bluuebunny/crossref_metadata_2025 huggingface dataset:
Placental Insufficiency Leads to Development of Hypertension in Growth-Restricted Offspring
Authors: Alexander Barbara T.
Published: March 2003

Low birth weight is a suggested risk factor for the development of hypertension. The purpose of the present study was to determine whether a model of intrauterine growth restriction produced in response to placental insufficiency in the pregnant rat was associated with marked elevations in blood pressure. Reduced uterine perfusion initiated in late gestation resulted in low-birth-weight offspring (5.8±0.1 versus 6.6±0.2 g,
P
<0.05, growth-restricted versus control, respectively). Mean arterial pressure, as measured in conscious, chronically instrumented rats, was significantly elevated as early as 4 weeks of age (113±3 versus 98±2 mm Hg,
P
<0.05) and was associated with significant decreases in body weight (66±2 versus 81±3 g,
P
<0.05) in growth-restricted (n=15) versus control (n=15) rats. Marked elevations in arterial pressure at 8 weeks of age (male: 133±3 versus 121±6 mm Hg,
P
<0.05; female: 137±4 versus 112±6 mm Hg,
P
<0.01) were associated with sex-specific decreases in body weight (male: 251±6 versus 275±10 g,
P
<0.05; female: 163±6 versus 180±6 g) in male growth-restricted (n=12) versus male control (n=9) rats and in female growth-restricted (n=8) versus female control (n=7) rats. At 12 weeks of age, hypertensive (144±4 versus 131±3 mm Hg,
P
<0.05) male growth-restricted offspring (n=10) had no alterations in glomerular filtration rate (2.3±0.3 versus 2.2±0.2 mL/min) compared with control (n=10) offspring; even when adjusted for kidney weight (1.7±0.3 versus 1.5±0.3 mL · min
−1
· g
−1
kidney), despite marked decreases in body weight (305±9 versus 343±10 g,
P
<0.05). These data suggest that placental insufficiency induced by reduced uterine perfusion in the pregnant rat results in low-birth-weight offspring predisposed to development of hypertension.
DASH Diet Lowers Blood Pressure and Lipid-Induced Oxidative Stress in Obesity
Authors: Lopes Heno F. , Martin Kelley L. , Nashar Khaled , Morrow Jason D. , Goodfriend Theodore L. , Egan Brent M.
Published: March 2003

Evidence suggests that obesity may raise blood pressure (BP) through oxidative stress–sensitive mechanisms and that the Dietary Approaches to Stop Hypertension combination diet (DASH-CD) may decrease BP by enhancing antioxidant capacity. To address this question, 12 obese patients with high-normal–to–stage 1 hypertension (hypertensives) and 12 lean normotensives were studied on their usual diets and after following the DASH-CD and a low-antioxidant diet in random sequence for 4 weeks each. Acute oxidative stress was induced by a 4-hour infusion of intralipid and heparin. Ferric-reducing activity of plasma (FRAP) and plasma F
2
-isoprostanes were measured as biomarkers of antioxidant capacity and oxidative stress, respectively. BP was lower in obese hypertensives on the DASH-CD than on the usual and low-antioxidant diets (−8.1±1.5/−7.4±1.6 mm Hg,
P
<0.05). BP did not change significantly in lean normotensives after 4 weeks on the DASH-CD but tended to rise on the low-antioxidant diet. FRAP on usual diets was higher in lean subjects than in obese subjects. FRAP increased in obese but not lean volunteers on the DASH-CD compared with usual diet, and the group difference disappeared. F
2
-isoprostanes increased from baseline during intralipid and heparin in both groups on the low-antioxidant diet but not in obese hypertensives on the DASH-CD. Among free-living obese hypertensives, the DASH-CD raises antioxidant capacity, lowers BP, and reduces oxidative stress induced by acute hyperlipidemia. The findings are consistent with evidence that elevated BP in obese subjects may reflect an imbalance between antioxidant capacity and oxidative stress that is improved by the DASH-CD.
Rapid Child Growth Raises Blood Pressure in Adolescent Boys Who Were Thin at Birth
Authors: Adair Linda S. , Cole Tim J.
Published: March 2003

Catch-up growth in previously growth-restricted children is a suggested risk factor for chronic disease risk. We use data from 2026 Filipino adolescents to identify periods of growth that matter more for risk of high blood pressure (BP). Subjects were drawn from the Cebu Longitudinal Health and Nutrition Survey, which enrolled pregnant women and followed up their offspring through age14 to 16 years. High BP was defined as the top 10% of residuals from gender-specific regressions of systolic and diastolic BP on age and height. After controlling for birth length, current body mass index, age, and height, the odds of high BP in males were significantly decreased with each kilogram increase in birth weight. The highest odds of elevated BP occurred among males who were relatively thin at birth but relatively heavy as adolescents. Larger weight increments from birth to 2 years decreased the odds of high BP in boys, whereas larger increments from 8 to 11 and 11 to 16 years increased the odds of high BP. Thinness at birth significantly interacted with growth rate after age 8, such that a high rate of weight gain increased risk only among boys who were in the lower two thirds of the body mass index distribution at birth. Results in girls indicated small or no effects of early growth. The synergistic effect on adolescent BP of rapid weight gain from late childhood into adolescence with thinness at birth is further evidence of fetal programming of BP in males and suggests long-term health risks associated with rapid growth, even in the absence of obesity.
ERK1/2-Dependent Contractile Protein Expression in Vascular Smooth Muscle Cells
Authors: Schauwienold Dag , Plum Claudia , Helbing Thomas , Voigt Philipp , Bobbert Thomas , Hoffmann Dorett , Paul Martin , Reusch Hans Peter
Published: March 2003

In vivo, vascular smooth muscle (VSM) cells change their contractile phenotype toward a more proliferative phenotype during the pathogenesis of vascular diseases. Because these dedifferentiated VSM cells may gradually regain contractile functions, we aimed to identify signaling pathways that result in an increased expression of contractile proteins in VSM cells. In vitro, serum and thrombin induced a reversible upregulation of smooth muscle myosin heavy-chain (SM-MHC) in cultured neonatal rat VSM cells. Cotransfection of a SM-MHC–promoter chloramphenicol acetyltransferase–construct with dominant-negative N17Ras or N17Raf or treatment with the mitogen-activated/ERK-activating kinase (MEK) inhibitor PD 98059 concentration dependently decreased the serum- or thrombin-induced SM-MHC promoter activity. Consistently, the serum- or thrombin-induced phosphorylation of MEK and extracellular signal-regulated kinase 1/2 (ERK1/2) coincided with a MEK-dependent nuclear accumulation of phosphorylated ERK1/2 and subsequent nuclear phosphorylation of the transcription factors c-myc and Elk-1. A 5′-deletion analysis of
cis
-elements within the SM-MHC promoter demonstrated that a conserved region (nucleotide −1346 to −1102) was required for both cell type–specific expression and serum- or thrombin-induced upregulation of the SM-MHC promoter in VSM cells. Within this region, 2 CArG-boxes, a GC-rich element, and a CTF/NF-1 site are critical positively acting
cis
-elements for the serum- or thrombin-induced upregulation of SM-MHC. We conclude that the serum- or thrombin-induced differentiation requires an intact Ras/Raf/MEK/ERK signaling cascade, nuclear translocation of activated ERK1/2, phosphorylation of transcription factors, and several
cis
-elements within the SM-MHC promoter.
Downregulation of Basal iNOS at the Rostral Ventrolateral Medulla Is Innate in SHR
Authors: Chan Julie Y.H. , Wang Ling-Lin , Chao Yung-Mei , Chan Samuel H.H.
Published: March 2003

We demonstrated recently that a significant reduction in both the molecular synthesis and functional expression of inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic vasomotor outflow, underlies the augmented sympathetic vasomotor tone during hypertension. This study further evaluated the hypothesis that this downregulation of basal iNOS at the RVLM during hypertension is innate. In adult spontaneously hypertensive rats (SHR) treated for 4 weeks with the antihypertensive captopril to normalize elevated blood pressure or in young prehypertensive SHR, the significantly lower iNOS mRNA and protein levels at the ventrolateral medulla under basal conditions or on activation by microinjection bilaterally into the RVLM of lipopolysaccharide (10 ng) remained unaltered. The retarded efficacy of lipopolysaccharide (10 ng) to elicit cardiovascular depression (hypotension, bradycardia, and reduction in sympathetic vasomotor tone) also persevered in captopril-treated adult or young normotensive SHR. On the other hand, compared with Wistar-Kyoto normotensive rats, the magnitude of cardiovascular depression induced in adult SHR by local administration into the RVLM of the NO precursor
l
-arginine (40 nmol) was significantly smaller. In addition, microinjection bilaterally into the RVLM of a selective iNOS inhibitor, aminoguanidine (125 or 250 pmol), was discernibly less efficacious in unmasking hypertension, tachycardia, and the increase in sympathetic vasomotor tone in adult SHR. We conclude that a predisposed reduction in molecular synthesis and functional expression of basal iNOS in the RVLM is associated with the sympathetic vasomotor overactivity during hypertension.
Vasopeptidase Inhibition
Authors: Campbell Duncan John
Published: March 2003

The enormous benefits of inhibition of ACE demonstrate that manipulation of the metabolism of peptide hormones is a valuable therapeutic strategy for cardiovascular disease. Recent attempts to expand these benefits have combined ACE inhibition with inhibition of other peptidases such as neutral endopeptidase (NEP) in a single molecule, a strategy known as vasopeptidase inhibition. NEP metabolizes natriuretic peptides, and NEP inhibition offers the prospect of combining the benefits of increased natriuretic peptide levels with those of ACE inhibition. However, peptidases such as ACE and NEP have many different substrates, and there are complex interactions between ACE inhibition and NEP inhibition. Both ACE and NEP metabolize the kinin peptides bradykinin and kallidin, and NEP also converts angiotensin (Ang) I to Ang-(1-7) and metabolizes Ang II and endothelin. Addition of NEP inhibition to ACE inhibition potentiates the ACE inhibitor–induced increase in kinin levels, increases Ang II levels, reduces Ang-(1-7) levels, and may increase endothelin levels. These additional consequences of combined ACE/NEP inhibition increase the risk of angioedema and may counteract any benefit of ACE inhibition that depends on reduced Ang II levels and increased Ang-(1-7) levels. Further considerations are that the ratio of ACE and NEP inhibition is fixed for vasopeptidase inhibitors, and there is uncertainty how these drugs should be compared with ACE inhibitors. Vasopeptidase inhibitors will therefore require careful evaluation before they are introduced to patient care.
Tissue Kallikrein Actions at the Rabbit Natural or Recombinant Kinin B
2
Receptors
Authors: Houle Steeve , Molinaro Giuseppe , Adam Albert , Marceau François
Published: March 2003

We have examined whether exogenous human tissue kallikrein exerts pharmacological actions via the bradykinin B
2
receptor; specifically, whether the protease can bind to, cleave, internalize, and/or activate a fusion protein composed of the rabbit B
2
receptor conjugated to the green fluorescent protein (B
2
R-GFP). The enzyme partially digested the fusion protein at 1 μmol/L, but not 100 nmol/L, and promoted B
2
R-GFP endocytosis in HEK 293 cells (≥50 nmol/L). Trypsin and endoproteinase Lys-C, but not plasma kallikrein, also cleaved B
2
R-GFP. Phospholipase A
2
was activated by 50 nmol/L tissue kallikrein in HEK 293 cells expressing B
2
R-GFP, and this was mediated by the receptor, as shown by the effect of a B
2
receptor antagonist and by the lack of response in untransfected cells. However, 500 nmol/L kallikrein elicited a strong receptor-independent activation of phospholipase A
2
. Tissue kallikrein competed for [
3
H]bradykinin binding to B
2
R-GFP only at 1 μmol/L. A simulation involving kallikrein treatment of HEK 293 cells, pretreated or not with human plasma, evidenced the formation of immunoreactive bradykinin. The enzyme (50 nmol/L) contracted the rabbit isolated jugular vein via its endogenous B
2
receptors, but the effect was tachyphylactic, and there was no cross-desensitization with bradykinin effects. Aprotinin prevented all pharmacological responses to tissue kallikrein, indicating that the enzyme activity is required for its effect. The local generation of kinins is a plausible mechanism for the pharmacological effects of lower concentrations of tissue kallikrein (50 to 100 nmol/L); higher levels (0.5 to 1 μmol/L) can not only initiate the degradation of rabbit B
2
receptors but also exert nonreceptor-mediated effects.
Myocardial Uptake and Biochemical and Hemodynamic Effects of ACE Inhibitors in Humans
Authors: Zeitz Christopher J. , Campbell Duncan J. , Horowitz John D.
Published: March 2003

There is little information on the processes affecting selective tissue ACE inhibition and the implications in human subjects. We compared intravenously administered ACE inhibitors, perindoprilat and enalaprilat, for myocardial drug uptake and effects on angiotensin and bradykinin peptides versus hemodynamic effects in 25 patients with stable angina and well-preserved left ventricular systolic function. Myocardial uptake was rapid and more efficient for perindoprilat than for enalaprilat (peak content at 26±3 and 30±4 seconds, 0.58±0.12% and 0.27±0.07% of the administered dose for perindoprilat and enalaprilat, respectively,
P
=0.04 for difference). Both drugs caused a decrease in angiotensin (Ang) II level, an increase in Ang I level, and reduction in Ang II/Ang I ratio in arterial and coronary sinus blood. Bradykinin (BK)-(1-9) and BK-(1-8) levels increased in arterial blood and BK-(1-8) levels increased in coronary sinus blood after drug administration. Perindoprilat and enalaprilat caused a small decrease in mean arterial pressure (−3±1%,
P
<0.05; and −4±1%,
P
<0.01, respectively) and LV+dP/dt (−5.8±1.7%,
P
<0.01 and −4.2±2.8%,
P
<0.05, respectively), whereas systemic vascular resistance index was unchanged. Despite relatively cardioselective uptake of perindoprilat, both drugs had similar effects on the cardiac metabolism of angiotensin and bradykinin and on cardiac function. Under resting conditions, both drugs exerted small negative inotropic effects.
Contrasting Regression of Blood Pressure and Cardiovascular Structure in Declipped Renovascular Hypertensive Rats
Authors: Kvist Stinne , Mulvany Michael J.
Published: March 2003

We investigated the time relationship between changes in blood pressure and changes in the structure of the resistance vasculature. Blood pressure, heart/body weight ratio, and morphology and function of mesenteric resistance arteries from 1-kidney, 1-clip renovascular hypertensive rats were followed before and after declipping at age 14 weeks. The rats were divided into 5 groups, which were investigated 6 hours, 24 hours, 1 week, 4 weeks, and 8 weeks after declipping and compared with 2 normotensive and 2 renovascular hypertensive control groups at 14 weeks and 18 weeks. Systolic blood pressure was elevated 2 weeks after application of the clip and stabilized after 6 weeks. Declipping induced a prompt fall in blood pressure within 6 hours, and blood pressure was normalized within 1 week. Heart/body weight ratio was increased in renovascular hypertensive rats, and declipping induced a gradual decrease in the ratio, which was normalized within 4 weeks. Media/lumen ratio and media area of mesenteric resistance arteries were increased in renovascular hypertensive rats, and declipping did not affect media/lumen ratio and media area within 8 weeks, although there was a tendency for some regression of media/lumen ratio. There were no differences in response to high potassium, noradrenaline, or acetylcholine. Thus, these findings show definitively that declipping causes rapid reversal of renovascular hypertension in rats accompanied by gradual reduction of the heart/body weight ratio but lack of normalization in the mesenteric resistance vessels. This provides clear evidence that neither vascular nor cardiac structural changes are capable of keeping rats hypertensive.
Echogenic Carotid Plaques Are Associated With Aortic Arterial Stiffness in Subjects With Subclinical Carotid Atherosclerosis
Authors: Zureik Mahmoud , Bureau Jeanne-Marie , Temmar Mohammed , Adamopoulos Chris , Courbon Dominique , Bean Kathryn , Touboul Pierre-Jean , Benetos Athanase , Ducimetière Pierre
Published: March 2003

