bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytotoxin-Associated Gene-A–Positive
Helicobacter pylori
Strains Are Associated With Atherosclerotic Stroke
Authors: Pietroiusti Antonio , Diomedi Marina , Silvestrini Mauro , Cupini Letizia Maria , Luzzi Ida , Gomez-Miguel Maria Jesus , Bergamaschi Antonio , Magrini Andrea , Carrabs Tiziana , Vellini Marina , Galante Alberto
Published: October 2002

Background

—

It is uncertain whether
Helicobacter pylori
is associated with ischemic syndromes and whether this association is mediated by the induction of atherosclerosis. In this study, we tested the hypothesis that atherosclerotic stroke shows a selective association with virulent
H pylori
strains.

Methods and Results

—

The seroprevalence of infection by
H pylori
and by strains bearing the cytotoxin-associated gene-A (CagA), a strong virulence factor, was assessed by ELISA in 138 patients with large-vessel stroke (group A), in 61 patients with cardioembolic stroke (group B), and in 151 healthy control subjects. The 3 groups had a similar socioeconomic status. Serum levels of C-reactive protein were also measured by ELISA. The prevalence of infection was 71% in group A, 63.9% in group B, and 70.2% in the control group (
P
=NS), whereas the prevalence of CagA-positive strains was higher in group A than in group B (42.8% versus 19.7%, respectively; odds ratio 3.04, 95% CI 1.43 to 6.49;
P
<0.001) and higher in group A than in the control group (42.8% versus 17.9%, respectively; odds ratio 4.3, 95% CI 2.12 to 8.64;
P
<0.001), after adjusting for main cardiovascular risk factors and social class. A trend toward a difference in C-reactive protein was observed between CagA-positive (2.00±3.43 [mean±SD] mg/dL) and CagA-negative (1.31±1.72 [mean±SD] mg/dL) patients (
P
=0.072, Mann-Whitney
U
test).

Conclusions

—

The association between
H pylori
and acute cerebrovascular disease seems to be due to a higher prevalence of more virulent
H pylori
strains in patients with atherosclerotic stroke.
Effect of Annular Shape on Leaflet Curvature in Reducing Mitral Leaflet Stress
Authors: Salgo Ivan S. , Gorman Joseph H. , Gorman Robert C. , Jackson Benjamin M. , Bowen Frank W. , Plappert Theodore , St John Sutton Martin G. , Edmunds L. Henry
Published: October 2002

Background

—

Leaflet curvature is known to reduce mechanical stress. There are 2 major components that contribute to this curvature. Leaflet billowing introduces the most obvious form of leaflet curvature. The saddle shape of the mitral annulus imparts a more subtle form of leaflet curvature. This study explores the relative contributions of leaflet billowing and annular shape on leaflet curvature and stress distribution.

Methods and Results

—

Both numerical simulation and experimental data were used. The simulation consisted of an array of numerically generated mitral annular phantoms encompassing flat to markedly saddle-shaped annular heights. Highest peak leaflet stresses occurred for the flat annulus. As saddle height increased, peak stresses decreased. The minimum peak leaflet stress occurred at an annular height to commissural width ratio of 15% to 25%. The second phase involved data acquisition for the annulus from 3 humans by 3D echocardiography, 3 sheep by sonomicrometry array localization, 2 sheep by 3D echocardiography, and 2 baboons by 3D echocardiography. All 3 species imaged had annuli of a similar shape, with an annular height to commissural width ratio of 10% to 15%.

Conclusion

—

The saddle shape of the mitral annulus confers a mechanical advantage to the leaflets by adding curvature. This may be valuable when leaflet curvature becomes reduced due to diminished leaflet billowing caused by annular dilatation. The fact that the saddle shape is conserved across mammalian species provides indirect evidence of the advantages it confers. This analysis of mitral annular contour may prove applicable in developing the next generation of mitral annular prostheses.
Frequent Mutation in the ABCC6 Gene (R1141X) Is Associated With a Strong Increase in the Prevalence of Coronary Artery Disease
Authors: Trip Mieke D. , Smulders Yvo M. , Wegman Jurgen J. , Hu Xiaofeng , Boer Jolanda M.A. , ten Brink Jacoline B. , Zwinderman Aeilko H. , Kastelein John J.P. , Feskens Edith J.M. , Bergen Arthur A.B.
Published: October 2002

Background—

Pseudoxanthoma elasticum (PXE) is an inborn disorder of the connective tissue with specific skin, ocular, and cardiovascular disease (CVD) manifestations. Recently, we and others have identified mutations in the gene coding for the ABCC6 transporter in PXE patients with ocular and skin involvement. In the Netherlands, as in the rest of Europe, a particular premature truncation variant ABCC6 (R1141X) was found in a large cohort of PXE patients. Given the association between CVD and PXE, we hypothesized that heterozygosity of this ABCC6 mutation could also confer an increased risk for CVD.

Methods and Results—

To assess the relationship between the frequent R1141X mutation in the ABCC6 gene and the prevalence of premature coronary artery disease (CAD), we conducted a case-control study of 441 patients under the age of 50 years who had definite CAD and 1057 age- and sex-matched population-based controls who were free of coronary disease. Strikingly, the prevalence of the R1141X mutation was 4.2 times higher among patients than among controls (3.2% versus 0.8%;
P
<0.001). Consequently, among subjects with the R1141X mutation, the odds ratio for a coronary event was 4.23 (95% CI: 1.76 to 10.20,
P
= 0.001).

