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11. |
Endogenous Angiotensin II Induces Atherosclerotic Plaque Vulnerability and Elicits a Th1 Response in ApoE−/−Mice |
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Hypertension,
Volume 44,
Issue 3,
2004,
Page 277-282
Lucia,
Mazzolai Michel,
Duchosal Martine,
Korber Karima,
Bouzourene Jean François,
Aubert Hiroyuki,
Hao Veronique,
Vallet Hans-R,
Brunner Jürg,
Nussberger Giulio,
Gabbiani Daniel,
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摘要:
Rupture of vulnerable plaques is the main cause of acute cardiovascular events. However, mechanisms responsible for transforming a stable into a vulnerable plaque remain elusive. Angiotensin II, a key regulator of blood pressure homeostasis, has a potential role in atherosclerosis. To study the contribution of angiotensin II in plaque vulnerability, we generated hypertensive hypercholesterolemic ApoE−/−mice with either normal or endogenously increased angiotensin II production (renovascular hypertension models). Hypertensive high angiotensin II ApoE−/−mice developed unstable plaques, whereas in hypertensive normal angiotensin II ApoE−/−mice plaques showed a stable phenotype. Vulnerable plaques from high angiotensin II ApoE−/−mice had thinner fibrous cap (P<0.01), larger lipid core (P<0.01), and increased macrophage content (P<0.01) than even more hypertensive but normal angiotensin II ApoE−/−mice. Moreover, in mice with high angiotensin II, a skewed T helper type 1-like phenotype was observed. Splenocytes from high angiotensin II ApoE−/−mice produced significantly higher amounts of interferon (IFN)-&ggr; than those from ApoE−/−mice with normal angiotensin II; secretion of IL4 and IL10 was not different. In addition, we provide evidence for a direct stimulating effect of angiotensin II on lymphocyte IFN-&ggr; production. These findings suggest a new mechanism in plaque vulnerability demonstrating that angiotensin II, within the context of hypertension and hypercholesterolemia, independently from its hemodynamic effect behaves as a local modulator promoting the induction of vulnerable plaques probably via a T helper switch.
ISSN:0194-911X
出版商:OVID
年代:2004
数据来源: OVID
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12. |
Transcriptional Regulation of Type B Human Natriuretic Peptide Receptor Gene PromoterDependence on Sp1 |
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Hypertension,
Volume 44,
Issue 3,
2004,
Page 283-288
Dolkun,
Rahmutula Junfeng,
Cui Songcang,
Chen David,
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摘要:
The type B natriuretic peptide receptor (NPR-B) is the cognate receptor for the C-type natriuretic peptide and, as such, is responsible for signaling growth-suppressant activity in vascular smooth muscle cells. Here we report the isolation and characterization of the human (h) NPR-B gene promoter. Using 5′ rapid amplification of cDNA ends analysis, we have identified the 5′ terminus of the hNPR-B gene transcript ≈732 base pairs upstream from the presumed translation start site of the protein. We generated a series of 5′ deletion mutants linked to a luciferase reporter and introduced these constructs into rat aortic smooth muscle cells or neonatal rat cardiac fibroblasts. Maximal expression was seen with a construct harboring 441 base pairs of 5′ flanking sequence. Site-directed mutagenesis of the proximal promoter revealed a series of GC-rich sequences, 5 of which contributed modestly (≈25%) to basal hNPR-B promoter activity. Mutation of a sixth GC-rich sequence led to a >90% reduction in promoter activity. This sequence was shown to associate with Sp1 and Sp3 in vitro. The same mutation that resulted in loss of functional activity also resulted in loss of binding activity in vitro. Overexpression of Sp1 or Sp3 inDrosophilaSchneider cells resulted in an increase in hNPR-B promoter activity that was completely nullified with the Sp1 binding site mutation described above. These studies provide the first description and characterization of the NPR-B gene promoter and suggest that this promoter’s activity is dominated by a single cluster of Sp1-binding elements in the proximal 5′ flanking sequence of the gene.
ISSN:0194-911X
出版商:OVID
年代:2004
数据来源: OVID
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13. |
Is the Extrapolated Adult Dose of Fosinopril Safe and Effective in Treating Hypertensive Children? |
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Hypertension,
Volume 44,
Issue 3,
2004,
Page 289-293
Jennifer,
Li Katherine,
Berezny Rakhi,
Kilaru Lydie,
Hazan Ronald,
Portman Ronald,
Hogg Randall,
Jenkins Prapti,
Kanani Carol,
Cottrill Tej,
Mattoo Ludmila,
Zharkova Ludmila,
Kozlova Irit,
Weisman David,
Deitchman Robert,
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摘要:
We evaluated the efficacy, safety, and dose–response relationship of fosinopril in children aged 6 to 16 years with hypertension or high-normal blood pressure with an associated medical condition requiring treatment. The study was a prospective, double-blind, placebo-controlled trial conducted in 78 clinical sites in the United States, Russia, and Israel. There were 4 phases: a screening phase of 10 days maximum, a 4-week dose–response phase, a placebo withdrawal phase of 2 weeks maximum, and a 52-week open-label safety phase. The primary objective of the dose–response phase was to determine whether low (0.1 mg/kg), medium (0.3 mg/kg), or high (0.6 mg/kg) doses of fosinopril based on established adult dosing affect trough seated systolic blood pressure. During the dose–response phase, all 3 doses were equally effective in lowering systolic blood pressure. During the placebo withdrawal phase, there was an adjusted mean systolic blood pressure increase of 5.2 mm Hg for the placebo group and 1.5 mm Hg for the fosinopril group, a net withdrawal effect of 3.7 mm Hg (P=0.013). Fosinopril was well tolerated; serious adverse events occurred infrequently and were generally not attributed to fosinopril. Because children appear to be more sensitive to lower doses of fosinopril than adults, starting doses for children should be ≤0.1 mg/kg.
ISSN:0194-911X
出版商:OVID
年代:2004
数据来源: OVID
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14. |
Effect of Angiotensin-Converting Enzyme Inhibition on Survival in 3773 Chinese Type 2 Diabetic Patients |
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Hypertension,
Volume 44,
Issue 3,
2004,
Page 294-299
Wing,
So Risa,
Ozaki Norman,
Chan Peter,
Tong Chung,
Ho Christopher,
Lam Gary,
Ko Chun,
Chow Wing,
Chan Ronald,
Ma Juliana,
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摘要:
We assessed the effects of angiotensin-converting enzyme (ACE) inhibition on survival and cardiorenal outcomes in a consecutive cohort of Chinese type 2 diabetic patients with varying degree of albuminuria, ranging from normoalbuminuria to macroalbuminuria. A total of 3773 consecutive Chinese type 2 diabetic patients were followed prospectively for a mean period of 35.8 months. Clinical end points included all-cause mortality, with cardiovascular end point defined as first hospitalization because of ischemic heart disease, congestive heart failure, revascularization procedures, or cerebrovascular accident as well as renal end point defined as dialysis, doubling of baseline plasma creatinine, or plasma creatinine ≥500 &mgr;mol/L. The use of ACE inhibitor was 26.3% in normoalbuminuric (NA), 70.1% in microalbuminuric (MI), and 82.6% in macroalbuminuric (MA) groups. Albuminuria was a major predictor for all-cause mortality with 4-fold difference between NA and MA patients. The 7-year cumulative mortality rate was 7.1%, 10.8%, and 21.7% in the NA, MI, and MA groups, respectively. The use of ACE inhibition was associated with significant reduction of mortality (hazard ratio 0.41 and 95% confidence interval, 0.29, 0.58) in the entire group and was most evident in high-risk patients who had cardiorenal complications or retinopathy at baseline for all albuminuric groups (NA 0.76 [0.31,1.87]; MI 0.32 [0.16, 0.65]; and MA 0.20 [0.13, 0.33]). The prognostic value of albuminuria for death in type 2 diabetes and the beneficial effects of ACE inhibitors in Chinese type 2 diabetic patients with micro- or macroalbuminuria has been confirmed. The effects of ACE inhibitors in type 2 diabetic patients with normoalbuminuria require further evaluation.
