bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral Arteriolar Structure in Mice Overexpressing Human Renin and Angiotensinogen
Authors: Baumbach Gary L. , Sigmund Curt D. , Faraci Frank M.
Published: January 2003

We examined the hypothesis that the renin-angiotensin system plays an important role in vascular remodeling (defined as reduced external diameter) during chronic hypertension. We measured pressure, diameter, and cross-sectional area of the vessel wall in maximally dilated cerebral arterioles in transgenic mice that overexpress both human renin and human angiotensinogen and in spontaneously hypertensive mice, a model of chronic hypertension that is thought to develop independently of the renin-angiotensin system. Systemic arterial pressure under conscious conditions was increased by similar amounts in transgenically hypertensive mice (153±6 versus 117±4 mm Hg in controls; mean±SE,
P
<0.05) and spontaneously hypertensive mice (148±5 versus 112±5 mm Hg;
P
<0.05). The external diameter of maximally dilated cerebral arterioles was reduced in transgenically hypertensive mice (52±2 versus 66±3 μm;
P
<0.05), but not in spontaneously hypertensive mice (58±4 versus 60±4 μm;
P
>0.05). The cross-sectional area of the vessel wall was increased in both transgenically hypertensive mice (504±53 versus 379±37 μm
2
;
P
<0.05) and spontaneously hypertensive mice (488±40 versus 328±38 μm
2
;
P
<0.05). During maximal dilatation, the stress-strain curves in cerebral arterioles of transgenically hypertensive mice and spontaneously hypertensive mice were shifted to the right of the curves in corresponding controls, an indication that arteriolar distensibility was increased in the transgenically and spontaneously hypertensive groups. Thus, cerebral arterioles undergo remodeling and hypertrophy in transgenically hypertensive mice, but only hypertrophy in spontaneously hypertensive mice. These findings support the hypothesis that the renin-angiotensin system is an important determinant of vascular remodeling during chronic hypertension.
G Protein β3 Gene Variant, Vascular Function, and Insulin Sensitivity in Type 2 Diabetes
Authors: Fernández-Real José Manuel , Peñarroja Georgina , Richart Cristóbal , Castro Antoni , Vendrell Joan , Broch Montserrat , López-Bermejo Abel , Ricart Wifredo
Published: January 2003

A common polymorphism (825 C/T) in exon 10 of the
GNB3
gene, that encodes for the β-3 subunit, has been associated with different degrees of activation of heterotrimeric guanine nucleotide binding proteins (G proteins). Many hormones and neurotransmitters use specific receptors that interact noncovalently with G proteins in the transmembrane signaling process. Among them, insulin uses an inhibitory G protein–sensitive mechanism that is involved in metabolic and vascular events, leading to enhanced glucose transport and vasodilation. We hypothesized differences in peripheral and vascular insulin sensitivity according to
GNB3
gene polymorphism in type 2 diabetic patients. To address this issue, we used an intervention-optimization protocol to examine whether diabetic patients with the variant show a different response in terms of insulin-sensitivity. Interindividual differences in baseline insulin sensitivity and vascular dysfunction (vasodilatory response to glyceryl trinitrate) were not attributable to this polymorphism of the
GNB3
gene. However, in contrast to normal homozygotes, insulin sensitivity (S
I
) significantly improved (
P
=0.01) in carriers of the 825T variant. Parallel to these findings, stimulated C-peptide tended to decrease, and the response to glyceryl trinitrate significantly improved (
P
=0.004) among 825T carriers. Body mass index, systolic and diastolic blood pressure, heart rate, or serum lipid levels did not significantly change in either group. Our findings suggest an effect of
GNB3
gene polymorphism on important phenotypic variations in type 2 diabetes mellitus. The
GNB3
gene polymorphism might be an example of pharmacogenetics, with the underlying etiological genetic defect altering the response to treatment.
Maternal and Paternal Influences on Left Ventricular Mass of Offspring
Authors: Kuznetsova Tatiana , Staessen Jan A. , Olszanecka Agnieszka , Ryabikov Andrew , Stolarz Katarzyna , Malyutina Sofia , Fagard Robert , Kawecka-Jaszcz Kalina , Nikitin Yuri
Published: January 2003

Significant intrafamilial correlations of left ventricular mass exist in first-degree relatives. However, the specific maternal and paternal influences on left ventricular mass of offspring remain unknown. We therefore evaluated familial aggregation of left ventricular mass by type of familial relation in two European populations. A random sample of 159 nuclear families (250 parents and 321 offspring) was investigated in Cracow, Poland, and Novosibirsk, Russia. The mean age of parents and offspring was 51.4 years and 25.1 years, respectively. Two-dimensionally guided M-mode echocardiography was performed, and left ventricular mass was calculated. As a measure of concordance, we computed correlation coefficients for left ventricular mass between first-degree relatives and between spouse pairs. After adjustment for center, gender, age, height, body weight, systolic blood pressure, antihypertensive treatment, smoking, alcohol intake, and physical activity, the intrafamilial correlations for left ventricular mass were 0.06 (
P
=0.57) in 91 spouse-spouse pairs, 0.14 (
P
=0.002) in 500 parent-offspring pairs, and 0.32 (
P
<0.001) in 179 sib-sib pairs. Across the four parent-offspring relations, the intrafamilial correlations of left ventricular mass differed. The mother-son (
n
=140,
r
=0.27,
P
<0.001) and mother-daughter (
n
=161,
r
=0.28,
P
<0.001) correlations were significant, whereas the father-son (
n
=101,
r
=0.04,
P
=0.69) and father-daughter (
n
=98,
r
=−0.09,
P
=0.38) correlations were not different from zero. Overall, the mother-offspring correlation coefficient was significantly higher than the father-offspring correlation (
r
=0.28 versus
r
=−0.04;
P
=0.005). Thus, maternal factors appear to have more impact on left ventricular mass of offspring than do paternal influences. Further studies are required to elucidate the genetic, epigenetic, and ecogenetic mechanisms underlying these divergent parent-offspring correlations.
TA Repeat Variation,
Npr1
Expression, and Blood Pressure
Authors: Tremblay Johanne , Hum David H.F. , Sanchez Rocio , Dumas Pierre , Pravenec Michal , Křenova Drahomira , Křen Vladimir , Kuneš Jaroslav , Pausova Zdenka , Gossard Francis , Hamet Pavel
Published: January 2003