Conclusion—

The presence of the R1141X mutation in the ABCC6 gene is associated with a sharply increased risk of premature CAD.
Rapid Effects of Aldosterone and Spironolactone in the Isolated Working Rat Heart
Authors: Barbato John C. , Mulrow Patrick J. , Shapiro Joseph I. , Franco-Saenz Roberto
Published: October 2002

Chronic administration of aldosterone promotes myocardial fibrosis in rats. The Randomized Aldactone Evaluation Study reported that the aldosterone antagonist spironolactone improved outcome in patients with congestive heart failure, suggesting a deleterious effect of aldosterone in the heart. Aldosterone has been shown to have rapid nongenomic effects in different tissues including the heart. However, the hemodynamic actions of aldosterone and spironolactone are not well characterized. In this study, we examined the hemodynamic effects of aldosterone and its receptor antagonist, spironolactone, in the isolated rat heart by use of the Langendorff-Neely technique. Perfusion with 10 nmol/L aldosterone increased contractility by 45% within 2 to 4 minutes (
P
<0.01). Similar to the aldosterone effect, 10 nmol/L spironolactone increased contractility by 41% (
P
<0.01). Furthermore, 100-fold molar excess of spironolactone did not block the aldosterone effect. Perfusion of aldosterone plus spironolactone resulted in the highest increase in contractility 106% (
P
<0.01). The threshold response for aldosterone occurred within physiological concentrations (0.5 to 1 nmol/L), and maximal contractility was achieved with 10 nmol/L aldosterone. For spironolactone, the threshold and maximal contractile responses occurred at concentrations readily achieved with clinical dosing, 0.1 to 0.5 nmol/L and 1.0 nmol/L, respectively. These data demonstrate that aldosterone and spironolactone have rapid, positive inotropic actions on the myocardium. Moreover, addition of spironolactone to aldosterone increased contractility beyond the maximal responses elicited by each agent when perfused alone, thus suggesting different pathways of action. Furthermore, the intrinsic inotropic effects of spironolactone might be relevant to the apparent beneficial effect this compound has in patients with congestive heart failure.
Mineralocorticoid and Angiotensin Receptor Antagonism During Hyperaldosteronemia
Authors: Mihailidou Anastasia S. , Mardini Mahidi , Funder John W. , Raison Matthew
Published: October 2002

Elevated aldosterone levels induce a spironolactone-inhibitable decrease in cardiac sarcolemmal Na
+
-K
+
pump function. Because pump inhibition has been shown to contribute to myocyte hypertrophy, restoration of Na
+
-K
+
pump function may represent a possible mechanism for the cardioprotective action of mineralocorticoid receptor (MR) blockade. The present study examines whether treatment with the angiotensin type 1 receptor antagonist losartan, with either spironolactone or eplerenone, has additive effects on sarcolemmal Na
+
-K
+
pump activity in hyperaldosteronemia. New Zealand White rabbits were divided into 7 different groups: controls, aldosterone alone, aldosterone plus spironolactone, aldosterone plus eplerenone, aldosterone plus losartan, aldosterone plus losartan and spironolactone, and aldosterone plus losartan and eplerenone. After 7 days, myocytes were isolated by enzymatic digestion. Electrogenic Na
+
-K
+
pump current (I
p
), arising from the 3:2 Na
+
:K
+
exchange ratio, was measured by the whole-cell patch clamp technique. Elevated aldosterone levels lowered I
p
; treatment with losartan reversed aldosterone-induced reduced pump function, as did MR blockade. Coadministration of spironolactone or eplerenone with losartan enhanced the losartan effect on pump function to a level similar to that measured in rabbits given losartan alone in the absence of hyperaldosteronemia. In conclusion, hyperaldosteronemia induces a decrease in I
p
at near physiological levels of intracellular Na
+
concentration. Treatment with losartan reverses this aldosterone-induced decrease in pump function, and coadministration with MR antagonists produces an additive effect on pump function, consistent with a beneficial effect of MR blockade in patients with hypertension and congestive heart failure treated with angiotensin type 1 receptor antagonists.
Exogenous Angiotensin II Does Not Facilitate Norepinephrine Release in the Heart
Authors: Lameris Thomas W. , de Zeeuw Sandra , Duncker Dirk J. , Alberts Gooitzen , Boomsma Frans , Verdouw Pieter D. , van den Meiracker Anton H.
Published: October 2002

Studies on the effect of angiotensin II on norepinephrine release from sympathetic nerve terminals through stimulation of presynaptic angiotensin II type 1 receptors are equivocal. Furthermore, evidence that angiotensin II activates the cardiac sympathetic nervous system in vivo is scarce or indirect. In the intact porcine heart, we investigated whether angiotensin II increases norepinephrine concentrations in the myocardial interstitial fluid (NE
MIF
) under basal conditions and during sympathetic activation and whether it enhances exocytotic and nonexocytotic ischemia-induced norepinephrine release. In 27 anesthetized pigs, NE
MIF
was measured in the left ventricular myocardium using the microdialysis technique. Local infusion of angiotensin II into the left anterior descending coronary artery (LAD) at consecutive rates of 0.05, 0.5, and 5 ng/kg per minute did not affect NE
MIF
, LAD flow, left ventricular dP/dt
max
, and arterial pressure despite large increments in coronary arterial and venous angiotensin II concentrations. In the presence of neuronal reuptake inhibition and α-adrenergic receptor blockade, left stellate ganglion stimulation increased NE
MIF
from 2.7±0.3 to 7.3±1.2 before, and from 2.3±0.4 to 6.9±1.3 nmol/L during, infusion of 0.5 ng/kg per minute angiotensin II. Sixty minutes of 70% LAD flow reduction caused a progressive increase in NE
MIF
from 0.9±0.1 to 16±6 nmol/L, which was not enhanced by concomitant infusion of 0.5 ng/kg per minute angiotensin II. In conclusion, we did not observe any facilitation of cardiac norepinephrine release by angiotensin II under basal conditions and during either physiological (ganglion stimulation) or pathophysiological (acute ischemia) sympathetic activation. Hence, angiotensin II is not a local mediator of cardiac sympathetic activity in the in vivo porcine heart.
Activation of NADPH Oxidase During Progression of Cardiac Hypertrophy to Failure
Authors: Li Jian-Mei , Gall Nick P. , Grieve David J. , Chen Mingyou , Shah Ajay M.
Published: October 2002

