These results indicate that geometric and functional changes in the common carotid artery accompany geometric changes in the left ventricle. More specifically, they suggest that a reduction in distensibility paralleled cardiac concentric hypertrophy and remodeling, whereas an increase in arterial volume paralleled increased left ventricular cavity size.
Fra
-1, a
Fos
Gene Family Member That Activates Atrial Natriuretic Peptide Gene Transcription
Authors: Kovacic-Milivojevic Branka , Gardner David G.
Published: June 2012

Abstract
Previous studies suggested that individual components of the activator protein 1 (AP-1) complex behave in a highly idiosyncratic fashion at the level of the human atrial natriuretic peptide (ANP) gene promoter. ANP gene transcription is activated by c-
jun
and is generally suppressed by c-
fos
. In the present study,
fra
-1, a close relative of the c-
fos
gene product in terms of its structure and functional activity, behaved like
fos
in cardiac atriocytes, effecting an approximately 50% reduction in c-
jun
–activatable expression of a human ANP chloramphenicol acetyltransferase (CAT) reporter. In cardiac ventriculocytes, however,
fra
-1 effected a synergistic amplification of the c-
jun
response (a 2.5-fold increase over c-
jun
alone). In atrial cells,
fos
-like proteins were not uniformly inhibitory in that a carboxy terminal deletion mutant of c-
fos
activated a human ANP-CAT reporter in the atriocyte cultures. Finally, using a series of domain-swap mutations in the
fos/fra
structural sequences, we showed that sequences at both the amino and the carboxy termini are required to realize the full
fra
-1–dependent stimulatory effect as well as the c-
fos
–dependent inhibition of ANP gene transcription. These findings suggest considerable heterogeneity in the response of the ANP promoter to different components of the AP-1 complex. Such heterogeneity may serve to broaden the range of biological responses available to this promoter as the cardiac cell attempts to adapt to perturbations in the extracellular environment.
Transcriptional Regulation of the Mouse Angiotensin II Type 2 Receptor Gene
Authors: Ichiki Toshihiro , Inagami Tadashi
Published: June 2012

Abstract
The promoter region of the mouse angiotensin II type 2 receptor gene was cloned, and the nucleotide sequences were determined. A computer homology search for a 1.5-kb promoter region showed that there are several consensus
cis
DNA elements such as
C/EBP
,
NF-IL6
, and
AP-1
in this region. Primer extension experiments showed that there are two transcription initiation sites 16 bp apart in the mouse type 2 receptor gene. Deletion mutants of this 1.5-kb segment were prepared and fused to a luciferase reporter gene. These type 2 receptor promoter–luciferase constructs were introduced into PC12W cells, which are from a pheochromocytoma cell line expressing the type 2 receptor, and luciferase activity was measured. It showed that a DNA segment between nucleotides −1497 and −874 suppresses the promoter activity of the type 2 receptor gene and that a DNA segment between nucleotides −47 and +56 is important for the basal promoter activity of the type 2 receptor gene. This proximal segment showed very weak promoter activity when introduced into vascular smooth muscle cells. Gel mobility shift assay with nuclear extracts from PC12W cells showed the presence of three DNA binding proteins that bound to a DNA probe between nucleotides −47 and +8. One DNA binding protein was only very weakly expressed in nuclear extracts from vascular smooth muscle cells, which do not express the type 2 receptor. Two other DNA binding proteins were not observed in nuclear extracts from vascular smooth muscle cells. These data suggest that this DNA segment between nucleotides −47 and +56 is important not only for basal transcription but for differential expression of the type 2 receptor gene in PC12W cells and vascular smooth muscle cells.
Effect of Inhibiting Renal Kallikrein on Prostaglandin E
2
, Water, and Sodium Excretion
Authors: Saitoh Shigeyuki , Scicli A. Guillermo , Peterson Edward , Carretero Oscar A.
Published: June 2012