The activity of the atrial natriuretic peptide receptor (
Npr1
) is altered in spontaneously hypertensive rats (SHR) in relation to its mRNA levels, suggesting abnormal transcriptional control in hypertension. A single-stranded conformational polymorphism caused by a repetitive dinucleotide segment of 10 TA in BN-
Lx
and of 40 TA in SHR was localized at position −943 relative to the transcription start site of the
Npr1
gene, downstream of a putative cGMP-regulatory region, and was the only sequence difference noted between the two strains. Transient transfections of −1520 to −920
Npr1
promoter-SV40-luciferase fusion vector showed that the construct from BN-
Lx
stimulated the SV40 promoter, whereas that from SHR slightly inhibited it. In contrast to the BN-
Lx
construct, the activity of the SHR fragment was refractory to downregulation by atrial natriuretic peptide. Genotype-phenotype correlation studies in recombinant inbred strains (RIS) derived from BN-
Lx
and SHR crosses revealed significant correlations of the TA repeat with basal guanylyl cyclase activity and
Npr1
mRNA levels. The correlations were heightened by a locus on chromosome 10 containing the
Ace
gene. The highest basal guanylyl cyclase activity and
Npr1
mRNA values were found in RIS with both genes (
Npr1
/
Ace
) of BN genotypes, whereas the lowest were recorded in RIS, with the SHR genotypes at both loci. This was inversely correlated with diastolic blood pressure in these strains. In conclusion, the longer TA repeat unit in the promoter of
Npr1
of SHR, in tandem with a putative cGMP responsive element, regulates the transcription of the
Npr1
gene with consequences on diastolic blood pressure.
Tissue-Specific Response to Interstitial Angiotensin II in Humans
Authors: Boschmann Michael , Jordan Jens , Adams Frauke , Christensen Niels-Juel , Tank Jens , Franke Gabriele , Stoffels Mandy , Sharma Arya M. , Luft Friedrich C. , Klaus Susanne
Published: January 2003

Angiotensin II is synthesized locally in various tissues; however, the role of interstitial angiotensin II in the regulation of regional metabolism and tissue perfusion is not clear. We characterized the effect of interstially applied angiotensin II in skeletal muscle and subcutaneous adipose tissue of young, normal-weight, healthy subjects by using the microdialysis technique. Furthermore, we tested the hypothesis that the effect of interstitial angiotensin II is modulated by nitric oxide. Tissues were perfused with 0.01, 0.1, and 1 μmol/L angiotensin II in the presence of the
l
- or
d
-isomer of
N
G
-nitro-arginine-methyl ester (L- or D-NAME), the effective and noneffective isomer, respectively, for blocking nitric oxide synthase. Dialysate ethanol, glycerol, glucose, lactate, and pyruvate concentrations were measured to assess changes in blood flow (ethanol dilution technique), lipolysis, and glycolysis, respectively. Baseline blood flow and dialysate concentrations of the metabolites were similar with L- and D-NAME in both tissues. Blood flow and dialysate glucose and lactate did not change significantly in both tissues during perfusion with angiotensin II. Dialysate glycerol dose-dependently increased in adipose tissue (
P
<0.0438) but decreased in muscle (
P
<0.007). In muscle, dialysate pyruvate increased (
P
<0.0002), whereas lactate/pyruvate ratio decreased (
P
<0.001), both dose-dependently. All effects were similar with L- and D-NAME and could be reversed by nitroprusside. We conclude that in contrast to the profound hemodynamic effect of intravascular angiotensin II, interstitial angiotensin II has a minimal acute effect on blood flow in both tissues. However, interstitial angiotensin II modulates lipid and carbohydrate metabolism in a tissue specific fashion. Thus, the physiology of interstitial angiotensin II cannot be predicted from intravascular studies.
Association of Endothelin-1 Gene Variant With Hypertension
Authors: Jin Jing Ji , Nakura Jun , Wu Zhihong , Yamamoto Miyuki , Abe Michiko , Tabara Yasuharu , Yamamoto Yoshikuni , Igase Michiya , Kohara Katsuhiko , Miki Tetsuro
Published: January 2003

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced by endothelial and smooth muscle cells. Many lines of biological evidence suggest that the ET-1 gene is a candidate gene for hypertension. Moreover, recent association studies suggested that a G/T polymorphism with an amino acid substitution (Lys/Asn) at codon 198 in exon 5 of the ET-1 gene interacts with body mass index (BMI) in association with blood pressure. They suggested that T carriers are more sensitive to weight gain than GG homozygotes in association with blood pressure. However, association studies are often irreproducible, and the first study often suggests a stronger genetic effect than is found by subsequent studies. We therefore assessed the interaction in 2 large Japanese populations. The present study showed a nonsignificant but similar trend to the results of previous reports. Moreover, in line with previous reports, this study revealed a significant interaction between the ET-1 K198N (G/T) polymorphism and BMI in association with hypertension in our populations (
P
=0.027). The interaction was significant, even after adjustment for gender and age (
P
=0.045) and for all confounding factors (
P
=0.044). T carriers were more sensitive to weight gain than GG homozygotes in association with hypertension. Considering the combined impact of obesity and hypertension on the development of cardiovascular and cerebrovascular disorders, T allele carriers might represent elective targets for therapy to lower their body weight.
Effectiveness of Aldosterone Blockade in Patients With Diabetic Nephropathy
Authors: Sato Atsuhisa , Hayashi Koichi , Naruse Mitsuhide , Saruta Takao
Published: January 2003