A better understanding of the interrelationships between the structure and function of the large arteries would lead to optimize cardiovascular disease prevention strategies. In this study, we investigated the relationships of aortic arterial stiffness assessed by carotid-femoral pulse-wave velocity (PWV), with carotid plaque echogenicity assessed by B-mode ultrasound. We analyzed 561 subjects (without coronary heart disease or stroke) who were volunteers for free health examinations (age, 58.3±10.8 years; 32.6% women). Extracranial carotid plaque echogenicity was graded from 1 (plaque appearing black or almost black) to 4 (plaque appearing white or almost white) according to the Gray-Weale classification. Plaques of grades 1 and 2 were defined as echolucent plaques, and plaques of grades 3 and 4 were defined as echogenic plaques. Fifty-one subjects (9.1%) had echolucent carotid plaques, 109 (19.4%) had echogenic plaques, and 401 (71.5%) had no plaques. Subjects with echogenic plaques had higher PWV mean (12.9±2.8 m/s) compared with those without plaques (11.1±2.3 m/s,
P
<0.001) and compared with those with echolucent plaques (11.3±2.3 m/s,
P
<0.01). The PWV means in subjects without plaques and those with echolucent plaques were similar and not statistically different (
P
=0.55). When multivariate adjustment for major known cardiovascular risk factors was performed, these results were not markedly modified. Similar patterns of results were also observed in many subgroups according to age, gender, and hypertensive status. This study provides the first evidence that echogenic but not echolucent carotid plaques are associated with aortic arterial stiffness. This association applies to individuals with normal blood pressure and those with elevated blood pressure. Assessment of the joint and interaction effects of plaque morphology and arterial stiffness on the occurrence of cardiovascular events would permit a better identification of high-risk subjects.
ST Segment Depression Criteria and the Prevalence of Silent Cardiac Ischemia in Hypertensives
Authors: Boon Diederik , van Goudoever Jeroen , Piek Jan J. , van Montfrans Gert A.
Published: March 2003

The reported prevalence of silent cardiac ischemia as assessed by ambulatory electrocardiographic recording varies widely. The influence of the stringency of the analysis criteria has never been reported. We performed 24-hour, 12-lead ambulatory electrocardiographic recording in patients with hypertension but without proven coronary artery disease. The recordings were analyzed according to strict ST segment depression criteria adapted from the American College of Cardiology/American Heart Association guidelines and according to basic ST segment depression criteria adapted from studies with only concise descriptions of ambulatory electrocardiographic recording analysis. Also, we performed 24-hour ambulatory blood pressure monitoring. More than 4400 hours of ambulatory electrocardiographic recording and ambulatory blood pressure monitoring in 194 patients with hypertension were analyzed. Medication was withdrawn in 45% of the patients. The average systolic blood pressure during the day was 152±13 (mean±SD); diastolic blood pressure was 94±17 mm Hg. According to the basic ST segment depression criteria, we found a prevalence of silent ischemia of 11.3%, and with the strict criteria the prevalence was 5.2%. The patients who were considered positive according to the basic criteria but not according to the strict criteria (false-positive) in the majority of cases (58%) had depression of an elevated baseline ST segment. We found a lower prevalence of silent cardiac ischemia as assessed by ambulatory electrocardiographic recording than generally reported. The stringency of applied analysis criteria appear to play an important role in this outcome.
Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy
Authors: Roberts James M. , Pearson Gail , Cutler Jeff , Lindheimer Marshall
Published: March 2003

A Working Group on Research in Hypertension in Pregnancy was recently convened by the National Heart, Lung, and Blood Institute to determine the state of knowledge in this area and suggest appropriate directions for research. Hypertensive disorders in pregnancy, especially preeclampsia, are a leading cause of maternal death worldwide and even in developed countries increase perinatal mortality rates 5-fold. Much has been learned about preeclampsia, but gaps in the knowledge necessary to direct therapeutic strategies remain. Oxidative stress is a biologically plausible contributor to the disorder that may be amenable to intervention. Hypertension that antedates pregnancy (chronic hypertension) bears many similarities to hypertension in nonpregnant women, but the special setting of pregnancy demands information to guide evidence-based therapy. The recommendations of the Working Group are to attempt a clinical trial of antioxidant therapy to prevent preeclampsia that is be complemented by mechanistic research to increase understanding of the genetics and pathogenesis of the disorder. For chronic hypertension, clinical trials are recommended to direct choice of drugs, evaluate degree of control, and assess implications to the mother and fetus. Recommendations to increase participation in this research are also presented.
Blood Lead Level Is Associated With Elevated Blood Pressure in Blacks
Authors: Vupputuri Suma , He Jiang , Muntner Paul , Bazzano Lydia A. , Whelton Paul K. , Batuman Vecihi
Published: March 2003

Chronic lead exposure has been associated with elevated blood pressure in epidemiological studies. It is not known whether the previously observed relation between blood lead and hypertension persists after significant reductions have been made in environmental lead contamination. We examined the relation between blood lead levels and blood pressure in a representative sample of 14 952 whites and blacks aged 18 years or older who participated in the Third National Health and Nutrition Examination Survey. Blood lead was measured by atomic absorption spectrophotometry and blood pressure by standard sphygmomanometry. Mean blood lead levels were significantly higher for black men and women (5.4 and 3.4 μg/dL, respectively) compared with white men and women (4.4 and 3.0 μg/dL, respectively). After multivariate adjustment for important covariables, each standard deviation higher blood lead (3.3 μg/dL) was associated with a 0.82 (95% confidence interval [CI], 0.19 to 1.44) mm Hg and a 1.55 (95% CI, 0.47 to 2.64) mm Hg higher systolic blood pressure among black men and women, respectively. In contrast, blood lead level was not associated with blood pressure among white men or women. The multivariate-adjusted odds ratio (95% CI) of hypertension associated with a 1-SD higher level of blood lead was 1.08 (95% CI, 0.99 to 1.19) for black men and 1.39 (95% CI, 1.21 to 1.61) for black women. These findings suggest that increased levels of blood lead remain an important environmental risk factor for elevated blood pressure in blacks.
Association of Coronary Artery Disease With Glucocorticoid Receptor N363S Variant
Authors: Lin Ruby C.Y. , Wang Xing Li , Morris Brian J.
Published: March 2003

Overweight is associated with the N363S variant in the glucocorticoid receptor (encoded by nuclear receptor subfamily 3, group C, member 1 gene:
NR3C1
). The present study examined whether the N363S polymorphism might also be associated with coronary artery disease (CAD). This involved 556 patients with CAD, of which 437 were analyzed, and 302 control subjects, all being of Anglo-Celtic descent residing in Sydney. An extensive range of phenotypic parameters was collected from the patients, and leukocyte DNA from all subjects was genotyped by polymerase chain reaction–restriction fragment length polymorphism analysis for the A1218G (N363S) variant. Frequency of the
S363
allele was 0.04 in healthy normal-weight control subjects but was 0.15 in patients with CAD (
P
=2.0×10
−5
) and was also elevated in subjects with CAD who were not overweight (0.14) (
P
=2.6×10
−5
), supporting a primary association with CAD. Frequency of
S363
allele carriers in subjects with CAD who had angina was particularly high: unstable angina (0.45), stable angina (0.29), and no angina (0.26) (
P
for trend=0.016). Elevated cholesterol (
P
=0.027), triglycerides (
P
=0.005), and total cholesterol/HDL ratio (
P
=0.011), after Bonferroni, tracked with the
S363
allele, consistent with accentuation of mechanisms that predispose to atheroma formation in coronary vessels. The data suggest a role for glucocorticoid receptor variation in the underlying cause of CAD.
Regional Sympathetic Effects of Low-Dose Clonidine in Heart Failure
Authors: Aggarwal Anuradha , Esler Murray D. , Morris Margaret J. , Lambert Gavin , Kaye David M.
Published: March 2003

This study examined the effects of low doses of intravenous clonidine on regional and global sympathetic nervous system activity in heart failure. In heart failure, adrenoceptor-blocking treatments have a limited sphere of activity. Centrally acting sympatholytic therapies should be further investigated, with a specific emphasis on targeting cardiac and renal sympathetic overactivity. In 10 patients with moderate-severe congestive heart failure, we examined the effect of intravenous clonidine on systemic, cardiac, and renal sympathetic activity and on brain monoamine turnover using the norepinephrine spillover method. In addition, we assessed the effect of clonidine on cardiac release of the sympathetic cotransmitter neuropeptide Y. A dose of 1 μg/kg of clonidine resulted in a fall in cardiac (326±73 to 160±40 pmol/min,
P
<0.001), renal (2.5±0.6 to 1.5±0.3 nmol/min,
P
=0.01), and global norepinephrine spillover (4.0±0.6 to 3.1±0.5 nmol/min,
P
<0.01), with a significantly disproportionate reduction in cardiac versus total-body sympathetic activity (
P
<0.05). No significant changes in cardiac neuropeptide Y release or in central monoamine turnover were demonstrated. Clonidine, at modest doses, significantly attenuates cardiac and renal sympathetic tone in heart failure. In addition to the beneficial effects of antiadrenergic therapy in the heart, the renal sympatholytic effect may counter the salt and water retention that is a hallmark of the condition.
Self-Perpetuating Effects of Birth Size on Blood Pressure Levels in Elderly People
Authors: Ylihärsilä Hilkka , Eriksson Johan G. , Forsén Tom , Kajantie Eero , Osmond Clive , Barker David J.P.
Published: March 2003

It has been suggested that essential hypertension is determined by 2 separate mechanisms: a growth-promoting process in childhood and a self-perpetuating mechanism in adult life. We report a clinical study of 500 people taken from a cohort of 7086 men and women who were born in Helsinki from 1924 to 1933, and whose body size at birth was recorded. As expected, blood pressure levels were inversely related to birthweight and birth length. These associations, however, were confined to the 213 people who had previously been diagnosed as having hypertension. In them, a 1-kg increase in birthweight was associated with a 6.4-mm Hg (95% confidence interval, 1.0 to 11.9) decrease in systolic blood pressure recorded at the clinic, and with a 9.3-mm Hg (95% confidence interval, 2.1 to 16.5) decrease recorded by ambulatory measurement. We conclude that pathological processes initiated in utero become self-perpetuating in adult life and lead to hypertension. Among elderly people with established hypertension, these processes have a strong effect on blood pressure levels, because they are processes that do not respond well to treatment.
Roles of Intercellular Adhesion Molecule-1 in Hypertensive Cardiac Remodeling
Authors: Kuwahara Fumitaka , Kai Hisashi , Tokuda Keisuke , Niiyama Hiroshi , Tahara Nobuhiro , Kusaba Ken , Takemiya Kiyoko , Jalalidin Ali , Koga Mitsuhisa , Nagata Tsuyoshi , Shibata Rei , Imaizumi Tsutomu
Published: March 2003

Recently, we have shown that in rats with a suprarenal abdominal aortic constriction (AC), pressure overload induces early perivascular fibro-inflammatory changes (transforming growth factor [TGF]-β induction and fibroblast proliferation) within the first week after AC and then causes the development of cardiac remodeling (myocyte hypertrophy and reactive myocardial fibrosis) associated with diastolic dysfunction. Intercellular adhesion molecule (ICAM)-1 is implicated in the recruitment of leukocytes, especially macrophages, in various inflammatory situations. Thus, we sought to investigate the causal relation of ICAM-1 to macrophage recruitment and cardiac remodeling in AC rats. In AC rats, immunoreactive ICAM-1 was observed transiently on endothelial cells of the intramyocardial coronary arterioles after day 1, with a peak at day 3, returning to baseline by day 7. Also, ED1
+
macrophage accumulation was found in the area adjacent to the arteries expressing ICAM-1. Chronic treatment with an anti–ICAM-1 neutralizing antibody, but not with control IgG, remarkably reduced the accumulations of macrophages and proliferative fibroblasts and inhibited the upregulation of TGF-β expression. Furthermore, the neutralizing antibody significantly prevented myocardial fibrosis without affecting arterial pressure and left ventricular and myocyte hypertrophy. In conclusion, ICAM-1 expression was induced by pressure overload in the intramyocardial arterioles, and triggered perivascular macrophage accumulation. In pressure-overloaded hearts, a crucial role in ICAM-1–mediated macrophage accumulation was suggested in the development of myocardial fibrosis, through TGF-β induction and fibroblast activation.
Downregulation of Vascular Angiotensin II Type 1 Receptor by Thyroid Hormone
Authors: Fukuyama Kae , Ichiki Toshihiro , Takeda Kotaro , Tokunou Tomotake , Iino Naoko , Masuda Satoko , Ishibashi Minako , Egashira Kensuke , Shimokawa Hiroaki , Hirano Katsuya , Kanaide Hideo , Takeshita Akira
Published: March 2003

Thyroid hormone has a broad effect on cardiovascular system. 3,3′,5-triiodo-
l
-thyronine (T3), a biologically active form of thyroid hormone, increases cardiac contractility. T3 causes arterial relaxation and reduction of systemic vascular resistance, resulting in an increase in cardiac output. However, the molecular mechanisms of vascular relaxation by T3 are incompletely characterized. We studied the effect of T3 on the angiotensin (Ang) II type 1 receptor (AT
1
R) expression in vascular smooth muscle cells. T3 dose-dependently decreased expression levels of AT
1
R mRNA, with a peak at 6 hours of stimulation. Binding assay using [
125
I]Sar
1
-Ile
8
-Ang II revealed that AT
1
R number was decreased by stimulation with T3 without changing the affinity to Ang II. T3 reduced calcium response of vascular smooth muscle cells to Ang II by 26%. AT
1
R promoter activity measured by luciferase assay was reduced by 50% after 9 hours of T3 administration. mRNA stability was also decreased by T3. Real-time quantitative reverse transcription–polymerase chain reaction and Western blot analysis revealed that AT
1
R mRNA and protein were downregulated in the aorta of T3-treated rats. These results suggest that T3 downregulates AT
1
R expression both at transcriptional and posttranscriptional levels, and attenuates biological function of Ang II. Our results suggest that downregulation of AT
1
R gene expression may play an important role for T3-induced vascular relaxation.
Association Between Periodontal Disease and Left Ventricle Mass in Essential Hypertension
Authors: Angeli Fabio , Verdecchia Paolo , Pellegrino Concetta , Pellegrino Rosaria Giulia , Pellegrino Giacinto , Prosciutti Lucio , Giannoni Claudia , Cianetti Stefano , Bentivoglio Maurizio
Published: March 2003

Chronic periodontitis has been associated with an increased risk for cardiovascular disease. Left ventricular mass is an established independent predictor of cardiovascular disease. In the present cross-sectional study, we tested the association between periodontitis and left ventricular mass in subjects with essential hypertension. One hundred four untreated subjects with essential hypertension underwent clinical examinations, including echocardiographic study, laboratory tests, and assessment of periodontal status according to the community periodontal index of treatment needs (CPITN). With increasing severity of periodontitis, there was a progressive increase in left ventricle mass. Mean values (g/height
2.7
) were 39.0 (±2.7) in CPITN 0 (periodontal health), 40.2 (±6.4) in CPITN 1 (gingival bleeding), 42.7 (±6.8) in CPITN 2 (calculus), 51.4 (±11.7) in CPITN 3 (pockets 4 to 5 mm), and 76.7 (±11.3) in CPITN 4 (pockets ≥6 mm) (overall F 51.2;
P
<0.0001). Body surface area (
P
=0.04), systolic (
P
<0.0001) and diastolic (
P
<0.01) blood pressure, and left ventricular mass (
P
<0.0001) were determinants of a composite of CPITN 3 and 4. In a multivariate logistic analysis, left ventricular mass was the sole determinant (
P
<0.0001) of CPITN stages 3 and 4. Our findings suggest a direct association between severity of periodontitis and left ventricular mass in subjects with essential hypertension. Periodontal evaluation might contribute to refine cardiovascular risk assessment in hypertensive subjects.
Role of Angiotensin II in the Neural Control of Renal Function
Authors: Le Fevre Marie E. , Guild Sarah-Jane , Ramchandra Rohit , Barrett Carolyn J. , Malpas Simon C.
Published: March 2003

The aim of the present study was to distinguish between the direct effects of the renal nerves on renal function and indirect effects via neurally mediated increased systemic angiotensin II. We applied low-level electrical stimulation (1 Hz) to the left renal nerves in pentobarbitone-anesthetized rabbits for 180 minutes and measured renal blood flow, sodium excretion, and urine flow rate from both the stimulated and the nonstimulated contralateral kidney in the presence and the absence of ACE inhibition (enalaprilat). Stimulation resulted in an angiotensin II–mediated rise in arterial pressure and decreases in renal blood flow, urine flow rate, and sodium excretion on the stimulated side. On the nonstimulated denervated side, we found no change in renal blood flow, but found a decrease in urine flow rate. With ACE inhibition, renal stimulation no longer caused an increase in arterial pressure, the antidiuretic responses of the stimulated kidney were attenuated, and, importantly, the decrease in urine flow rate on the nonstimulated kidney was completely abolished. We therefore propose that although a direct effect of the renal nerves on sodium excretion is clearly present, the antidiuresis and antinatriuresis observed during renal activation is further supported by a neurally mediated increase in systemic angiotensin II.
β-Adrenergic Activation Initiates Chamber Dilatation in Concentric Hypertrophy
Authors: Badenhorst Danelle , Veliotes Demetri , Maseko Muzi , Tsotetsi Oupa J. , Brooksbank Richard , Naidoo Alvin , Woodiwiss Angela J. , Norton Gavin R.
Published: March 2003

It is uncertain whether chronic β-adrenoreceptor (β-AR)–activation in hypertension could initiate the progression from compensated left ventricular (LV) hypertrophy to pump dysfunction. It is also uncertain if this effect is through adverse LV remodeling (chamber dilatation with wall thinning and pump dysfunction) or intrinsic myocardial contractile dysfunction. We evaluated the effect of 5 months of isoprenaline (0.02 mg · kg
−1
· d
−1
) on hemodynamics, LV wall thickness, cavity size, and interstitial characteristics in spontaneously hypertensive rats (SHR) with compensated LV hypertrophy. In the absence of myocyte necrosis, changes in volume preload, pressure afterload, and heart rate or decreases in baseline systolic myocardial elastance (load independent measure of intrinsic myocardial contractility), ISO produced a right shift in LV diastolic pressure–volume (P-V) relations (chamber dilatation), a decrease in LV wall thickness despite a further increase in LV weight in SHR, LV pump dysfunction (right shift in LV systolic P-V relations), and deleterious interstitial remodeling (increments in total and noncrosslinked myocardial collagen concentrations). The isoprenaline-induced LV geometric, chamber performance, and interstitial changes were similar to alterations noted during decompensation in older SHR. In summary, in the absence of tissue necrosis and baseline intrinsic myocardial contractile dysfunction, chronic β-AR activation induces interstitial and chamber remodeling and, hence, pump dysfunction. These data suggest that chronic sympathetic activation initiates the progression from compensated concentric LV hypertrophy in hypertension to cardiac dysfunction primarily through deleterious cardiac remodeling rather than intrinsic myocardial contractile dysfunction.
Enhancement of Intrarenal Angiotensinogen in Dahl Salt-Sensitive Rats on High Salt Diet
Authors: Kobori Hiroyuki , Nishiyama Akira , Abe Youichi , Navar L. Gabriel
Published: March 2003

This study was performed to examine whether there is an inappropriate regulation of intrarenal angiotensinogen in Dahl-salt sensitive rats (DS) fed a high salt diet (HS). Dahl salt-resistant rats (DR) and DS were maintained on HS (8% NaCl) or low salt diet (LS, 0.3% NaCl) for 4 weeks. Systolic blood pressure (SBP), measured by tail-cuff plethysmography, was unaltered in DR (DR+HS, 127±3 mm Hg, n=5; DR+LS, 126±3, n=5); however, SBP was significantly increased in DS+HS (208±7, n=9) compared with DS+LS (134±2, n=5). HS suppressed plasma renin activity in both strains (0.7±0.2 ng of angiotensin I/mL per hour in DS+HS, 3.1±0.5 in DS+LS, 0.8±0.2 in DR+HS, 5.1±0.7 in DR+LS). Plasma angiotensinogen levels, measured by Western blot analysis, were also suppressed by HS in both strains (36 919±2170 integrated densitometric unit in DS+HS, 53 028±2752 in DS+LS, 44 722±1721 in DR+HS, 55782±3785 in DR+LS). However, kidney angiotensinogen levels were significantly increased in DS+HS (75 850±4171, integrated densitometric unit) compared with DS+LS (47 232±3470), DR+HS (44 748±8236), and DR+LS (42 504±4052). Urinary excretion of angiotensinogen, measured by radioimmunoassay of angiotensin I after incubation with excess renin, had a similar profile. Urinary excretion of angiotensinogen was significantly increased in DS+HS (2958±531 pmol/d) compared with DS+LS (56±4), DR+HS (31±12), and DR+LS (21±7). These data indicate that intrarenal angiotensinogen is enhanced in DS+HS, which is reflected by the increased urinary excretion of angiotensinogen. The results suggest that DS on HS have an inappropriate augmentation of intrarenal angiotensinogen, which may contribute to impaired sodium excretion during a high salt diet and the development of hypertension in this strain.
Na/H Exchange Isoform 1 Is Involved in Mineralocorticoid/Salt-Induced Cardiac Injury
Authors: Fujisawa Genro , Okada Koji , Muto Shigeaki , Fujita Nobuya , Itabashi Naoki , Kusano Eiji , Ishibashi Shun
Published: March 2003

Long-term exposure of uninephrectomized rats to desoxycorticosterone acetate (DOCA)/salt induces cardiac fibrosis and hypertrophy through mineralocorticoid receptors (MRs). However, the underlying cellular mechanisms remain unclear. To determine whether Na/H exchange isoform 1 (NHE1) is involved in the cellular mechanisms, we examined the effects of a specific NHE1 inhibitor, cariporide, and an MR antagonist, spironolactone, on DOCA/salt-induced cardiac fibrosis and hypertrophy. Uninephrectomized rats were given 20 mg of DOCA (single subcutaneous injection) plus 0.9% NaCl/0.3% KCl to drink and were killed at 8 days. Two groups of rats given DOCA/salt were treated with either spironolactone (50 mg/kg per day SC) or cariporide (30 mg/kg per day PO) for 8 days. Control rats were treated with only high salt after the operation. The DOCA/salt-induced perivascular collagen deposition was completely abolished by cariporide and spironolactone. DOCA/salt-induced interstitial collagen deposition was partially and completely suppressed by spironolactone and cariporide, respectively. The rats exposed to DOCA/salt had cardiocyte hypertrophy in the subendocardial and subepicardial regions, a finding that was completely inhibited by cariporide but not by spironolactone. In rats given DOCA/salt, NHE1 protein expression was markedly increased. This was partially and completely reversed by spironolactone and cariporide, respectively. We concluded that cardiac NHE1 contributes to DOCA/salt-induced cardiac fibrosis and hypertrophy and that the NHE1 inhibitor cariporide completely prevents the detrimental effects of DOCA/salt on the heart. We also demonstrated that DOCA/salt-induced cardiac injury through the MRs partly occurs through NHE1 activation.
Family History of Hypertension and Type 2 Diabetes in Relation to Preeclampsia Risk
Authors: Qiu Chunfang , Williams Michelle A. , Leisenring Wendy M. , Sorensen Tanya K. , Frederick Ihunnaya O. , Dempsey Jennifer C. , Luthy David A.
Published: March 2003

In a case-control study of 190 preeclamptic patients and 373 control subjects, we assessed maternal family history of chronic hypertension and type 2 diabetes in relation to preeclampsia risk. Participants provided information on first-degree family history of the 2 conditions and other covariates during postpartum interviews. Logistic regression was used to estimate odds ratios and 95% confidence intervals adjusted for confounding by age, race, and obesity. Compared with women with no parental history of hypertension, women with maternal only (odds ratio=1.9), paternal only (odds ratio=1.8), or both maternal and paternal history of hypertension (odds ratio=2.6) had a statistically significant increased risk of preeclampsia. The odds ratio for women with at least one hypertensive parent and a hypertensive sibling was 4.7 (95% confidence interval, 1.9 to 11.6). Both maternal only (odds ratio=2.1; 95% confidence interval, 0.9 to 4.6) and paternal only (odds ratio=1.9; 95% confidence interval, 1.0 to 3.2) history of diabetes was associated with an increased risk of preeclampsia. Women with a diabetic sibling had a 4.7-fold increased risk of preeclampsia (95% confidence interval, 1.1 to 19.8). For women with at least one hypertensive parent and at least one diabetic parent, relative to those with parents with neither diagnosis, the odds ratio for preeclampsia was 3.2 (95% confidence interval, 1.6 to 6.2). Our results are consistent with the thesis that family history of hypertension and diabetes reflects genetic and behavioral factors whereby women may be predisposed to an increased preeclampsia risk.
Low-Density Lipoprotein Subfractions and Cardiovascular Risk in Hypertension
Authors: Felmeden Dirk C. , Spencer Charles G.C. , Blann Andrew D. , Beevers D. Gareth , Lip Gregory Y.H.
Published: March 2003

Although hypertensive patients are at particular risk of vascular complications, the possible contribution of an atherogenic lipoprotein profile and endothelial dysfunction to this risk is unclear. We investigated this by measuring LDL subfractions and flow-mediated dilation (FMD) (reflecting endothelial dysfunction) in a cohort of high-risk hypertensive patients. We studied 84 hypertensive patients (74 men; mean age, 64 years; SD 8). Chylomicron-free LDL subfractions were analyzed by disc polyacrylamide gel electrophoresis, producing an LDL score, with higher scores being equivalent to a greater proportion of the more atherogenic LDL subfractions. High-resolution ultrasound was used to assess endothelium-dependent brachial artery FMD after reactive hyperemia after vessel occlusion. Baseline levels were compared with 61 age- and gender-matched healthy normotensive control subjects. Mean LDL score was higher and FMD impaired in hypertensive subjects compared with control subjects. These indexes were significantly improved after 6 months of cardiovascular risk factor management. LDL score correlated significantly with the 10-year Framingham coronary heart disease risk score, with a negative correlation with FMD (both
P
<0.001). Abnormal atherogenesis and endothelial dysfunction are both present in hypertension and appear to be related to each other, potentially leading to vascular complications. The abnormal LDL scores also correlate with the 10-year cardiovascular risk and can be positively influenced by cardiovascular risk management.
α
2A
-Adrenergic Receptors Mediate Sympathoinhibitory Responses to Atrial Natriuretic Peptide in the Mouse Anterior Hypothalamic Nucleus
Authors: Peng Ning , Chambless Brandon D. , Oparil Suzanne , Wyss J. Michael
Published: March 2003

In the rat, activation of α
2
-adrenergic receptors in the anterior hypothalamic nucleus inhibits sympathetic nervous system activity. Furthermore, local release of atrial natriuretic peptide inhibits norepinephrine release in this nucleus, blocking local activation of α
2
-adrenergic receptors, and thereby contributes to NaCl-sensitive hypertension in spontaneously hypertensive rats. To further test the specificity of this mechanism, either α
2
-adrenergic receptor agonists or atrial natriuretic peptide was microinjected into anterior hypothalamic nucleus of conscious C57BL/6 mice in which the α
2
-adrenergic receptor was functionally deleted by a single point mutation (n=10 per group). In control mice, microinjection of either clonidine or guanabenz (10
−3
to 10
−7
mol/L) caused a rapid fall in mean arterial pressure that lasted for several minutes. In the knockout mice there was no response to the injection of either dose of either agonist. Microinjection of atrial natriuretic peptide (10
−6
to 10
−7
mol/L) caused a rapid increase in mean arterial pressure (8.2±1.3 and 6.55±1.2 mm Hg, respectively) in the control mice that was similar to the responses previously observed in Wistar-Kyoto rats. In contrast, the microinjections did not significantly alter mean arterial pressure in the knockout mice. These experiments demonstrate that in the anterior hypothalamic nucleus of the mouse (and probably in the rat) α
2A
-adrenergic receptors mediate both sympathoinhibitory responses to α
2
-adrenergic receptor agonists and the action of atrial natriuretic peptide.