Abstract
To test the hypothesis that renal kinins act as natriuretic and diuretic hormones, we examined the effect of inhibiting glandular kallikrein on renal function in normotensive unanesthetized rats during normal sodium intake. To inhibit kallikrein at both the luminal and basolateral sides of the distal nephron, we used Fab fragments of monoclonal antibodies to rat urinary kallikrein (Fab-kallikrein). Fab fragments have advantages over intact IgG: they are filtered through the glomerulus and reach the lumen of the distal nephron, where kallikrein is localized and urinary kinins are released. Furthermore, the Fab fragment–antigen complex does not activate the complement system, avoiding the side effects associated with intact antibodies. Fab-kallikrein effectively blocked generation of kinins in the nephron lumen, decreasing urinary kininogenase activity (kallikrein) by 74% to 85% and kinin excretion by 76% to 79%. Fab-kallikrein induced a 30% decrease in urine volume and a 20% to 40% decrease in urinary sodium excretion but did not alter blood pressure, glomerular filtration rate, or renal blood flow. Although urinary prostaglandin E
2
excretion also tended to decrease, this change was slower and of lesser magnitude than those of kinin and kininogenase excretion and did not attain statistical significance after Bonferroni’s correction. In controls injected with either vehicle or Fab fragments of monoclonal antibodies to ricin (a vegetable protein not present in mammals), none of these parameters decreased significantly. We conclude that renal kinins participate in the short-term regulation of water and sodium excretion in normotensive unanesthetized rats, acting as diuretic and natriuretic hormones. Kinins acting on the distal nephron, either directly or via release of nitric oxide and/or prostaglandins, are likely responsible.
Angiotensin Peptides in Spontaneously Hypertensive and Normotensive Donryu Rats
Authors: Campbell Duncan J. , Duncan Ann-Maree , Kladis Athena , Harrap Stephen B.
Published: June 2012

Abstract
The renin-angiotensin system has been implicated in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). Given that SHR may have normal or suppressed plasma levels of renin and angiotensin peptides, we examined whether the tissue levels of angiotensin peptides are elevated in these rats. We measured angiotensin-(1-7) [Ang-(1-7)], Ang II, and Ang I in plasma, kidney, adrenal, heart, aorta, brown adipose tissue, lung, and brain of male SHR and normotensive Donryu rats at 6, 10, and 20 weeks of age. SHR had higher blood pressures and ratios of heart weight to body weight at all ages. Plasma renin levels of SHR were 13% to 32% of the levels of Donryu rats. Although plasma angiotensin-converting enzyme activity was lower in SHR than in Donryu rats, lung was the only SHR tissue with a reduced Ang II–Ang I ratio. Ang II levels in SHR adrenal were 24% to 42% of the levels of Donryu adrenal, and for SHR plasma, aorta, brown adipose tissue, and lung, Ang II levels were 38% to 93% of the levels of Donryu rats. For kidney and heart, Ang II levels were similar in SHR and Donryu rats at 6 weeks of age although suppressed in SHR at 10 and 20 weeks. Moreover, brain Ang II levels were higher in SHR than Donryu rats at 6 weeks of age and similar at 10 and 20 weeks of age. Our finding that all SHR tissues, except for brain at 6 weeks of age, showed Ang II levels similar to or less than the levels of Donryu rats indicates that, apart from a possible role for brain of young rats, the hypertension of SHR is not due to increased Ang II levels.
Endothelin: Potential Role in Hypertension and Vascular Hypertrophy
Authors: Schiffrin E. L.
Published: June 2012

Abstract
The endothelins are a family of 21–amino acid peptides that are powerful vasoconstrictors. They may also induce vascular hypertrophy. These peptides may participate through these two mechanisms in the pathogenesis of the elevation of blood pressure and/or in the maintenance of hypertension in both experimental animal models and human essential hypertension. This review presents evidence both in favor and against the involvement of endothelins in hypertension. Plasma levels of endothelin-1 are either normal or slightly elevated in experimental and human essential hypertension. Responses of blood vessels to endothelin-1 may be normal or depressed in many models of experimental hypertension and also in essential hypertension in humans. It has recently been demonstrated that endothelin content and mRNA are increased in blood vessels of deoxycorticosterone acetate–salt hypertensive rats. When endothelin receptor antagonists are administered chronically, elevation of blood pressure and development of vascular hypertrophy are blunted in this experimental model of hypertension. In contrast, spontaneously hypertensive rats do not exhibit any increase in either endothelin-1 mRNA or immunoreactive endothelin in blood vessels and fail to respond with lowering of blood pressure to long-term treatment with endothelin receptor antagonists. Blood pressure development in young spontaneously hypertensive rats is also unaffected by long-term administration of endothelin antagonists. Molecular genetic studies appear to support a genetic role of components of the endothelin system in Dahl salt-sensitive rats. In human essential hypertension, there is some evidence of activation of the endothelin system despite depressed responses of small arteries to endothelin-1 and normal circulating levels of endothelin-1 in plasma. Thus, a role of endothelins in high blood pressure is possible. Further research is necessary to establish in a more definitive way whether endothelins are involved in the pathophysiology of human essential hypertension.
Association Between the Natriuretic Action of Angiotensin-(1-7) and Selective Stimulation of Renal Prostaglandin I
2
Release
Authors: Hilchey Sean D. , Bell-Quilley Caroline P.
Published: June 2012