ISSN:0194-911X
出版商:OVID
年代:2004
数据来源: OVID
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15. |
Impaired Endothelial Release of Tissue-Type Plasminogen Activator in Patients With Chronic Kidney Disease and Hypertension |
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Hypertension,
Volume 44,
Issue 3,
2004,
Page 300-304
Thórdís,
Hrafnkelsdóttir Pia,
Ottosson Thorarinn,
Gudnason Ola,
Samuelsson Sverker,
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摘要:
We have shown that the capacity for local release of tissue-type plasminogen activator (tPA) from the vascular endothelium is impaired in patients with primary hypertension. Because this response is an important protective mechanism against intravascular clotting, we investigated whether this system is also defective in patients with advanced chronic kidney disease and hypertension. Nine nondiabetic nonsmoking men with chronic kidney disease (glomerular filtration rate 11 to 28 mL/min×1.73 m2; aged 33 to 75 years) were compared with age-matched healthy controls. Intraarterial infusions of desmopressin, methacholine, and sodium nitroprusside were given locally in the brachial artery. Forearm blood flow was measured by venous occlusion plethysmography and blood collected repeatedly during the desmopressin infusion for determination of stimulated net and total cumulated release of tPA. The maximal release rate of active tPA (P<0.05) and the capacity for acute tPA release were markedly impaired in the renal patients as compared with healthy subjects (ANOVA,P=0.013). Accordingly, the accumulated release of tPA was 1905 (SEM 366) and 3387 (718) ng/L tissue, respectively (P<0.05). However, there were no significant differences in vasodilator responses between the groups. Thus, patients with advanced chronic kidney disease and hypertension have a markedly impaired capacity for acute release of tissue plasminogen activator, despite preserved endothelium-dependent vasodilation. This defect may contribute to a defective local defense against arterial thrombosis.
ISSN:0194-911X
出版商:OVID
年代:2004
数据来源: OVID
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16. |
Nebivolol Increases Arterial Distensibility In Vivo |
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Hypertension,
Volume 44,
Issue 3,
2004,
Page 305-310
Carmel,
McEniery Matthias,
Schmitt Ahmad,
Qasem David,
Webb Alberto,
Avolio Ian,
Wilkinson John,
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摘要:
Arterial stiffness is a key determinant of cardiovascular risk in hypertensive patients. &bgr;-Blockers appear to be less effective than other drugs in improving outcome in hypertensive patients, and a potential explanation may be that &bgr;-blockers are less effective in reducing arterial stiffness. The aim of this study was to assess the direct effect of &bgr;-blockade on pulse wave velocity (PWV), a robust measure of arterial distensibility, using a local, ovine, hind-limb model. In addition, we hypothesized that the vasodilating &bgr;-blocker nebivolol, but not atenolol, would increase arterial distensibility in vivo. All studies were conducted in anesthetized sheep. PWV was recorded in vivo using a dual pressure-sensing catheter placed in the common iliac artery. Intraarterial infusion of nebivolol reduced PWV by 6±3% at the higher dose (P<0.001), but did not alter mean arterial pressure (change of −1±3 mm Hg,P=0.1). In contrast, atenolol had no effect on PWV (P=0.11) despite a small drop in mean pressure (change of −5±3 mm Hg,P<0.01). Infusion of glyceryl trinitrate led to a dose-dependent fall in PWV, and 2 nmol/min produced a similar reduction in PWV to the higher dose of nebivolol (500 nmol/min). The effect of nebivolol on PWV was significantly attenuated during coinfusion ofNG-monomethyl-l-arginine (P=0.003) and also during coinfusion of butoxamine (P=0.02). These results demonstrate that nebivolol, but not atenolol, increases arterial distensibility. This effect of nebivolol is mediated through the release of NO via a &bgr;2adrenoceptor–dependent mechanism. Thus, nebivolol may be of benefit in conditions of increased large artery stiffness, such as isolated systolic hypertension.
ISSN:0194-911X
出版商:OVID
年代:2004
数据来源: OVID
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17. |
Disruption of Ultradian and Circadian Rhythms of Blood Pressure in Nondipper Hypertensive Patients |
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Hypertension,
Volume 44,
Issue 3,
2004,
Page 311-315
Santiago,
Perez-Lloret Alejandro García,
Aguirre Daniel,
Cardinali Jorge,
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摘要:
Ultradian rhythms in blood pressure (BP) are known to exist, but their modification in hypertension is largely unknown. The present study was undertaken to assess the integrity of ultradian and 24-hour BP rhythms in dipper (n=100) and nondipper (n=20) hypertensive patients compared with 44 dipper normotensive individuals. Fourier analysis was used to fit ultradian (12, 8, and 6 hour) and 24-hour rhythms in BP and heart rate (HR). Mesor, amplitude, and acrophase were calculated for individual and overall rhythm curves. All subjects showed significant ultradian or 24-hour BP and HR rhythms. Systolic and diastolic BP mesor was higher in hypertensive patients compared with normotensive patients. The percentage of variability in ambulatory BP that could be explained by fitting ultradian and 24-hour rhythms was reduced in nondippers compared with normotensives or dippers. Amplitude of ultradian and 24-hour rhythms in BP increased in dippers and decreased in nondippers. Ultradian and 24-hour rhythms in HR did not differ among the 3 groups examined. Results indicate that in nondippers, blunted ultradian and 24-hour rhythm amplitude in BP was accompanied by a loss of rhythm integrity.
ISSN:0194-911X
出版商:OVID
年代:2004
数据来源: OVID
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18. |
Differences in Circadian Pattern of Ambulatory Pulse Pressure Between Healthy and Complicated Pregnancies |
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Hypertension,
Volume 44,
Issue 3,
2004,
Page 316-321
Ramón,
Hermida Diana,
Ayala Manuel,
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摘要:
With the use of ambulatory monitoring, a circadian blood pressure pattern has been shown to characterize normotensive as well as hypertensive pregnant women. However, the potential differences between healthy and complicated pregnancies in pulse pressure, an independent marker of cardiovascular risk in the general population, have not yet been investigated. We analyzed 2523 blood pressure series sampled for 48 hours once every 4 weeks from the first obstetric visit until delivery in 245 women with uncomplicated pregnancies, 140 with gestational hypertension, and 49 who developed preeclampsia. Compared with uncomplicated pregnancies, a statistically significant elevation in the 24-hour mean of pulse pressure is found in complicated pregnancies in all trimesters (P<0.001). Results further indicate similar 24-hour mean of pulse pressure between gestational hypertension and preeclampsia in the first trimester of pregnancy (P=0.158). The increase in pulse pressure among women who developed preeclampsia compared with women with gestational hypertension, although small, was statistically significant in the second trimester (1.4 mm Hg;P=0.010) and, to a larger extent, in the third trimester of pregnancy (1.8 mm Hg;P<0.001). The differences in pulse pressure between healthy and complicated pregnancies, observed already in the first trimester of gestation, are found when systolic and diastolic blood pressure for women with a later diagnosis of gestational hypertension or preeclampsia are within the accepted range of normotension. Moreover, ambulatory pulse pressure provides higher sensitivity than clinic measurements for the diagnosis of hypertension in pregnancy.
ISSN:0194-911X
出版商:OVID
年代:2004
数据来源: OVID
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19. |
Cellular-Free Magnesium Depletion in Brain and Muscle of Normal and Preeclamptic PregnancyA Nuclear Magnetic Resonance Spectroscopic Study |
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Hypertension,
Volume 44,
Issue 3,
2004,
Page 322-326
Lawrence,
Resnick Mario,
Barbagallo Mordechai,
Bardicef Orit,
Bardicef Yoram,
Sorokin Jeffrey,
Evelhoch Ligia,
Dominguez Brian,
Mason David,
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摘要:
Preeclampsia is a pregnancy disorder of unknown origin, characterized by vasospasm, elevated blood pressure, and increased neuromuscular irritability, features common to syndromes of magnesium deficiency. Evidence of serum and ionized magnesium metabolism disturbances have been observed in women with preeclampsia. This and the therapeutic utility of magnesium in preeclampsia led us to investigate the extent to which an endogenous tissue magnesium deficiency might be present in and contribute to its pathophysiology. We used31P nuclear magnetic resonance spectroscopy to noninvasively measure in situ intracellular-free magnesium levels in brain and skeletal muscle of fasting nonpregnant women (n=12), and of third trimester women with uncomplicated pregnancies (n=11) and preeclampsia (n=7). Compared with nonpregnant controls (brain 519±59 &mgr;mol/L; muscle 604±34 &mgr;mol/L), brain and skeletal muscle intracellular magnesium levels were significantly lower in both normal pregnant (brain 342±23 &mgr;mol/L; muscle 482±40 &mgr;mol/L;P=0.05 for both tissues) and preeclamptic women (brain 229±17 &mgr;mol/L; muscle 433±46 &mgr;mol/L;P=0.05 for both tissues). Brain intracellular magnesium was further reduced in preeclamptics compared with normal pregnant subjects (P=0.05). For all pregnant subjects, blood pressure was significantly and inversely related to the concomitantly measured intracellular magnesium level in brain (systolic,r=−0.59,P=0.01; diastolic,r=−0.52,P=0.02) but not in muscle. Cellular magnesium depletion is characteristic of normal pregnancy and may be one factor contributing to the pathophysiology of preeclampsia. Furthermore, the influence of central nervous system factors on blood pressure may be mediated, at least in part, by ambient intracellular magnesium levels.
ISSN:0194-911X
出版商:OVID
年代:2004
数据来源: OVID
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20. |
Moderate Hyperhomocysteinemia Decreases Endothelial-Dependent Vasorelaxation in Pregnant But Not Nonpregnant Mice |
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Hypertension,
Volume 44,
Issue 3,
2004,
Page 327-333
Robert,
Powers Robin,
Gandley David,
Lykins James,
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摘要:
Increased homocysteine is associated with the pregnancy complication preeclampsia and with later-life cardiovascular disease. Although elevated homocysteine persists after pregnancy, the vascular changes of preeclampsia abate with delivery, and cardiovascular disease occurs decades later. This suggests the vasculature during pregnancy may manifest increased sensitivity to homocysteine. We used the cystathionine-&bgr; synthase (CBS)–deficient transgenic mouse to investigate whether hyperhomocysteinemia would differentially affect vascular function in nonpregnant and pregnant animals. Mesenteric arteries from nonpregnant and midpregnant (14 to 16 days) wild-type, heterozygous, and homozygous CBS-deficient transgenic mice were investigated for their response to vasoconstriction, endothelial-dependent, and endothelial-independent relaxation using an isometric wire myograph system. Endothelial-dependent vasodilation was similar in arteries from nonpregnant heterozygous and wild-type mice. In contrast, endothelial-dependent relaxation was reduced significantly in arteries from pregnant heterozygous animals compared with wild-type mice. Inhibition of NO synthesis blunted relaxation in arteries from pregnant wild-type but not pregnant heterozygous mice. Endothelial-dependent relaxation was restored by in vitro pretreatment with the tetrahydrobiopterin precursor sepiapterin. These data indicate that in pregnant mice, endothelial-dependent vasodilation is more sensitive to the effect of increased homocysteine than arteries from nonpregnant mice. This effect appears to result from a loss in NO-mediated relaxation that may be mediated by the oxidative inactivation of the NO synthase cofactor tetrahydrobiopterin.
ISSN:0194-911X
出版商:OVID
年代:2004
数据来源: OVID
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