摘要:

The chloride channel ClC-Kb is expressed in the basolateral cell membrane of the distal nephron and participates in renal NaCl reabsorption. Loss-of-function mutations of ClC-Kb lead to classic Bartter syndrome, a rare salt-wasting disorder. Recently, we identified the ClC-KbT481Spolymorphism, which confers a strong gain-of-function effect on the ClC-Kb chloride channel. The present study has been performed to explore the prevalence of the mutation and its functional significance in renal salt handling and blood pressure regulation. As evident from electrophysiological analysis with the 2-electrode voltage-clamp technique, heterologous expression of ClC-KbT481Sin Xenopus oocytes gave rise to a current that was 7-fold larger than the current produced by wild-type ClC-Kb. The prevalence of the mutant allele was significantly higher in an African population from Ghana (22%) than in whites (12%). As tested in 1 white population, carriers of ClC-KbT481Swere associated with significantly higher systolic (by ≈6.0 mm Hg) and diastolic (by ≈4.2 mm Hg) blood pressures and significantly higher prevalence (45% versus 25%) of hypertensive (≥140/90 mm Hg) blood pressure levels. Individuals carrying ClC-KbT481Shad significantly higher plasma Na+concentrations and significantly decreased glomerular filtration rate. In conclusion, the mutation ClC-KbT481Sof the renal epithelial Cl−channel ClC-Kb strongly activates ClC-Kb chloride channel function in vitro and may predispose to the development of essential hypertension in vivo.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

The degree to which ethnic differences in left ventricular structure among hypertensive adults are independent of clinical and hemodynamic factors remains uncertain. We assessed whether left ventricular mass and geometry differ between black and white hypertensives after accounting for differences in such factors. Our study group comprised 1060 black and 580 white hypertensive participants free of valvular or coronary disease in a population-based cohort. Blood pressure was measured during a clinic visit and echocardiography was performed using standardized protocols. After controlling for clinical and hemodynamic parameters (cardiac index, peripheral resistance index, and pulse pressure/ stroke index), both left ventricular mass and relative wall thickness were higher in blacks than whites (173.9±30.9 versus 168.3±24.3 grams,P=0.006, and 0.355±0.055 versus 0.340±0.055 grams,P<0.001). Similarly, the adjusted risk of having left ventricular hypertrophy, whether indexed by height2.7or by body surface area, was greater for blacks than for whites (odds ratio: 1.80; 95% CI: 1.29 to 2.51; and odds ratio: 2.50; 95% CI: 1.58 to 3.96, respectively), and this was also true for concentric geometry (odds ratio: 2.28; 95% CI: 1.22 to 4.25). Further adjustment for relatedness in this genetic epidemiological study did not attenuate these differences. Our findings confirm the strong association between black ethnicity and increased left ventricular mass and relative wall thickness in hypertensive adults and demonstrate that these differences are independent of standard clinical and hemodynamic parameters. Whether such differences relate to distinct ambulatory pressure profiles or an ethnic propensity to cardiac hypertrophy requires further investigation.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