Abstract
We previously reported that angiotensin-(1-7) [Ang-(1-7)], a heptapeptide derived from the metabolism of either Ang I or Ang II, was biologically active in the rat isolated kidney, producing a marked diuresis and natriuresis that could be dissociated from the modest increase in glomerular filtration rate. The natriuretic response was accompanied by an increase in sodium concentration and concomitant decrease in urinary potassium concentration. Ang-(1-7) has also been shown to stimulate arachidonic acid release from isolated proximal tubules and elicit prostaglandin release from a number of tissues. Therefore, in the present study we tested the hypothesis that prostaglandins participate in the renal actions of Ang-(1-7). Rat isolated kidneys were perfused at 37°C with gassed (95% O
2
/5% CO
2
) Krebs-Henseleit buffer containing oncotic agents and amino acids for six 10-minute clearance periods at a constant pressure of 90 mm Hg. Ang-(1-7) was infused at a rate that achieved a final concentration of 3 pmol/mL in the presence and absence of 10 μmol/L indomethacin. Prostaglandin E
2
(PGE
2
) and PGI
2
released into ureteral and venous effluents were measured by enzyme-linked immunoassay. During Ang-(1-7) infusion there was a selective increase in 6-keto-PGF
1α
, an index of PGI
2
, appearing in both urine and perfusate; PGE
2
levels were unchanged. Inhibition of stimulated 6-keto-PGF
1α
release with indomethacin halved the fourfold increase in urine flow and sevenfold increase in sodium excretion rate without altering the increase in urinary sodium concentration produced by Ang-(1-7). In contrast, the increased potassium excretion rate was unchanged, despite the reduction in urine flow, as indomethacin abolished the fall in urinary potassium concentration caused by Ang-(1-7) infusion alone. Thus, Ang-(1-7) is a specific stimulus for renal PGI
2
versus PGE
2
release. This effect may mediate Ang-(1-7)–induced natriuresis and diuresis and fall in urinary potassium concentration but does not appear to be involved in the doubling of urinary sodium concentration. It is possible that these observations have relevance to the link between prostaglandins and converting enzyme inhibitors in view of earlier reports that these antihypertensive agents substantially increase Ang-(1-7).
Sympathectomy and Cardiovascular Spectral Components in Conscious Normotensive Rats
Authors: Daffonchio Anna , Franzelli Cristina , Radaelli Alberto , Castiglioni Paolo , Di Rienzo Marco , Mancia Giuseppe , Ferrari Alberto U.
Published: June 2012

Abstract
We examined the extent to which sympathetic influences are reflected by spectral powers of blood pressure and pulse interval in specific frequency bands in spontaneously behaving Wistar-Kyoto rats subjected to continuous intra-arterial blood pressure recording. The rats were pretreated with 6-hydroxydopamine (150 mg/kg twice in 1 week, n=19) to produce chemical sympathectomy or received vehicle (n=15). In the sympathectomized group, additional monitoring sessions were performed with rats under α-adrenergic receptor blockade with phenoxybenzamine (n=8), β-receptor blockade with propranolol (n=7), or cholinergic receptor blockade with atropine (n=8). Blood pressure signals were analyzed by a computer to calculate spectral powers (fast Fourier transform) in the low-frequency (0.025 to 0.1 Hz), mid-frequency (0.1 to 0.6 Hz), and high-frequency (0.8 to 3.0 Hz) bands. In sympathectomized rats, low-frequency power of blood pressure was 70% greater than in intact rats, whereas mid-frequency power was 60% smaller (
P
<.05 for both) and high-frequency power was unchanged. High-frequency power of pulse interval was also unchanged in sympathectomized rats, whereas low- and mid-frequency powers were reduced by approximately 50% (
P
<.05). No further alterations in spectral powers were observed by adding α- or β-adrenergic blockade to sympathectomy, whereas adding cholinergic blockade caused a striking reduction in all pulse interval powers. Thus, mid-frequency blood pressure power depends on sympathetic but also to a substantial extent on nonsympathetic influences. Sympathetic influences do not contribute to low-frequency blood pressure power, having instead a restraining effect. The low- and mid-frequency pulse interval powers depend on both sympathetic and vagal influences. Thus, no blood pressure or pulse interval power in the mid- and low-frequency ranges can be regarded as a specific marker of sympathetic activity.
Albuminuria in Association With Insulin and Sodium-Lithium Countertransport in Young African Americans With Borderline Hypertension
Authors: Falkner Bonita , Kushner Harvey , Levison Sandra , Canessa Mitzy
Published: June 2012

Abstract
The purpose of this study was to determine whether early nephropathy, evidenced by urinary albumin excretion, can be detected in young African American subjects with only borderline hypertension, and whether there is a relationship of albuminuria with insulin resistance and with sodium-lithium countertransport activity. Clinically well young African American men and women including normotensive (blood pressure <135/85 mm Hg, n=41) and borderline hypertensive (blood pressure ≥135/85 mm Hg, n=26) individuals were studied. Each subject underwent an oral glucose tolerance test and euglycemic hyperinsulinemic clamp study. Albuminuria was measured on timed urine collections. Sodium-lithium countertransport activity was assayed in fresh red blood cells at 280 mmol/L Na
+
for full saturation of external Na
+
sites. The sum of insulin levels during glucose tolerance was significantly greater in the borderline hypertensive compared with the normotensive subjects (
P
=.014), and insulin-stimulated glucose utilization during the clamp was significantly lower in borderline hypertensive compared with normotensive subjects (
P
=.016). Albuminuria was greater in borderline hypertensive compared with normotensive subjects (
P
=.002). Albuminuria was significantly correlated with fasting plasma insulin concentration (
r
=.44,
P
<.002) and the sum of insulins during the glucose tolerance test (
r
=.45,
P
<.002). Sodium-lithium countertransport correlated with albuminuria (
r
=.31,
P
<.05) as well as significantly with insulin-stimulated glucose utilization during the clamp (
r
=.44,
P
<.001). These data indicate that young African Americans with only borderline hypertension have greater albuminuria than normotensive subjects and suggest that albuminuria is linked with insulin resistance and alterations of sodium-lithium countertransport that may increase the risk for nephropathy.
A Randomized, Placebo-Controlled, Double-Blind, Parallel Study of Various Doses of Losartan Potassium Compared With Enalapril Maleate in Patients With Essential Hypertension
Authors: Gradman Alan H. , Arcuri Karen E. , Goldberg Allan I. , Ikeda Leila S. , Nelson Edward B. , Snavely Duane B. , Sweet Charles S.
Published: June 2012

Abstract
The efficacy and safety of various doses of losartan potassium, a specific and selective angiotensin II receptor antagonist, were compared with those of placebo and enalapril maleate 20 mg in patients with mild to moderate essential hypertension in a randomized, double-blind, parallel study. We randomly allocated 576 patients at the end of a 4-week placebo baseline period to 8 weeks of once-daily double-blind treatment with losartan potassium 10, 25, 50, 100, or 150 mg, enalapril maleate 20 mg, or placebo. After 8 weeks of treatment, mean reductions from baseline in supine systolic/diastolic pressure 24 hours after dosing (trough) for losartan potassium 10, 25, 50, 100, and 150 mg, enalapril maleate 20 mg, and placebo were 7.6/7.9, 7.8/6.8, 13.0/10.1, 8.9/9.9, 10.5/9.7, 14.7/11.2, and 3.8/5.6 mm Hg, respectively. Compared with mean changes in supine diastolic pressure in the placebo group, losartan potassium 50 to 150 mg and enalapril maleate 20 mg produced clinically important and statistically significant reductions (
P
≤.01) in blood pressure. At 24 hours after dosing, the blood pressure changes obtained with losartan potassium 50 mg were essentially identical to those obtained with enalapril maleate 20 mg. While there was a dose-related effect with losartan potassium from 10 to 50 mg at peak (6 hours after dosing), doses of 10 and 25 mg were not consistently different from placebo 24 hours after dosing. To assess the once-daily effect of losartan potassium, trough-to-peak ratios of the mean changes in supine diastolic pressure after 8 weeks of treatment were calculated. These placebo-adjusted ratios (losartan potassium 10 mg, 78%; 25 mg, 23%; 50 mg, 60%; 100 mg, 72%; 150 mg, 49%) indicated that losartan potassium had sustained antihypertensive effects at 24 hours that were not the result of large peak effects; consequently, once-daily dosing is appropriate. In terms of safety and tolerability, there were no dose-related trends for losartan potassium with respect to the percentage of patients with any adverse experiences, serious adverse experiences, or drug-related adverse experiences or patients who withdrew because of an adverse experience. Headache was a common adverse experience for almost all the treatment groups. Dry cough was reported as an adverse experience in 8% of the enalapril maleate–treated patients compared with 3% in both the placebo- and losartan potassium 50 mg–treated groups.