It has been reported that continuous ACE inhibitor therapy does not necessarily produce a maintained decrease in plasma aldosterone levels, which may remain high or increase eventually during long-term use (aldosterone escape). We have examined the role of aldosterone escape in 45 patients with type 2 diabetes and early nephropathy treated with an ACE inhibitor for 40 weeks. With treatment, there was a 40% reduction in average urinary albumin excretion, although urinary albumin excretion in patients with aldosterone escape (18 patients) was significantly higher than that in patients without escape (27 patients). In the 18 patients with escape, spironolactone (25 mg/d) was added to ACE inhibitor treatment in 13. After a 24-week study period, urinary albumin excretion and left ventricular mass index were significantly reduced without blood pressure change. In conclusion, the present study demonstrates that aldosterone escape is observed in 40% of patients with type 2 diabetes with early nephropathy despite the use of ACE inhibitors. Our study suggests the possibility that aldosterone blockade may represent optimal therapy for patients with early diabetic nephropathy who show aldosterone escape during ACE inhibitor treatment and who no longer show maximal antiproteinuric effects of ACE inhibition. Additional, larger, prospectively randomized, double-blind studies will be needed before adaptation of this strategy.
Angiotensinogen Gene Haplotype and Hypertension
Authors: Tsai Chia-Ti , Fallin Daniele , Chiang Fu-Tien , Hwang Juey-Jen , Lai Ling-Ping , Hsu Kuan-Lih , Tseng Chuen-Den , Liau Chiau-Suong , Tseng Yung-Zu
Published: January 2003

There are many reports demonstrating the association of renin-angiotensin system gene polymorphisms with hypertension in different populations. In the present study, we used haplotype analyses of the angiotensinogen gene with a new permutation-based hypothesis testing method to determine the association between multilocus angiotensinogen gene polymorphisms and hypertension in a relatively homogeneous Taiwanese population. We also genotyped angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin II type 1–receptor gene A1166C polymorphism to detect epistatic gene-gene interactions. There were 408 patients with hypertension (hypertensives) and 286 controls. The angiotensinogen gene haplotype frequencies were significantly different between hypertensives and controls, and this finding was only present in subjects with angiotensin-converting enzyme gene II genotypes when the analysis was stratified by genotype of this polymorphism. In addition, the angiotensinogen gene haplotype structure of hypertensives was more heterogeneous than that of controls. Our results showed that angiotensinogen gene haplotypes were associated with hypertension and might act synergistically with I allele of the angiotensin-converting enzyme gene.
Echocardiographic Wall Motion Abnormalities in Hypertensive Patients With Electrocardiographic Left Ventricular Hypertrophy
Authors: Palmieri Vittorio , Okin Peter M. , Bella Jonathan N. , Gerdts Eva , Wachtell Kristian , Gardin Julius , Papademetriou Vasilios , Nieminen Markku S. , Dahlöf Björn , Devereux Richard B.
Published: January 2003

There is limited information on correlates of left ventricular wall motion (WM) abnormalities in ambulatory patients with hypertension and ECG left ventricular hypertrophy by Cornell voltage-duration product and/or Sokolow-Lyon voltage criteria. Therefore, we assessed the prevalence and the correlates of echocardiographic global and segmental left ventricular WM abnormalities in 942 hypertensive patients with hypertrophy enrolled in the Losartan Intervention For End-point reduction in hypertension (LIFE) echo substudy. Patients were separated into groups of those with normal WM or those with segmental or global WM abnormalities. Segmental and global WM abnormalities were mostly of mild degree and were detected in 7% and 6% of the study sample. Compared with subjects with normal motion, those with WM abnormalities were mostly men and had higher prevalences of self-reported coronary heart disease, ECG signs of myocardial infarction, ST-strain pattern, and higher Cornell voltage-duration product, echo-left ventricular mass, and albuminuria, but lower total and high-density lipoprotein cholesterol. Blood pressure was similar among groups. No significant differences were found between patients with global or segmental WM abnormalities. Only half of patients with WM abnormalities had a history or ECG signs of coronary heart disease. Independent correlates of WM abnormalities were higher albuminuria and Cornell voltage-duration product, male gender, and echo-left ventricular hypertrophy, but lower cholesterol. In a subanalysis restricted to patients with WM abnormalities, those with evident cardiovascular disease had a higher prevalence of ST-strain pattern than those with subclinical WM abnormalities, but other clinical, ECG, or echocardiographic parameters were indistinguishable between the 2 groups. Thus, in hypertensives with ECG left ventricular hypertrophy, WM abnormalities, mostly of mild degree, occurred in one eighth of the patients and were associated with male gender, left ventricular hypertrophy, and albuminuria. No significant differences were found between patients with global or segmental wall motion abnormalities.
Does Brain Natriuretic Peptide Have a Direct Renal Effect in Human Hypertensives?
Authors: van der Zander Kim , Houben Alphons J.H.M. , Kroon Abraham A. , Wierema Thomas K.A. , Fuss-Lejeune Monique J.M.J. , Koster Derk , de Leeuw Peter W.
Published: January 2003

Systemic infusion of brain natriuretic peptide (BNP) stimulates natriuresis and diuresis but has variable effects on the renal vasculature. In this study, we investigated whether BNP has any direct effects on the kidney in hypertensive patients. Three stepwise increasing doses of BNP (60, 120, and 180 pmol/min) or placebo were infused into the renal artery of 26 hypertensive patients. Renal blood flow was determined with the
133
Xenon washout technique. Before and after infusion of BNP, arterial and venous blood samples were taken for cGMP, renin, and creatinine concentration. Intra-arterial blood pressure and heart rate were monitored continuously. Intrarenal BNP infusion did not induce significant changes in renal blood flow despite increases in circulating levels of cGMP. The latter, however, was not associated with changes in the cGMP gradient across the kidney. In addition, we did not find any BNP-related changes in the secretion of active renin and in creatinine extraction. At the highest dose, heart rate increased after BNP infusion without a change in mean intra-arterial blood pressure. In conclusion, this study suggests that at least in hypertensive subjects, BNP has no direct intrarenal hemodynamic effects and that the rise in circulating cGMP without changes in net renal extraction of this second messenger is related to a primary extrarenal target of BNP.
Hepatocyte Growth Factor and Left Ventricular Geometry in End-Stage Renal Disease
Authors: Malatino Lorenzo S. , Cataliotti Alessandro , Benedetto Francesco A. , Stancanelli Benedetta , Bellanuova Ignazio , Belluardo Paola , Bonaiuto Lorena , Tripepi Giovanni , Mallamaci Francesca , Castellino Pietro , Zoccali Carmine
Published: January 2003

Hepatocyte growth factor is a pleiotropic cytokine with cardioprotective properties. Its serum concentration is markedly raised in end-stage renal disease. This study assessed the relation of hepatocyte growth factor (HGF) with left ventricular mass and geometry in end-stage renal disease. Serum HGF measurements and echocardiographic studies were performed in 185 patients receiving hemodialysis. Patients with serum HGF above the median (1.85 ng/mL) had more frequent cardiovascular complications. This cytokine was directly related to mean left ventricular wall thickness (
r
=0.23,
P
=0.002) and relative wall thickness (
r
=0.25,
P
=0.0001); a multivariate analysis showed that this relation was independent of other risk factors. Accordingly, the prevalence of left ventricular concentric geometry (either concentric left ventricular hypertrophy or remodeling) was much higher (n=49, 53%) among patients with HGF values above the median that in those with values ≤1.85 ng/mL (n=31, 34%). Furthermore, the risk for left ventricular concentric geometry was higher in patients with HGF values above the median (odds ratio, 2.57; 95% CI, 1.33 to 4.98;
P
=0.005), and multiple logistic regression analysis confirmed that this association was independent of other risk factors. In patients receiving hemodialysis, elevated serum HGF is associated with concentric left ventricular geometry. This is consistent with reports that link this cytokine to arterial remodeling and survival in patients with end-stage renal disease and suggests that it is part of a counterregulatory response aimed at attenuating cardiovascular damage in this high-risk population.
Heme Oxygenase Inhibitor Restores Arteriolar Nitric Oxide Function in Dahl Rats
Authors: Johnson Fruzsina K. , Durante William , Peyton Kelly J. , Johnson Robert A.
Published: January 2003

Vascular tissues express heme oxygenase (HO), which metabolizes heme to form carbon monoxide (CO). CO relaxes vascular smooth muscle but inhibits nitric oxide (NO) formation. Decreased NO synthesis may contribute to salt-induced hypertension in Dahl salt-sensitive (DS) rats. The current study examines the hypothesis that elevated levels of endogenous CO contribute to NO dysfunction in salt-induced hypertensive DS rats. Male DS rats were placed on high-salt (8% NaCl, HS) or low-salt (0.3% NaCl, LS) diets for 4 weeks. With respect to the LS group, the HS group’s blood pressure and carboxyhemoglobin levels were elevated, and abdominal aortas showed 6-fold higher HO-1 protein levels. Experiments used isolated pressurized first-order gracilis muscle arterioles superfused with oxygenated modified Krebs buffer. An inhibitor of NO synthase,
N
ω-nitro-
l
-arginine methyl ester (L-NAME), caused concentration-dependent vasoconstriction in both groups, with attenuated responses in HS arterioles. HS arterioles also showed attenuated vasodilatory responses to an endothelium-dependent vasodilator, acetylcholine. Acute pretreatment with an inhibitor of HO, chromium mesoporphyrin, enhanced vascular responses to L-NAME and acetylcholine in both groups but abolished the differences between HS and LS arterioles. These data show that HO-1 protein levels and CO production are increased in HS rats. Arteriolar responses to L-NAME and acetylcholine are impaired in HS rats compared with LS animals, and this difference can be abolished by an inhibitor of endogenous CO production. These results suggest that elevated levels of endogenous CO contribute to arteriolar NO dysfunction in DS rats with salt-induced hypertension.
Effect of Smoking on Arterial Stiffness and Pulse Pressure Amplification
Authors: Mahmud Azra , Feely John
Published: January 2003