A common intronic polymorphism, (−1332 G/A) of the angiotensin type-2 receptor gene, located on the X-chromosome, has been reported to be functional. The aim of our study was to evaluate this polymorphism for an association with left ventricular hypertrophy. Left ventricle (LV) mass was measured in 197 patients with systemic hypertension and 60 normal volunteers using a 1.5-Tesla Philips MRI system. Genotyping was performed using a restriction enzyme digestion of an initial 310-bp polymerase chain reaction product that included the angiotensin type-2 (−1332 G/A) locus. The mean LV mass index for the male patients was 94.3±19.6 g/m2(n= 125) and for the female patients was 71.2±12.0 g/m2(n=72). Seventy-three (37.1%) of all patients had an elevated LV mass index, defined as the mean LV mass index for normal volunteers plus 2 SD (males 77.8±9.1 g/m2, n= 30; females 61.5±7.5g/m2, n= 30). Comparison of LV mass index of the A_/AA genotype (mean LV mass index= 82.4±21.1 g/m2; n= 123) against that of the G_/GG genotype (mean LV mass index= 88.1±19.0 g/m2; n= 89) as a continuous variable was significant by ANOVA (P= 0.044). χ2Comparison between subjects with and subjects without left ventricular hypertrophy revealed an excess of the G_/GG genotype among the group with LV hypertrophy (P= 0.031). We observed an association between the angiotensin type-2 receptor (−1332 G) allele and the presence of left ventricular hypertrophy in hypertensive subjects.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Osteopontin (OPN) is upregulated in several experimental models of cardiac fibrosis and remodeling. However, its direct effects remain unclear. We examined the hypothesis that OPN is important for the development of cardiac fibrosis and remodeling. Moreover, we examined whether the inhibitory effect of eplerenone (Ep), a novel aldosterone receptor antagonist, was mediated through the inhibition of OPN expression against cardiac fibrosis and remodeling. Wild-type (WT) and OPN-deficient mice were treated with angiotensin II (Ang II) for 4 weeks. WT mice receiving Ang II were divided into 2 groups: a control group and an Ep treatment group. Ang II treatment significantly elevated blood pressure and caused cardiac hypertrophy and fibrosis in WT mice. Ep treatment and OPN deficiency could reduce the Ang II–induced elevation of blood pressure and ameliorate the development of cardiac fibrosis, whereas Ep-only treatment abolished the development of cardiac hypertrophy. Most compelling, the reduction of cardiac fibrosis led to an impairment of cardiac systolic function and subsequent left ventricular dilatation in Ang II–treated OPN-deficient mice. These results suggest that OPN has a pivotal role in the development of Ang II–induced cardiac fibrosis and remodeling. Moreover, the effect of Ep on the prevention of cardiac fibrosis, but not cardiac hypertrophy, might be partially mediated through the inhibition of OPN expression.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Race has been considered an important factor in determining blood pressure response to treatment and selection of antihypertensive drug therapy. Data collected during a clinical trial that evaluated rapidity of medication up-titration with blood pressure response to monotherapy with the angiotensin-converting enzyme (ACE) inhibitor quinapril were used to characterize response in 533 black and 2046 white participants. Our objectives were to examine the influence of race and other factors on blood pressure response and to assess the degree to which nonrace factors account for apparent racial differences in response. Average systolic and diastolic blood pressure responses (baseline minus follow-up) to treatment were assessed with treatment groups combined. Crude systolic and diastolic blood pressure responses averaged 4.7 and 2.4 mm Hg less, respectively, in black compared with white participants; however, the response distributions largely overlapped. In multivariate linear regression models adjusted for study design variables and measured participant characteristics, the racial difference in systolic response was reduced by 51% to 2.3 mm Hg, and diastolic response by 21% to 1.9 mm Hg. In these models, participant characteristics, including age, gender, body size, and pretreatment blood pressure severity, significantly predicted either attenuated or enhanced blood pressure response to treatment. Our findings demonstrate that a large source of variability of blood pressure response to treatment is within, not between, racial groups, and that factors that vary at the level of the individual contribute to apparent racial differences in response to treatment.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. However, the underlying mechanism of endothelial cell injury in hyperhomocysteinemia has not been elucidated. In this study, we examined the effect of homocysteine (Hcy) on Fas-mediated apoptosis in endothelial cells. Hcy-induced upregulation of Fas in endothelial cells (ECs) in a dose-dependent manner. At the same time, Hcy increased intracellular peroxide in ECs. Hcy-induced Fas expression was inhibited by the treatment with catalase. Hcy increased NF-κinding activity, and adenovirus-mediated transfection of aIκ-Bmutant (Iκ-B mt) gene inhibited Hcy-induced Fas expression. ECs were sensitive to Fas-mediated apoptosis when exposed to Hcy. Under these condition, Iκ-B mt protected ECs from Fas-mediated apoptosis. In addition, Hcy inhibited expression of the caspase-8 inhibitor FLICE-inhibitory protein (FLIP). Adenovirus-mediated transfection of constitutively activeAktgene abolished the Hcy-mediated downregulation of FLIP. These data suggest that upregulation of Fas expression and downregulation of FLIP is a mechanism through which Hcy induces EC apoptosis.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are widely prescribed to lower cholesterol. Recent reports suggest that statins may promote angiogenesis in ischemic tissues. It remains to be elucidated whether statins potentially enhance unfavorable angiogenesis associated with tumor and atherosclerosis. Here, we induced hind limb ischemia in wild-type mice by resecting the right femoral artery and subsequently inoculated cancer cells in the same animal. Cerivastatin enhanced blood flow recovery in the ischemic hind limb as determined by laser Doppler imaging, whereas tumor growth was significantly retarded. Cerivastatin did not affect capillary density in tumors. Cerivastatin, pitavastatin, and fluvastatin inhibited atherosclerotic lesion progression in apolipoprotein E-deficient mice, whereas they augmented blood flow recovery and capillary formation in ischemic hind limb. Low-dose statins were more effective than high-dose statins in both augmentation of collateral flow recovery and inhibition of atherosclerosis. These results suggest that statins may not promote the development of cancer and atherosclerosis at the doses that augment collateral flow growth in ischemic tissues.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