Increased reactive oxygen species (ROS) production is implicated in the pathophysiology of left ventricular (LV) hypertrophy and heart failure. However, the enzymatic sources of myocardial ROS production are unclear. We examined the expression and activity of phagocyte-type NADPH oxidase in LV myocardium in an experimental guinea pig model of progressive pressure-overload LV hypertrophy. Concomitant with the development of LV hypertrophy, NADPH-dependent O
2
−
production in LV homogenates, measured by lucigenin (5 μmol/L) chemiluminescence or cytochrome c reduction assays, significantly and progressively increased (by ≈40% at the stage of LV decompensation;
P
<0.05). O
2
−
production was fully inhibited by diphenyleneiodonium (100 μmol/L). Immunoblotting revealed a progressive increase in expression of the NADPH oxidase subunits p22
phox
, gp91
phox
, p67
phox
, and p47
phox
in the LV hypertrophy group, whereas immunolabeling studies indicated the presence of oxidase subunits in cardiomyocytes and endothelial cells. In parallel with the increase in O
2
−
production, there was a significant increase in activation of extracellular signal–regulated kinase 1/2, extracellular signal–regulated kinase 5, c-Jun NH2-terminal kinase 1/2, and p38 mitogen-activated protein kinase. These data indicate that an NADPH oxidase expressed in cardiomyocytes is a major source of ROS generation in pressure overload LV hypertrophy and may contribute to pathophysiological changes such as the activation of redox-sensitive kinases and progression to heart failure.
Rostral Ventrolateral Medulla Neurons of Neonatal Wistar-Kyoto and Spontaneously Hypertensive Rats
Authors: Matsuura Tomokazu , Kumagai Hiroo , Kawai Akira , Onimaru Hiroshi , Imai Masaki , Oshima Naoki , Sakata Katsufumi , Saruta Takao
Published: October 2002

We compared the electrophysiological properties of neurons in the rostral ventrolateral medulla (RVLM) of neonatal Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), and responses to angiotensin II and its type 1 receptor antagonist candesartan. Using the whole-cell patch-clamp technique, we examined the characteristics of RVLM neurons in brainstem–spinal cord preparations with a preserved sympathetic neuronal network. The baseline membrane potential of irregularly firing neurons was less negative (−50.1±0.6 versus −52.0±0.6 mV) and the firing rate was faster (3.0±0.2 versus 2.0±0.2 Hz) in SHR (n=56) than in WKY (n=38). Superfusion with angiotensin II (6 μmol/L) significantly depolarized the RVLM bulbospinal neurons in SHR (5.4±1.1 mV, n=15) but not in WKY. In contrast, candesartan (0.12 μmol/L) induced a significant membrane hyperpolarization (−3.7±0.4 mV; n=14) and a decrease in the firing rate in RVLM bulbospinal neurons of SHR but not of WKY. These results suggest that endogenously generated angiotensin II binds to type 1 receptors on RVLM bulbospinal neurons, thus tonically contributing to a higher membrane potential and a faster firing rate in SHR. The electrophysiological properties of RVLM neurons and their responses to angiotensin II and candesartan differ between neonatal WKY and SHR. These differences in RVLM neurons suggest a mechanism that possibly leads to elevation in blood pressure.
Role of p47

phox

in Vascular Oxidative Stress and Hypertension Caused by Angiotensin II
Authors: Landmesser Ulf , Cai Hua , Dikalov Sergey , McCann Louise , Hwang Jinah , Jo Hanjoong , Holland Steven M. , Harrison David G.
Published: October 2002

Hypertension caused by angiotensin II is dependent on vascular superoxide (O
2
·−) production. The nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase is a major source of vascular O
2
·− and is activated by angiotensin II in vitro. However, its role in angiotensin II-induced hypertension in vivo is less clear. In the present studies, we used mice deficient in p47

phox

, a cytosolic subunit of the NADPH oxidase, to study the role of this enzyme system in vivo. In vivo, angiotensin II infusion (0.7 mg/kg per day for 7 days) increased systolic blood pressure from 105±2 to 151±6 mm Hg and increased vascular O
2
·− formation 2- to 3-fold in wild-type (WT) mice. In contrast, in p47

phox-/-

mice the hypertensive response to angiotensin II infusion (122±4 mm Hg;
P
<0.05) was markedly blunted, and there was no increase of vascular O
2
·− production. In situ staining for O
2
·− using dihydroethidium revealed a marked increase of O
2
·−production in both endothelial and vascular smooth muscle cells of angiotensin II-treated WT mice, but not in those of p47

phox-/-

mice. To directly examine the role of the NAD(P)H oxidase in endothelial production of O
2
·−, endothelial cells from WT and p47

phox-/-

mice were cultured. Western blotting confirmed the absence of p47

phox

in p47

phox-/-

mice. Angiotensin II increased O
2
·− production in endothelial cells from WT mice, but not in those from p47

phox-/-

mice, as determined by electron spin resonance spectroscopy. These results suggest a pivotal role of the NAD(P)H oxidase and its subunit p47

phox

in the vascular oxidant stress and the blood pressure response to angiotensin II in vivo.
Polymorphism in Soluble Epoxide Hydrolase and Blood Pressure in Spontaneously Hypertensive Rats
Authors: Fornage Myriam , Hinojos Cruz A. , Nurowska Barbara W. , Boerwinkle Eric , Hammock Bruce D. , Morisseau Christophe H.P. , Doris Peter A.
Published: October 2002

We measured soluble epoxide hydrolase (sEH) renal gene expression in prehypertensive (4 to 5 weeks old) spontaneously hypertensive rats of the Heidelberg SP substrain (SHR [Heid]) and when blood pressure levels entered the hypertensive plateau (17 to 18 weeks old) and compared expression with matched Wistar-Kyoto (WKY [Heid]) rats. Less expression of the gene encoding sEH (EPHX2) was observed in SHR (Heid) than in WKY (Heid). Analysis of sEH protein abundance showed a similar difference. However, no correlation between sEH abundance and blood pressure was observed in the F
2
progeny of a parental strain cross. Measurement of protein abundance in SHR and WKY obtained from Charles River confirmed a recent report that abundance of sEH was greater in SHR (CRiv) than WKY (CRiv) strains. Polymorphisms were detected in EPHX2. Resequencing revealed that 2 alleles of EPHX2 exist in these 4 rat strains, differing by 4 single nucleotide polymorphisms, of which 3 produce nonsynonymous amino acid substitutions. The ancestral allele was shared by SHR (Heid) and WKY (CRiv), and the variant allele was shared by WKY (Heid) and SHR (CRiv). Activity of sEH was greater in animals carrying the variant allele. However, inheritance of this allele was not correlated with blood pressure in the F
2
progeny of a cross between SHR (Heid) and WKY (Heid). These data indicate that sequence variation determining functional alterations in EPHX2 is not likely to contribute to blood pressure levels in SHR.
Impaired Fasting Glucose, Blood Pressure and Cardiovascular Disease Mortality
Authors: Henry Patrick , Thomas Frédérique , Benetos Athanase , Guize Louis
Published: October 2002

Impaired fasting glucose (fasting plasma glucose 6.1 to 6.9 mmol/L [110 to 125 mg/dL]) is a common glycemic disorder which usually progress to diabetes mellitus. The relationships between impaired fasting glucose, other risk factors including blood pressure, and mortality have never been clearly investigated. We studied 63 443 consecutive men (ages 21 to 60 years), each of whom had a routine health examination with a fasting plasma glucose measurement. Men with known ischemic cardiac disease and treatment for diabetes or hypertension were excluded. Impaired fasting glucose was found in 10 773 (17.0%) of these men. Mean body mass index, serum triglyceride and cholesterol levels, and systolic, diastolic, and pulse blood pressure were significantly higher for men with impaired fasting glucose compared with those men with normal fasting glucose (fasting plasma glucose 3.9 to 6.0 mmol/L). When adjusted for confounding variables, relative risk of 8-year cardiovascular mortality associated with impaired fasting glucose was dependent on systolic blood pressure level (1.02 [95% CI: 0.62 to 1.70] when <140 mm Hg and 2.10 [95% CI: 1.16 to 3.80] between 140 and 160 mm Hg). Inversely, relative risk of 8-year cardiovascular mortality associated with moderate systolic hypertension (140 to 159 mm Hg) compared with normal systolic blood pressure (<140 mm Hg) was highly dependent on the glycemic status (2.97 [95% CI: 1.58 to 5.55] for men with impaired fasting glucose compared with 1.35 [95% CI: 0.84 to 2.18] in those with normal fasting glucose). Similar results were found concerning overall mortality. In conclusion, the presence of moderate systolic hypertension can identify subjects with impaired fasting glucose who are at risk of cardiovascular and overall mortality, and vice versa, probably through the metabolic syndrome.
Acute Antihypertrophic Actions of Bradykinin in the Rat Heart
Authors: Rosenkranz Anke C. , Hood Sally G. , Woods Robyn L. , Dusting Gregory J. , Ritchie Rebecca H.
Published: October 2002

The antihypertrophic action of angiotensin (Ang)-converting enzyme (ACE) inhibitors in the heart is attributed in part to potentiation of bradykinin. Bradykinin prevents hypertrophy of cultured cardiomyocytes by releasing nitric oxide (NO) from endothelial cells, which increases cardiomyocyte guanosine 3′5′-cyclic monophosphate (cyclic GMP). It is unknown whether cyclic GMP is essential for the action of bradykinin, or whether findings in isolated cardiomyocytes apply in whole hearts, in the presence of other cell types and mechanical/dynamic activity. We now examine the contribution of cyclic GMP to the antihypertrophic action of bradykinin in cardiomyocytes and perfused hearts. In adult rat isolated cardiomyocytes cocultured with bovine aortic endothelial cells, the inhibitory action of bradykinin (10 μmol/L) against Ang II (1 μmol/L)–induced [
3
H]phenylalanine incorporation was abolished by the soluble guanylyl cyclase inhibitor [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (10 μmol/L). In Langendorff-perfused rat hearts, Ang II (10 nmol/L)–induced increases in [
3
H]phenylalanine incorporation and atrial natriuretic peptide mRNA expression were prevented by bradykinin (100 nmol/L), the NO donor sodium nitroprusside (3 μmol/L), and the ACE inhibitor ramiprilat (100 nmol/L). The acute antihypertrophic action of bradykinin was accompanied by increased left ventricular cyclic GMP, and the ramiprilat effect was attenuated by HOE 140 (1 μmol/L, a B
2
-kinin receptor antagonist) or [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (100 nmol/L). In conclusion, bradykinin exerts a direct inhibitory action against the acute hypertrophic response to Ang II in rat isolated hearts, and elevation of cardiomyocyte cyclic GMP may be an important antihypertrophic mechanism used by bradykinin and ramiprilat in the heart.
Obesity Hypertension in Children
Authors: Sorof Jonathan , Daniels Stephen
Published: October 2002

Obesity has become an increasingly important medical problem in children and adolescents. In national surveys from the 1960s to the 1990s, the prevalence of overweight in children grew from 5% to 11%. Outcomes related to childhood obesity include hypertension, type 2 diabetes mellitus, dyslipidemia, left ventricular hypertrophy, nonalcoholic steatohepatitis, obstructive sleep apnea, orthopedic problems, and psychosocial problems. Once considered rare, primary hypertension in children has become increasingly common in association with obesity and other risk factors, including a family history of hypertension and an ethnic predisposition to hypertensive disease. Obese children are at approximately a 3-fold higher risk for hypertension than nonobese children. In addition, the risk of hypertension in children increases across the entire range of body mass index (BMI) values and is not defined by a simple threshold effect. As in adults, a combination of factors including overactivity of the sympathetic nervous system (SNS), insulin resistance, and abnormalities in vascular structure and function may contribute to obesity-related hypertension in children. The benefits of weight loss for blood pressure reduction in children have been demonstrated in both observational and interventional studies. Obesity in childhood should be considered a chronic medical condition that is likely to require long-term management. Ultimately, prevention of obesity and its complications, including hypertension, is the goal.
Hemodynamic and Humoral Effects of Vasopeptidase Inhibition in Canine Hypertension
Authors: Maniu Calin V. , Meyer Donna M. , Redfield Margaret M.
Published: October 2002

Vasopeptidase inhibitors are potent new antihypertensive agents. The dual inhibition of ACE and neutral endopeptidase may result in synergistic humoral effects with unique hemodynamic actions. We investigated the hemodynamic and neurohumoral effects of vasopeptidase inhibition in conscious dogs made hypertensive by bilateral renal wrapping and subsequently instrumented for long-term assessment of left ventricular pressure and volume (n=8). Intravenous vasopeptidase inhibition (omapatrilat, 30 μmol/kg over 10 minutes) reduced peak left ventricular pressure (171±6 versus 130±6 mm Hg immediately after infusion,
P
<0.01) through arterial vasodilation (arterial elastance, 9.8±0.8 to 5.8±1.6 mm Hg/mL,
P
<0.01) and preload reduction (left ventricular end-diastolic volume, 51.1±6.8 to 46.0±6.9 mL,
P
<0.01). At 60 minutes, preload decreased further (40.5±5.9 mL,
P
<0.01 versus baseline). Vasopeptidase inhibition increased plasma levels of adrenomedullin (41.2±9.6 versus 72.3±15 pg/mL,
P
<0.01), whereas levels of the natriuretic peptides and cGMP were unchanged. Similar hemodynamic and humoral effects were observed with long-term therapy. Neither an equimolar dose of an ACE inhibitor (fosinopril) nor exogenous adrenomedullin had as potent of a hypotensive effect, and neither reduced preload. In summary, the potent short-term and long-term hypotensive effects of vasopeptidase inhibition were prominently mediated by preload reduction, an effect not reproduced by ACE inhibition nor adrenomedullin augmentation and not associated with enhanced natriuretic peptide levels. Combined arterial vasodilation and preload reduction may confer additional potency as well as unique cardioprotective effects. Synergistic effects on humoral and probably endothelial vasodilatory factors appear to be important in mediating the unique hemodynamic profile of vasopeptidase inhibition in this form of experimental hypertension.
AT
2
Receptor-Mediated Relaxation Is Preserved After Long-Term AT
1
Receptor Blockade
Authors: Widdop Robert E. , Matrougui Khalid , Levy Bernard I. , Henrion Daniel
Published: October 2002

Angiotensin II type 2 receptor (AT
2
R) stimulation may cause vasodilation per se and may contribute to the antihypertensive effect produced by Angiotensin II type 1 receptor (AT
1
R) antagonists, given that AT
1
R blockade increases endogenous levels of Ang II, suggesting a physiological role for the unblocked AT
2
R. Thus, we first directly assessed whether or not there is desensitization to AT
2
R-mediated vasorelaxation because this is an important consideration, given the raised Ang II levels and the marked desensitization that is known to occur after AT
1
R stimulation. Second, we examined if AT
2
R-mediated vasorelaxation is preserved after long-term treatment with the AT
1
R antagonist candesartan cilexetil. Consecutive concentration-response curves to AT
2
R stimulation, with either Ang II (with AT
1
R blockade) or the selective agonist CGP42112, were studied in rat isolated mesenteric resistance arteries mounted in an arteriograph. AT
2
R stimulation with Ang II induced a concentration-dependent relaxation without desensitization. Similarly, CGP42112 evoked highly reproducible relaxation, which, like Ang II, was abolished by the AT
2
R antagonist PD123319. By contrast, AT
1
R-mediated contraction exhibited marked desensitization. In rats treated with candesartan cilexetil (2 mg/kg per day for 2 weeks), AT
1
R-mediated contraction was abolished, whereas AT
2
R-mediated relaxation evoked by either Ang II or CGP42112 was highly reproducible, PD123319-sensitive, and of a magnitude similar to that observed in naïve animals. Therefore, this study has provided unequivocal evidence for the reproducible nature of AT
2
R-mediated vasorelaxation during short-term and long-term AT
1
R blockade. Such preservation of AT
2
R function is a prerequisite for the consideration of physiological role(s) of AT
2
R during AT
1
R blockade.
Effect of Estrogen and AT
1
Receptor Blocker on Neointima Formation
Authors: Liu Hong-Wei , Iwai Masaru , Takeda-Matsubara Yuko , Wu Lan , Li Jian-Mei , Okumura Midori , Cui Tai-Xing , Horiuchi Masatsugu
Published: October 2002

The present study explored the possibility that estrogen may enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT
1
) receptor blocker on neointima formation in vascular injury, and investigated the signaling mechanism involved in their actions. Polyethylene cuff placement around the femoral artery of mice induced neointima formation and increased bromodeoxyuridine (BrdU) incorporation into vascular smooth muscle cells. These changes were significantly smaller in female mice than in male mice. Ovariectomy enhanced neointima formation and BrdU incorporation in the injured artery, which were reversed by 17β-estradiol (80 μg/kg per day) replacement. Treatment with a selective AT
1
receptor blocker, olmesartan (3 mg/kg per day), significantly inhibited neointima formation and BrdU incorporation, whereas the inhibitory effects of olmesartan were more marked in intact female mice than in male or ovariectomized mice. Phosphorylation of extracellular signal–regulated kinase (ERK), signal transducer and activator of transcription (STAT) 1, and STAT3 was increased in the injured artery. These increases were significantly smaller in intact female mice than in male or ovariectomized mice. Olmesartan or estrogen attenuated the phosphorylation of ERK and STAT in the injured artery, whereas these inhibitory effects were greater in intact female mice. Lower doses of olmesartan (0.5 mg/kg per day) or 17β-estradiol (20 μg/kg per day) did not influence neointima formation, BrdU incorporation, and ERK and STAT phosphorylation in ovariectomized mice, whereas coadministration of olmesartan and 17β-estradiol at these doses attenuated these parameters. These results indicate that estrogen and an AT
1
receptor blocker synergistically attenuate vascular remodeling, which is at least partly via inhibition of ERK and STAT activity.
Angiotensin II Constriction of Rat Vasa Recta Is Partially Thromboxane Dependent
Authors: Silldorff Erik P. , Hilbun Layla R. , Pallone Thomas L.
Published: October 2002

We tested the hypothesis that thromboxane generation mediates vasoconstriction of isolated outer medullary descending vasa recta (OMDVR) by angiotensin (Ang) II. The lipoxygenase and cyclooxygenase (COX) inhibitor eicosatetraynoic acid (1 μmol/L) and the COX inhibitor indomethacin (1 μmol/L) partially reversed Ang II (1 nmol/L) constriction of in vitro perfused OMDVR. To determine whether thromboxane is a mediator of Ang II–induced vasoconstriction, a thromboxane synthase inhibitor, U63577A (1 μmol/L), and thromboxane receptor antagonists, SQ-29548 or BMS-180,291 (1 μmol/L, each), were introduced into the bath of vessels that had been preconstricted by Ang II (1 nmol/L). These agents significantly inhibited vasoconstriction induced by Ang II. In contrast, SQ-29548 and U63557A did not affect vessels preconstricted by raising extracellular KCl from 5 to 100 mmol/L. The thromboxane receptor agonist U46619 (1 μmol/L) constricted OMDVR, an effect that was blocked by the antagonist BMS-180,291. In separate protocols, microperfused OMDVR were pretreated with U63577A or SQ-29548, after which they were exposed to luminal Ang II to induce vasoconstriction. Both agents inhibited vasoconstriction whether preexposure to them was via the bath or the perfusate. We conclude that Ang II–induced constriction of OMDVR is partly mediated by metabolites of arachidonic acid, including thromboxanes.
Effect of Arterial Baroreceptor Denervation on Sodium Balance
Authors: DiBona Gerald F. , Sawin Linda L.
Published: October 2002

During chronic increased dietary sodium intake, arterial baroreceptors buffer against sustained increases in arterial pressure, and renal sympathoinhibition contributes importantly to the maintenance of sodium balance by decreasing renal tubular sodium reabsorption and increasing urinary sodium excretion. The present study examined the effect of arterial baroreceptor denervation on sodium balance in conscious rats during low, normal, and high dietary sodium intake. Compared with measurements made before arterial baroreceptor denervation, arterial baroreceptor–denervated rats had similar sodium balance during normal dietary sodium intake but significantly more negative sodium balance during low dietary sodium intake and significantly more positive sodium balance during high dietary sodium intake. At the end of the high dietary sodium intake period, arterial pressure (under anesthesia) was 159±5 mm Hg after arterial baroreceptor denervation and 115±1 mm Hg before arterial baroreceptor denervation. Sham arterial baroreceptor denervation in time control rats had no effect on sodium balance or arterial pressure during the different dietary sodium intakes. These studies indicate that (1) arterial baroreceptor denervation impairs the ability to establish sodium balance during both low and high dietary sodium intake, and (2) arterial baroreceptor denervation leads to the development of increased arterial pressure during high dietary sodium intake in association with increased renal sodium retention.
Ventrolateral Medulla AT
1
Receptors Support Blood Pressure in Hypertensive Rats
Authors: Ito Satoru , Komatsu Kazutoshi , Tsukamoto Kazuyoshi , Kanmatsuse Katsuo , Sved Alan F.
Published: October 2002

Angiotensin within the central nervous system appears to be important for the maintenance of hypertension in spontaneously hypertensive rats. This study addresses the hypothesis that blockade of AT
1
receptors in the rostral ventrolateral medulla would decrease blood pressure in spontaneously hypertensive rats and that this tonically active AT
1
-mediated input to the rostral ventrolateral medulla arises from the hypothalamic paraventricular nucleus. Injection of the nonpeptide AT
1
receptor antagonist valsartan bilaterally into the rostral ventrolateral medulla of choralose-anesthetized adult spontaneously hypertensive rats produced a dose-related decrease in mean arterial pressure, with a maximal effect of ≈30 mm Hg. Inhibition of the paraventricular nucleus by local injection of muscimol elicited a similar response, which was inhibited by prior injection of valsartan into the rostral ventrolateral medulla. In contrast, in control Wistar-Kyoto rats, neither valsartan injected into the rostral ventrolateral medulla nor muscimol injected into the paraventricular nucleus had a substantial effect on arterial pressure. These data indicate that in spontaneously hypertensive rats but not in Wistar-Kyoto rats, rostral ventrolateral medulla vasomotor neurons are tonically excited by endogenous stimulation of AT
1
receptors, and this input is apparently driven from the hypothalamus. These results suggest that the rostral ventrolateral medulla is one site that the brain renin-angiotensin system acts to maintain elevated blood pressure in spontaneously hypertensive rats.
Association of eNOS Glu298Asp Polymorphism With End-Stage Renal Disease
Authors: Noiri Eisei , Satoh Hiroaki , Taguchi Jun-ichi , Brodsky Sergey V. , Nakao Akihide , Ogawa Yumiko , Nishijima Satomi , Yokomizo Takehiko , Tokunaga Katsushi , Fujita Toshiro
Published: October 2002

Nitric oxide (NO) derived from endothelial cells is profoundly related to the maintenance of physiological vascular tone. Impairment of endothelial NO generation brought about by gene polymorphism is considered the major deterioration factor for progressive renal disease, including diabetic nephropathy. The present study aimed to elucidate the Glu298Asp polymorphism of endothelial NO synthase (eNOS) in patients with end-stage renal disease (ESRD) and its role as a predisposing factor for cardiovascular complications. Glu298Asp in exon 7 of the eNOS gene was determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis, in ESRD patients (n=185) and compared with that of unrelated healthy individuals (n=304). The occurrence of 298Asp was significantly higher in the ESRD group (
P
=0.0020; odds ratio [OR] 1.65; 95% confidential interval [CI]: 1.21 to 2.25). In this group, 72 patients had type 2 diabetes mellitus (DM). Although 298Asp did not reach a significant level in the non-DM ESRD subgroup, the occurrence of 298Asp was significantly higher in DM-derived ESRD patients (
P
=0.0010; OR 2.02; 95% CI: 1.37 to 3.07). The functional effect of the Glu298Asp was examined using Chinese hamster ovary (CHO) cells stably overexpressing either 1917G or 1917T. NO-selective electrode measurements and fluorometric nitrite assay revealed a statistically significant difference in NO production or nitrite accumulation between CHO 1917G and 1917T (
P
<0.01). These data indicated that Glu298Asp is the predisposing factor in ESRD, especially DM-derived ESRD. The functional difference in NO generation depending on eNOS with either glutamate or aspartate at position 298 was also confirmed in vitro.
Spironolactone Improves Angiotensin-Induced Vascular Changes and Oxidative Stress
Authors: Virdis Agostino , Neves Mario Fritsch , Amiri Farhad , Viel Emilie , Touyz Rhian M. , Schiffrin Ernesto L.
Published: October 2002

Angiotensin II plays an important role in vascular remodeling. We investigated the role of aldosterone, which is stimulated by angiotensin II, as a mediator of angiotensin II–induced vascular structural and functional alterations. Sprague-Dawley rats (n=8 to 12/group) received angiotensin II (120 ng/kg per minute, subcutaneously) for 14 days ± spironolactone or hydralazine (25 mg/kg per day). An additional group received aldosterone (750 ng/h, subcutaneously) ± spironolactone. Systolic blood pressure was increased by angiotensin II (
P
<0.001) and reduced by spironolactone and hydralazine (
P
<0.001). Aldosterone-induced increase of blood pressure was reduced by spironolactone (
P
<0.05). In mesenteric small arteries studied on a pressurized myograph, media/lumen ratio was increased (
P
<0.001) and acetylcholine-mediated relaxation was impaired in angiotensin II–infused rats (
P
<0.001); both were partially improved by spironolactone (
P
<0.05) but not by hydralazine. Aldosterone-induced increase of media/lumen ratio (
P
<0.001) and impaired response to acetylcholine (
P
<0.001) were normalized by spironolactone. Response to sodium nitroprusside was similar in all groups. Aortic NADPH oxidase activity was increased (
P
<0.01) by angiotensin II and reduced by spironolactone and hydralazine. Aldosterone also increased (
P
<0.05) activation of NADPH oxidase, an effect abolished by spironolactone. Plasma thiobarbituric acid–reactive substances (a marker of oxidative stress), higher in angiotensin II and aldosterone rats (
P
<0.001), were normalized by spironolactone. In conclusion, spironolactone, which inhibited aldosterone actions, partially corrected structural and functional angiotensin II–induced abnormalities. These effects were associated with reduced vascular NADPH oxidase activity and decreased plasma markers of oxidative stress. Our findings suggest that aldosterone may mediate some of angiotensin II–induced vascular effects in hypertension, in part via increased oxidative stress.
Prognosis of Inappropriate Left Ventricular Mass in Hypertension
Authors: de Simone Giovanni , Verdecchia Paolo , Pede Sergio , Gorini Marco , Maggioni Aldo Pietro
Published: October 2002

To evaluate the prognostic impact of left ventricular (LV) mass exceeding individual needs to compensate hemodynamic load, the percentage of excess of echocardiographic LV mass in relation to individual ideal value predicted by gender, stroke work, and height (in meter
2.7
) from a reference population was assessed in 1019 white hypertensives (627 women [24% obese] and 392 men [17% obese,
P
<0.02 versus women]) without prevalent cardiovascular disease or type 1 diabetes, from the Italian multicenter, prospective study MAVI. Low LV mass (<73% of predicted) was found in 36 patients (3.5%), 661 had appropriate LV mass, and 322 (37%) had inappropriate LV mass. During follow-up (35±11 months), 52 fatal or nonfatal primary cardiovascular events occurred. Age, systolic blood pressure, and LV mass as a percentage of the predicted value were significant predictors of cardiovascular events (all
P
<0.01), independently of gender, glycemia, antihypertensive treatments, and body mass index, even in subgroups with or without LV hypertrophy. Survival analysis showed that cardiovascular risk increased stepwise from the lowest to the highest quintile of LV mass as a percentage of predicted value (
P
<0.01). The excess LV mass showed incremental prognostic value compared with assessment of traditional LV mass (
P
<0.01). Thus, inappropriate LV mass predicts a risk of cardiovascular events, independently of risk factors, and remains a significant predictor of risk either in the presence or in the absence of traditionally defined LV hypertrophy.
Angiotensin II AT
1
Receptor Antagonists Inhibit Platelet Adhesion and Aggregation by Nitric Oxide Release
Authors: Kalinowski Leszek , Matys Tomasz , Chabielska Ewa , Buczko Włodzimierz , Malinski Tadeusz
Published: October 2002

This study investigated the process of nitric oxide (NO) release from platelets after stimulation with different angiotensin II type 1 (AT
1
)-receptor antagonists and its effect on platelet adhesion and aggregation. Angiotensin II AT
1
-receptor antagonist–stimulated NO release in platelets was compared with that in human umbilical vein endothelial cells by using a highly sensitive porphyrinic microsensor. In vitro and ex vivo effects of angiotensin II AT
1
-receptor antagonists on platelet adhesion to collagen and thromboxane A
2
analog U46619-induced aggregation were evaluated. Losartan, EXP3174, and valsartan alone caused NO release from platelets and endothelial cells in a dose-dependent manner in the range of 0.01 to 100 μmol/L, which was attenuated by NO synthase inhibitor N
G
-nitro-
l
-arginine methyl ester. The angiotensin II AT
1
-receptor antagonists had more than 70% greater potency in NO release in platelets than in endothelial cells. The degree of inhibition of platelet adhesion (collagen-stimulated) and aggregation (U46619-stimulated) elicited by losartan, EXP3174, and valsartan, either in vitro or ex vivo, closely correlated with the NO levels produced by each of these drugs alone. The inhibiting effects of angiotensin II AT
1
-receptor antagonists on collagen-stimulated adhesion and U46619-stimulated aggregation of platelets were significantly reduced by pretreatment with N
G
-nitro-
l
-arginine methyl ester. Neither the AT
2
receptor antagonist PD123319, the cyclooxygenase synthase inhibitor indomethacin, nor the selective thromboxane A
2
/prostaglandin H
2
receptor antagonist SQ29,548 had any effect on angiotensin II AT
1
-receptor antagonist–stimulated NO release in platelets and endothelial cells. The presented studies clearly indicate a crucial role of NO in the arterial antithrombotic effects of angiotensin II AT
1
-receptor antagonists.
Goal-Oriented Hypertension Management
Authors: Singer Gregory M. , Izhar Munavvar , Black Henry R.
Published: October 2002

Several clinical trials using a blood pressure (BP) treatment algorithm focused on a predetermined goal have achieved better control rates than those of national survey data. These trials reached the Sixth Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI) diastolic blood pressure (DBP) goal of <90 mm Hg in >90% of volunteers and systolic blood pressure (SBP) goal of <140 mm Hg in >60% of volunteers. We evaluated BP control of 437 consecutive patients after at least one year of follow up in a specialist clinic which employed “goal-oriented management,” ie, treating to a specific BP goal without a formal drug treatment algorithm, to determine whether JNC VI goals could be achieved. Overall, 276 (63%) patients achieved SBP goal, with 376 (86%) at DBP goal and 358 (59%) at both goals. Only 23% of patients were on monotherapy, with 34% requiring 2 drugs and 37% requiring 3 or more medications. There was no substantial difference in BP control rates among age, gender, and ethnicity subgroups. However, in the 20% of patients who were diabetic, only 52% had a BP of <140 mm Hg and <90 mm Hg, whereas fewer (22% and 15%, respectively) achieved the more stringent goals of JNC VI and the American Diabetic Association (ADA)/National Kidney Foundation (NKF). Goal-oriented management achieved dramatically better control rates than what is reported. Although DBP control was easy to achieve, achieving SBP goal still remained difficult. Employing goal-oriented management can translate BP control results achieved in clinical trials into outpatient practice.
Gene Dosage-Dependent Effects of Cardiac-Specific Overexpression of the A
3
Adenosine Receptor
Authors: Black Richard G. , Guo Yiru , Ge Zhi-Dong , Murphree Sidney S. , Prabhu Sumanth D. , Jones W. Keith , Bolli Roberto , Auchampach John A.
Published: October 2002

We used a genetic approach to determine whether increasing the level of A
3
adenosine receptors (A
3
ARs) expressed in the heart confers protection against ischemia without causing cardiac pathology. We generated mice carrying one (A
3
tg.1) or six (A
3
tg.6) copies of a transgene consisting of the cardiomyocyte-specific α-myosin heavy chain gene promoter and the A
3
AR cDNA. A
3
tg.1 and A
3
tg.6 mice expressed 12.7±3.15 and 66.3±9.4 fmol/mg of the high-affinity G protein–coupled form of the A
3
AR in the myocardium, respectively. Extensive morphological, histological, and functional analyses demonstrated that there were no apparent abnormalities in A
3
tg.1 transgenic mice compared with nontransgenic mice. In contrast, A
3
tg.6 mice exhibited dilated hearts, expression of markers of hypertrophy, bradycardia, hypotension, and systolic dysfunction. When A
3
tg mice were subjected to 30 minutes of coronary occlusion and 24 hours of reperfusion, infarct size was reduced ≈30% in A
3
tg.1 mice and ≈40% in A
3
tg.6 mice compared with nontransgenic littermates. The reduction in infarct size in the transgenic mice was not related to differences in risk region size, systemic hemodynamics, or body temperature, indicating that the cardioprotection was a result of increased A
3
AR signaling in the ischemic myocardium. The results demonstrate that low-level expression of A
3
ARs in the heart provides effective protection against ischemic injury without detectable adverse effects, whereas higher levels of A
3
AR expression lead to the development of a dilated cardiomyopathy.