The brachial artery pressure waveform is abnormal in smokers, but the effect of smoking on the aortic pressure waveform in both smokers and nonsmokers, particularly in the younger population, is unknown. We compared the acute and chronic effects of smoking on large-artery properties in 185 healthy young smokers and nonsmokers (mean±SD, 22±5 years). We matched 41 chronic smokers for age, height, weight, and gender with 116 nonsmokers. The augmentation index, a measure of arterial wave reflection in the aorta, was measured by applanation tonometry (Sphygmocor). We also compared augmentation index, aortic pulse wave velocity (Complior), and blood pressure in 28 subjects (11 chronic smokers) before and for 15 minutes after smoking 1 cigarette (nicotine content, 1.2 mg). Although brachial blood pressure was not different, the aortic systolic blood pressure (101±8 versus 97±9 mm Hg) and augmentation index (0.7±13 versus −5.7±14) were higher (
P
<0.01) in chronic smokers than in nonsmokers, whereas aortic-brachial pulse pressure amplification was reduced (13.7±8 versus 17.7±5 mm Hg,
P
<0.01). These effects were seen in both male and female subjects. Acutely in both groups, smoking significantly increased (
P
<0.01) both brachial and aortic blood pressure, augmentation index, and pulse wave velocity. No changes were seen after sham smoking. This study shows an acute increase in arterial stiffness after smoking 1 cigarette in chronic smokers and nonsmokers. Higher aortic systolic blood pressure and greater arterial stiffness, in part due to reduced pulse pressure amplification and increased arterial wave reflection, suggest that the adverse hemodynamic effects have hitherto been underestimated in young chronic smokers.
Angiotensinogen 235T Allele “Dosage” Is Associated With Blood Pressure Phenotypes
Authors: Pereira Alexandre C. , Mota Glória F.A. , Cunha Roberto S. , Herbenhoff Fernando L. , Mill José G. , Krieger José E.
Published: January 2003

The genetic mechanisms underlying interindividual blood pressure variation among humans may reflect, at least in part, clustering of functional gene variants belonging to complex blood pressure control systems. In this study, we investigated the association of specific functional gene variants of the renin-angiotensin system, ACE (I/D) and angiotensinogen (M/T) genes, with blood pressure phenotypes (systolic, mean, diastolic, and pulse pressure), in an ethnically mixed urban population in Brazil. Individuals (n=1421) were randomly selected from the general population of the Vitoria City Metropolitan area. Neither gender, age, smoking status, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, or diabetes was associated with ACE or AGT polymorphism in univariate analysis. No association was found between ACE variants and blood pressure phenotypes. However, a statistically significant association was revealed between the AGT 235T variant and all blood pressure phenotypes, consistent with an additive/codominant mode of action even after adjustment for age and gender (
P
<0.01). Genotypic analysis contemplating both ACE and AGT variants in the same model did not show any significant interaction between both genetic polymorphisms. In addition, the AGT 235T allele was significantly associated with hypertension in a recessive model, which remained as an independent risk factor for hypertension even after adjustment for age, gender, and ethnicity (OR, 1.33; 95% CI, 1.04 to 1.70). Taken together, these data indicate a linear relation between AGT 235T allele number (“dosage”) and blood pressure in an ethnically mixed urban population and confirmed its role as an independent risk factor for hypertension for men and women when in homozygosity.
Phase-Contrast Magnetic Resonance Flow Quantification in Renal Arteries
Authors: de Haan Michiel W. , van Engelshoven Jos M.A. , Houben Alphons J.H.M. , Kaandorp Dave W. , Kessels Alfons G.H. , Kroon Abraham A. , de Leeuw Peter W.
Published: January 2003

To assess the accuracy of 2D phase-contrast magnetic resonance (2D PC MR) renal artery flow measurements, data obtained with this technique were compared with those acquired with the
133
Xenon-washout procedure. In addition, the 2D PC MR flow data were related to functional renal information as derived from selective arterial and venous renin sampling. In 53 patients suspected of having renovascular hypertension, MR angiography of the renal arteries was performed, followed by a 3-step angiographic procedure: (1) selective venous and arterial renin sampling; (2) assessment of the renal blood flow by means of the
133
Xenon washout technique, and (3) conventional renal angiography. After initial assessment, 71 kidneys were left for analysis. The overall prevalence of renovascular disease ≥50% stenosis was 18%. Mean renal blood flow as assessed with the 2D PC MR technique showed a significant correlation with the
133
Xenon washout flow measurements, with a Pearson correlation coefficient of 0.69 (2-tailed;
P
<0.01). PC MR blood flow measurements correlated poorly with the presence and/or severity of renovascular disease on conventional angiography (
r
=0.1,
P
=0.36). Likewise, no statistically significant correlation with either renal venous renin levels or the renin ratio could be identified. Measurement of renal artery blood flow with the use of a 2D PC MR technique is technically feasible. However, the mean renal artery blood flow correlates poorly with either the presence of renovascular disease on angiography or with renin levels. Further improvement of this technique is necessary before it can be applied on a larger scale.
Gender-Linked Hypertension in Offspring of Lard-Fed Pregnant Rats
Authors: Khan Imran Y. , Taylor Paul D. , Dekou Vasia , Seed Paul T. , Lakasing Lorin , Graham Delyth , Dominiczak Anna F. , Hanson Mark A. , Poston Lucilla
Published: January 2003

Epidemiological studies suggest an association between maternal nutrition and offspring cardiovascular disease. We previously demonstrated endothelial dysfunction and abnormal aortic fatty acid composition in adult female offspring of rats fed animal lard during pregnancy. We have now further investigated this model. Female Sprague-Dawley rats were fed a control breeding diet (5.3% fat) or a diet rich in lard (25.7% fat) 10 days before and throughout pregnancy and lactation. Male and female offspring were implanted with radiotelemeters for recording of blood pressure, heart rate, and activity at 80, 180, and 360 days of age. Reactivity to acetylcholine and to nitric oxide were assessed in isolated small mesenteric arteries from 80- and 180-day-old littermates. Systolic blood pressure (awake phase) was raised in female offspring (180 days: offspring of control, 130.7±1.6 mm Hg, n=5, versus offspring of lard-fed, 138.1±2.9, n=5,
P
=0.029; 360 days: offspring of control, 129.7±3.7 mm Hg, n=6, versus offspring of lard-fed, 142.1±3.2, n=6,
P
=0.005). Diastolic blood pressure was also raised at 180 days (offspring of control, 87.6±1.0 mm Hg, n=5, versus offspring of lard-fed, 94.7±2.6, n=5,
P
=0.011). Blood pressure was not raised in male offspring. Endothelium-dependent relaxation to acetylcholine was blunted in male and female offspring of lard-fed dams (80 and 180 days). Feeding a diet rich in lard to pregnant rats leads to gender-related cardiovascular dysfunction in normally fed offspring.
Angiotensin II Receptor Blockade
Authors: Forclaz Andrei , Maillard Marc , Nussberger Jürg , Brunner Hans R. , Burnier Michel
Published: January 2003

We assessed the blockade of the renin-angiotensin system (RAS) achieved with 2 angiotensin (Ang) antagonists given either alone at different doses or with an ACE inhibitor. First, 20 normotensive subjects were randomly assigned to 100 mg OD losartan (LOS) or 80 mg OD telmisartan (TEL) for 1 week; during another week, the same doses of LOS and TEL were combined with 20 mg OD lisinopril. Then, 10 subjects were randomly assigned to 200 mg OD LOS and 160 mg OD TEL for 1 week and 100 mg BID LOS and 80 mg BID TEL during the second week. Blockade of the RAS was evaluated with the inhibition of the pressor effect of exogenous Ang I, an ex vivo receptor assay, and the changes in plasma Ang II. Trough blood pressure response to Ang I was blocked by 35±16% (mean±SD) with 100 mg OD LOS and by 36±13% with 80 mg OD TEL. When combined with lisinopril, blockade was 76±7% with LOS and 79±9% with TEL. With 200 mg OD LOS, trough blockade was 54±14%, but with 100 mg BID it increased to 77±8% (
P
<0.01). Telmisartan (160 mg OD and 80 mg BID) produced a comparable effect. Thus, at their maximal recommended doses, neither LOS nor TEL blocks the RAS for 24 hours; hence, the addition of an ACE inhibitor provides an additional blockade. A 24-hour blockade can be achieved with an angiotensin antagonist alone, provided higher doses or a BID regimen is used.
Modulation of Angiotensin II Responses in Sympathetic Neurons by Cytosolic Calcium
Authors: Fernandez Stanley F. , Huang Ming-He , Davidson Bruce A. , Knight Paul R. , Izzo Joseph L.
Published: January 2003

Both stimulatory and suppressive responses of the sympathetic nervous system to angiotensin II (AII) have been reported in intact animals. To elucidate possible cellular mechanisms, we studied AII-induced changes in cytosolic Ca
2+
([Ca
2+
]i) in primary cultures of rat stellate ganglion neurons. Two different patterns of [Ca
2+
]i responses to AII were observed: dose-dependent increases in [Ca
2+
]i in cells with intrinsically low baseline [Ca
2+
]i (n=64) and dose-dependent suppression of [Ca
2+
]i in neurons with intrinsically higher baseline [Ca
2+
]i (n=46). Individual neurons could express both response patterns to AII. In neurons with low basal [Ca
2+
]i, superfusion with Ca
2+
ionophore (ionomycin) increased [Ca
2+
]i and reversed the initial AII-induced stimulatory pattern. L-type Ca
2+
channel antagonism (nifedipine) in neurons with high baseline [Ca
2+
]i lowered [Ca
2+
]i and reversed the initial AII-induced suppressive response. Both stimulatory and suppressive responses were abolished by AT
1
receptor antagonism (losartan). AII-induced stimulatory responses were blocked by IP
3
receptor antagonism (2-APB) and by thapsigargin. AII-induced suppression of neuronal [Ca
2+
]i was blunted when Na-Ca exchange was impaired. We conclude that [Ca
2+
]i acts as a switch for AII-mediated stimulatory and suppressive responses in individual sympathetic neurons. AT
1
receptor-mediated neuronal stimulation and suppression may allow local homeostatic adaptation to meet complex systemic needs.
Alteration of Lipids, G Proteins, and PKC in Cell Membranes of Elderly Hypertensives
Authors: Escribá Pablo V. , Sánchez-Dominguez José M. , Alemany Regina , Perona Javier S. , Ruiz-Gutiérrez Valentina
Published: January 2003

In this study, we quantified the levels of lipids and signaling proteins in erythrocyte membranes from elderly normotensive and hypertensive subjects. In hypertensive subjects, the cholesterol/phospholipid ratio increased significantly in erythrocyte membranes, owing to the reduction of phospholipid levels concomitant with a rise in the levels of cholesterol. In addition, differences were also found in the amount of fatty acids in both phospholipid and cholesterol esters. Erythrocyte membranes from hypertensive subjects contained higher levels of monounsaturated and lower levels of polyunsaturated fatty acids. On the other hand, signaling proteins such as G proteins and protein kinase C have been implicated in the control of blood pressure. Previous studies have shown that the cellular localization and the activity of these proteins are modulated by the type and the abundance of membrane lipids. For this reason, we assessed the levels of these signaling molecules in the membrane. We found that the levels of membrane-associated (active/preactive) G proteins (Gαi, Gαo, and Gβ) and protein kinase C were significantly reduced in hypertensive subjects. We believe that these alterations could be related to the etiopathology of hypertension in elderly subjects or alternatively may correspond to adaptive compensatory mechanisms.
Greater Age-Related Reductions in Central Arterial Compliance in Resistance-Trained Men
Authors: Miyachi Motohiko , Donato Anthony J. , Yamamoto Kenta , Takahashi Kouki , Gates Phillip E. , Moreau Kerrie L. , Tanaka Hirofumi
Published: January 2003

Reductions in the compliance of central arteries exert a number of adverse effects on systemic cardiovascular function and disease risk. Using the cross-sectional study design, we determined the relation between chronic resistance training and carotid arterial compliance. A total of 62 healthy normotensive men, 20 to 39 years of age (young) and 40 to 60 years of age (middle-aged), who were either sedentary or resistance-trained, were studied. In both activity groups, carotid arterial compliance (simultaneous ultrasound and applanation tonometry) was lower (
P
<0.05) in the middle-aged compared with the young men. There was no significant difference between young sedentary and resistance-trained men. In the middle-aged group, carotid arterial compliance in the resistance-trained men was ≈30% lower (
P
<0.01) than their sedentary peers. Femoral artery compliance and arm pulse wave velocity (measures of peripheral artery stiffness) were not different among any groups. Left ventricular hypertrophy index (echocardiography) was greater (
P
<0.05) in resistance-trained compared with sedentary men and was associated with carotid arterial compliance (
r
=−0.35;
P
<0.01). We concluded that (1) resistance training is associated with the smaller central arterial compliance in healthy middle-aged men; (2) age-related reductions in arterial compliance was greater in resistance-trained men than in sedentary men; and (3) the lower arterial compliance in the resistance-trained men is associated with left ventricular hypertrophy. In marked contrast to the beneficial effect of regular aerobic exercise, the present findings are not consistent with the idea that resistance training exerts beneficial influences on arterial wall buffering functions.
A Diffusible Substance(s) Mediates Endothelium-Dependent Contractions in the Aorta of SHR
Authors: Yang Di , Félétou Michel , Levens Nigel , Zhang Ji Nan , Vanhoutte Paul M.
Published: January 2003

A modified bioassay system was designed to demonstrate the diffusible nature of endothelium-derived contracting factor(s) released by acetylcholine in the aorta of spontaneously hypertensive rat. In “sandwich”-like layered preparation, isometric tension was recorded from a bioassay strip (without endothelium) in the presence of
N
G
-nitro-
l
-arginine and tetrahydrobiopterin to selectively potentiate endothelium-dependent contractions. A donor strip (with or without endothelium) was stitched on the bioassay tissue so that it did not directly contribute to the recorded contractions. Acetylcholine induced contractions that occurred only when the donor strip was with endothelium. Superoxide dismutase did not affect but catalase and the combination of superoxide dismutase plus catalase significantly decreased the endothelium-dependent contraction. The contractions in the layered preparations were abolished when the donor strip with endothelium was treated previously with valeryl salicylate, an irreversible cyclooxygenase-1 inhibitor, but remained unaffected when the bioassay strip was treated with the compound. Previous treatment of the bioassay strip alone with S 18886 abolished the contractile response, whereas treatment of the donor strip with endothelium by the selective TP receptor antagonist only produced a moderate inhibition. These results indicate that in the aorta of spontaneously hypertensive rats, endothelium-dependent contractions to acetylcholine involve a diffusible substance(s) released by the endothelium. The production of this contracting factor(s) requires the activation of endothelial cyclooxygenase-1, and its action the activation of TP receptors on the vascular smooth muscle cells.
Myocardial Fatty Acid Metabolism
Authors: de las Fuentes Lisa , Herrero Pilar , Peterson Linda R. , Kelly Daniel P. , Gropler Robert J. , Dávila-Román Víctor G.
Published: January 2003

The expression of myocardial fatty acid β-oxidation enzymes is downregulated at the gene transcriptional level in animal models of left ventricular hypertrophy and of heart failure. Humans with idiopathic dilated cardiomyopathy have decreased myocardial fatty acid oxidation. The extent to which molecular mechanisms, such as a reduction in myocardial fatty acid oxidation, regulate the cardiac hypertrophic response in humans in vivo is unknown. Positron emission tomography was used to measure myocardial blood flow, oxygen consumption, fatty acid utilization, and oxidation in two groups of patients: (1) hypertensive left ventricular hypertrophy (n=19; left ventricular mass, 211±39 g; left ventricular ejection fraction, 67±4%) and (2) left ventricular dysfunction (n=9; left ventricular mass, 210±36 g; left ventricular ejection fraction, 31±10%); these were compared with a normal control group (n=36; left ventricular mass, 139±25 g; left ventricular ejection fraction, 66±6%). Left ventricular mass showed significant correlation with gender, diastolic and systolic blood pressure, myocardial fatty acid uptake, utilization and oxidation, myocardial blood flow, body mass index, and left ventricular ejection fraction (all
P
<0.02). Independent predictors of increased left ventricular mass were male gender (
r
=0.38,
P
<0.001), myocardial fatty acid oxidation (
r
=−0.24,
P
<0.018), systolic blood pressure (
r
=0.41,
P
<0.001), and left ventricular ejection fraction (
r
=−0.29,
P
=0.005). Thus, myocardial fatty acid metabolism is an independent predictor of left ventricular mass in hypertension and in left ventricular dysfunction. The extent to which reduced myocardial fatty acid metabolism affects cardiovascular morbidity and mortality and whether pharmacologic modulation results in improved outcomes remains to be determined.
Specific Potentiation of Endothelium-Dependent Contractions in SHR by Tetrahydrobiopterin
Authors: Yang Di , Levens Nigel , Zhang Ji Nan , Vanhoutte Paul M. , Félétou Michel
Published: January 2003

This study was designed to determine the effect of pteridines, R- and S-tetrahydrobiopterin, sepiapterin, and dihydrobiopterin on endothelium-dependent contractions to acetylcholine in isolated aortas from spontaneously hypertensive rat and normotensive Wistar-Kyoto rat. The noncumulative addition of redox-active pteridines R- and S-tetrahydrobiopterin (but not the oxidized analogues sepiapterin and dihydrobiopterin) produced a concentration-dependent transient contraction in isolated aortic rings from both normotensive and hypertensive rats. R- and S-tetrahydrobiopterin (but not sepiapterin or dihydrobiopterin) potentiated the endothelium-dependent contractions to acetylcholine but only in aortas from hypertensive rats and in the presence of
N
G
-nitro-
l
-arginine. In these aortas, the generation of oxygen-derived free radicals by the combination of xanthine plus xanthine oxidase also potentiated the endothelium-dependent contractions to acetylcholine. The presence of R-tetrahydrobiopterin did not alter the characteristics of the endothelium-dependent contractions because they were inhibited by valeryl salicylate, an inhibitor of cyclooxygenase-1, by S18886, a TP-receptor antagonist or by Tiron, a cell permeable superoxide anion scavenger. However, the contractions to acetylcholine, which are unaffected by the combination of superoxide dismutase and catalase, become significantly inhibited by these two scavengers in the presence of R-tetrahydrobiopterin. In the presence of
N
G
-nitro-
l
-arginine, R-tetrahydrobiopterin did not affect the contractions to phenylephrine, U 46619, or to oxygen-derived free radicals generated by xanthine plus xanthine oxidase. These results indicate that the production of superoxide by the autoxidation of tetrahydrobiopterin selectively enhances endothelium-dependent contractions in the spontaneously hypertensive rat when nitric oxide synthase is inhibited.
Cardiac Angiotensin II Type 2 Receptor Activates the Kinin/NO System and Inhibits Fibrosis
Authors: Kurisu Satoshi , Ozono Ryoji , Oshima Tetsuya , Kambe Masayuki , Ishida Takafumi , Sugino Hiroshi , Matsuura Hideo , Chayama Kazuaki , Teranishi Yasuhiro , Iba Osamu , Amano Katsuya , Matsubara Hiroaki
Published: January 2003

We have previously demonstrated that stimulation of the angiotensin (Ang) II type 2 receptor in vascular smooth muscle cells caused bradykinin production by activating kininogenase in transgenic mice. The aim of this study was to determine whether overexpression of AT
2
receptors in cardiomyocytes attenuates Ang II–induced cardiomyocyte hypertrophy or interstitial fibrosis through a kinin/nitric oxide (NO)-dependent mechanism in mice. Ang II (1.4 mg/kg per day) or vehicle was subcutaneously infused into transgenic mice and wild-type mice for 14 days. The amount of cardiac AT
2
receptor relative to AT
1
receptor in transgenic mice was 22% to 37%. Ang II caused similar elevations in systolic blood pressure (by ≈45 mm Hg) in transgenic mice and wild-type mice. Myocyte hypertrophy assessed by an increase in myocyte cross-sectional area, left ventricular mass, and atrial natriuretic peptide mRNA levels were similar in transgenic and wild-type mice. Ang II induced prominent perivascular fibrosis of the intramuscular coronary arteries, the extent of which was significantly less in transgenic mice than in wild-type mice. Inhibition of perivascular fibrosis in transgenic mice was abolished by cotreatment with HOE140, a bradykinin B
2
receptor antagonist, or L-NAME, an inhibitor of NO synthase. Cardiac kininogenase activity was markedly increased (≈2.6-fold,
P
<0.001) after Ang II infusion in transgenic mice but not in wild-type mice. Immunohistochemistry indicated that both bradykinin B
2
receptors and endothelial NO synthase were expressed in the vascular endothelium, whereas only B
2
receptors were present in fibroblasts. These results suggest that stimulation of AT
2
receptors present in cardiomyocytes attenuates perivascular fibrosis by a kinin/NO-dependent mechanism. However, the effect on the development of cardiomyocyte hypertrophy was not detected in this experimental setting.
Urinary Angiotensinogen as an Indicator of Intrarenal Angiotensin Status in Hypertension
Authors: Kobori Hiroyuki , Nishiyama Akira , Harrison-Bernard Lisa M. , Navar L. Gabriel
Published: January 2003

Angiotensin II (AngII) infusions augment renal angiotensinogen mRNA and protein and urinary angiotensinogen excretion (U
AGT
). Further experiments were performed in 4 groups of rats: normal salt diet with sham operation, NS+Sham, n=6; NS with AngII infusion at 40 ng/min via osmotic minipump, NS+AngII(40), n=9; NS with AngII infusion at 80 ng/min, NS+AngII(80), n=9; high-salt diet with deoxycorticosterone acetate salt pellet (100 mg), HS+DOCA, n=4. These experiments sought to determine whether enhanced U
AGT
is specifically associated with increased kidney AngII levels or is a nonspecific consequence of the hypertension. Systolic BP (SBP) was significantly increased to 131±2 and 162±2 mm Hg at day 11 in NS+AngII(40) and NS+AngII(80), respectively, compared with NS+Sham (110±1). Regression analysis demonstrated a positive relationship (
R
=0.49) between SBP and U
AGT
for NS+Sham (1.1±0.3 nmol AngI/d), NS+AngII(40) (2.5±0.9), and NS+AngII(80) (5.5±1.5). U
AGT
was also highly correlated (
R
=0.70) with kidney AngII content for NS+Sham (49±6 fmol/g), NS+AngII(40) (215±49), and NS+AngII(80) (347±47); but not with plasma AngII (
R
=0.12). HS+DOCA rats also exhibited increased SBP to 134±1 mm Hg, but U
AGT
(1.4±0.4 nmol AngI/d) and intrarenal AngII content (13±2 fmol/g) were not increased despite the hypertension. Infused human angiotensinogen could not be detected in urine of sham-operated or AngII-infused rats (n=4 each). These data demonstrate that U
AGT
increases in AngII-dependent hypertension in a dose- and time-dependent manner, but not in hypertension elicited by HS+DOCA. The results support the hypothesis that AngII-dependent hypertension results in elevated intrarenal AngII and angiotensinogen levels, reflected by increased U
AGT
, which does not occur in an AngII-independent hypertensive model.