The heme-heme oxygenase (HO) system has been implicated in the regulation of vascular reactivity and blood pressure. This study examines the notion that overexpression of HO decreases pressor responsiveness to angiotensin II (Ang II). Five-day-old Sprague-Dawley rats received an intraleft ventricular injection of ≈5×109cfu/mL of retroviruses containing human HO-1 sense (LSN-HHO-1), rat HO-1 antisense (LSN-RHO-1-AS), or control retrovirus (LXSN). Three months later, rats were instrumented with femoral arterial and venous catheters for mean arterial pressure (MAP) determination and Ang II administration, respectively. Rats injected with LSN-HHO-1, but not with LXSN, expressed human HO-1 mRNA and protein in several tissues. BP increased with administration of Ang II in rats expressing and not expressing human HO-1. However, the Ang II-induced pressor response (mm Hg) in LSN-HHO-1 rats (16±3, 27±3, and 38±3 at 0.5, 2, and 10 ng) was surpassed (P<0.05) in LXSN rats (23±1, 37±2, and 52±2 at 0.5, 2, and 10 ng). Importantly, treating LSN-HHO-1 rats with the HO inhibitor tin mesoporphyrin (SnMP) enhanced (P<0.05) the Ang II-induced pressor response to a level not different from that observed in LXSN rats. Rats injected with LSN-RHO-1-AS showed a decrease in renal HO-1 protein expression and HO activity relative to control LXSN rats. Administration of Ang II (0.1 to 2 ng) caused small (4 to 5 mm Hg) but significant increases in MAP in rats injected with LSN-RHO-1-AS (P<0.05) compared with rats injected with LXSN. These data demonstrate that overexpression of HO-1 brings about a reduction in pressor responsiveness to Ang II, which is most likely due to increased generation of an HO-1 product, presumably CO, with the ability to inhibit vascular reactivity to constrictor stimuli.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Neuronal reuptake (uptake-1) constitutes the main route of inactivation of the sympathetic neurotransmitter norepinephrine in the heart and therefore contributes importantly to cardiac sympathetic neuroeffector function. In laboratory animals and in vitro preparations, half saturation of the transporter occurs at norepinephrine concentrations of 0.1 to 1 μmol/L. This study addressed whether endogenous norepinephrine can attain high enough plasma concentrations in humans to inhibit cardiac uptake-1. Patients with increased plasma norepinephrine levels due to pheochromocytoma were assessed by 6-[18F]fluorodopamine positron emission tomography. Above an antecubital venous plasma concentration of 3 nmol/L (≈500 pg/mL), left ventricular myocardial 6-[18F]fluorodopamine–derived radioactivity varied inversely with the logarithm of the plasma norepinephrine concentration (r=−0.77,P<0.0001). Reduction of plasma norepinephrine levels by treatment of the pheochromocytoma increased myocardial 6-[18F]fluoro-dopamine–derived radioactivity. At sufficiently high plasma concentrations, endogenous norepinephrine can compete with sympathetic imaging agents for uptake-1. The results call for caution in drawing quantitative conclusions about uptake-1 in the setting of high circulating concentrations of endogenous norepinephrine.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

The role of the angiotensin II type-2 receptor (AT2R) in cardiac hypertrophy remains elusive despite its demonstrated involvement in cardiovascular development. We have previously shown that a lentiviral vector gene delivery system is able to transduce cardiac tissue with high efficiency in vivo. Using such an approach, our objectives in the present study were 2-fold: (1) to overexpress the AT2R in cardiac tissue after completion of natural embryonic development of the heart and (2) to determine the effects of this overexpression on cardiac hypertrophy and basal blood pressure (BP). A lentiviral vector encoding the AT2R (lenti-AT2R) was administered (1.5×108transducing units) into the left ventricular space of 5-day-old spontaneously hypertensive rats (SHRs). AT2R transgene expression increased in these animals and persisted for 30 weeks. In contrast, the expression of the angiotensin II type-1 receptor remained unchanged following lenti-AT2R treatment. At 21 weeks following gene transduction, the lenti-AT2R–treated SHRs exhibited decreased left ventricular wall thickness compared with control animals. In contrast, basal BP did not differ between the two SHR groups. Finally, heart weight to body weight ratios indicated a significant decrease in lenti-AT2R-treated SHRs compared with SHR controls. Our data indicate that AT2R overexpression attenuates cardiac hypertrophy in the SHR. This beneficial outcome was observed despite the existence of elevated BP.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID