Alteration of erythrocyte membrane Na,K-ATPase in children with borderline or essential hypertension

The aim of this study was to evaluate the substrate (ATP) kinetics of erythrocyte membrane Na, K-ATPase in children with borderline or essential hypertension. Although the activity of Na, K-ATPase in the presence of in vivo concentrations of ATP was not significantly altered, kinetic studies showed an obvious inhibition of enzyme activity in the erythrocyte membrane of children with borderline or essential hypertension. Hanes plot analysis revealed a decrease of V_max from 7·19 in erythrocytes from control subjects to 4·93 and 3·33 in those from children with borderline or essential hypertension, respectively. A mean value of the K_m decreased from 0·10 in the control to 0·08 and 0·02 in children with borderline or essential hypertension, respectively. The energy status of erythrocytes, estimated by ATP, ADP and AMP levels, ATP/ADP ratio, and adenylate energy charge (AEC) was not significantly changed in the cells from hypertensive children. The use of a free radical-generating system (FeSO₄/ascorbate) in vitro significantly reduced enzyme activity in the control erythrocytes while in those from hypertensive children it was abolished completely. The level of lipid peroxides was considerably higher (+37 per cent) in the plasma, while that of reduced glutathione was significantly lower both in the erythrocytes and the plasma of children with essential hypertension than in healthy children. These results indicate significant alterations of the antioxidant status which could be the cause of the inhibited Na,K-ATPase activity in erythrocyte membranes from hypertensive children.     

Enantioselectivity in the steady‐state pharmacokinetics of metoprolol in hypertensive patients

In the present study we investigated the enantioselectivity in the pharmacokinetics of metoprolol administered in a multiple‐dose regimen as the racemate. The study was conducted on 10 patients of both sexes with mild to severe essential hypertension, aged 28 to 76 years, with normal hepatic and renal function and phenotyped as extensive metabolizers of debrisoquine (urine debrisoquine to 4‐hydroxydebrisoquine ratios of 0.28 to 6.56). The patients were treated with racemic metoprolol (two 100 mg tablets every 24 h) for 7 days. Serial blood samples were collected at times zero, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20, 22, and 24 h and urine at each 6 h period until 24 h after metoprolol administration. The plasma concentrations of the (−)‐(S)‐ and (+)‐(R)‐metoprolol enantiomers were determined by HPLC using a chiral stationary phase (Chiralpak AD, 4.6 × 250 mm) and fluorescence detection. The enantiomeric ratios differing from one were evaluated by the paired t test and the results are reported as means (95% CI). No differences were observed between metoprolol enantiomers in half‐lives and absorption, distribution and elimination rate constants. However, the following differences (p < 0.05) were observed between the (−)‐(S) and (+)‐(R) enantiomers: maximum plasma concentration, C_max, 179.99 (123.33–236.64) versus 151.30 (95.04–207.57) ng/mL; area under the plasma concentration versus time curve, AUC, 929.85 (458.02–1401.70) versus 782.11 (329.80–1234.40) ng h/mL; apparent total clearance, Cl_T/f, 1.70 (0.79–2.61) versus 2.21 (1.06–3.36) L/h/kg, apparent distribution volume, Vd/f, 10.51 (6.35–14.68) versus 13.80 (6.93–20.68) L/kg, and renal clearance, Cl_R, 0.06 (0.05–0.08) versus 0.07 (0.05–0.09) L/kg. The enantiomeric ratios AUC_(−)‐(S)/AUC_(+)‐(R) ranged from 1.14 to 1.44, with a mean of 1.29. The data obtained demonstrate enantioselectivity in the kinetic disposition of metoprolol, with plasma accumulation of the pharmacologically more active (−)‐(S)‐metoprolol enantiomer in hypertensive patients phenotyped as extensive metabolizers of debrisoquine. Chirality 11:591–597, 1999. © 1999 Wiley‐Liss, Inc.     

线粒体DNA U4b单倍群:中国塔吉克族高原原发性高血压的遗传易感因素

目的:探讨线粒体DNA变异与中国塔吉克族高原原发性高血压的关系.方法:在中国塔吉克族人群中,收集了 53例高原原发性高血压病例和46例正常对照.通过PCR扩增线粒体DNA片段,经测序拼接获得线粒体全基因组,与剑桥序列比对以筛选线粒体DNA变异,分析在病例组与对照组中的分布差异,采用生物信息学工具预测阳性相关变异的功能....     

MMP-10 from M1 macrophages promotes pulmonary vascular remodeling and pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by muscularized pulmonary blood vessels, leading to right heart hypertrophy and cardiac failure. However, state-of-the-art therapeutics fail to target the ongoing remodeling process. Here, this study shows that matrix metalloproteinases (MMP)-1 and MMP-10 levels are increased in the medial layer of vessel wall, serum, and M1-polarized macrophages from patients with PAH and the lungs of monocrotaline- and hypoxia-induced PAH rodent models. MMP-10 regulates the malignant phenotype of pulmonary artery smooth muscle cells (PASMCs). The overexpression of active MMP-10 promotes PASMC proliferation and migration via upregulation of cyclin D1 and proliferating cell nuclear antigen, suggesting that MMP-10 produced by infiltrating macrophages contributes to vascular remodeling. Furthermore, inhibition of STAT1 inhibits hypoxia-induced MMP-10 but not MMP-1 expression in M1-polarized macrophages from patients with PAH. In conclusion, circulating MMP-10 could be used as a potential targeted therapy for PAH.     

中枢5-羟色胺缺损引起的高血压及其中枢机理

目的：建立中枢５羟色胺（５－ＨＴ）缺损所致的实验性高血压大鼠（ＥＨＲ）模型并探讨其中枢机理。方法：侧脑室埋植瘘管及药物注射。大鼠尾动脉血压及心率启示仪记录清醒大鼠动脉压（ＡＰ）及心率（ＨＲ）。高效液相色谱－电化学检测法ＨＰＬＣ－ＥＣＤ）检测大鼠脑内单胺类递质含量。结果：（１）给大鼠侧脑室（ＩＣＶ）注射选择性神经化学切除剂５,６－双羟色胺（５,６－ＤＨＴ）引起中枢５－ＨＴ神经元缺损,使脑同５－ＨＴ含     

双肾双夹肾性高血压大鼠左心室肌球蛋白重链同型异构 …

目的和方法：测定双肾双夹（２Ｋ２Ｃ）肾性高血压大鼠早期,左心室α－肌球蛋白重链（α－ＭＨＣ）和β－肌球蛋白重链（β－ＭＨＣ）ｍＲＮＡ水平的变化。实验分四组：对照组、２Ｋ２Ｃ组、巯甲丙脯酸组、巯甲丙脯酸对照组。术后２４ｈ、３６ｈ、４８ｈ、７２ｈ测动脉血压,提取左心室中样本取８．０μｇ,与＾３２Ｐ标记的α－ＭＨＣ和β－ＭＨＣ ｃＤＮＡ探针作班点杂交。结果：高血压大鼠左心室α－ＭＨＣ ｍＲＡ水平明显降低     

门脉高压兔胃壁的NADPH黄递酶组织化学观察

已证实还原型尼克酰胺腺嘌呤二核苷酸（NADPH）黄递酶即是一氧化氮合酶,因而可应用简便的NADPH黄递酶哗学染色法来观察机体组织一氧化氮合酶的存在与分布,从而间接了解NO的合成。我们用此法观察了站静脉部分结扎的门脉高压兔胃壁内一氧化氮合酶的分布,发现其胃壁内血管内皮细胞与神经丛神经元及神经纤维一氧化氮合酶活性较正常兔明显增加。结果提示,一氧化氮可能参与了门脉高压胃粘膜病的发生。     

Catecholamine biosynthesis and vasopressin and oxytocin secretion in the spontaneously hypertensive rat: an in vitro study of localized brain regions

The in vitro synthesis of catecholamines and the secretion of vasopressin (AVP) and oxytocin (OT) was measured in localized regions of the hypothalamo-neurohypophyseal system in the spontaneously hypertensive rat (SHR). The posterior pituitary (PP), median eminence (ME) and supraoptic (SON) and paraventricular (PVN) nuclear regions were incubated in vitro in media containing 3H-tyrosine. Media and tissue levels of AVP and OT were measured as well as norepinephrine and dopamine content and biosynthesis. There were no differences in peptide release in either the PP, ME or SON. However, there was a marked increase in peptide release from the PVN of the SHR. Media AVP levels were 0.3 pg/ml/micrograms protein in the WKY as compared to 2.1 pg/ml/micrograms protein in the SHR. OT release was increased 2 fold, from 0.85 to 1.7 pg/ml/micrograms protein. PVN content of both AVP and OT was significantly lower in the SHR. ME and SON peptide levels were not changed, while neurohypophyseal AVP levels were increased in the SHR. With regard to the catecholamines appreciable norepinephrine synthesis was measured in the PVN and SON while there was little 3H-norepinephrine in the ME or PP. In the hypertensive rat, there was an increase in norepinephrine synthesis in the PVN with no change in the SON. These results provide further support for fundamental changes in the catecholaminergic and peptidergic systems of the hypothalamo-neurohypophyseal axis of the SHR.     

原发性高血压和卒中患者的正常血压子女白细胞钠钾含量的观察

本文报道对原发性高血压患者子女38例、卒中患者子女14例及健康家族子女23例白细胞钠钾含量测定的结果。三组均为正常血压者,高血压患者子女组的白细胞钠含量较低、钾含量较高,且在不同性别、不同高血压家族史间比较,亦存在差别。卒中患者子女组的白细胞钠钾含量无显著变化,虽他们的舒张压显著高于对照组。本文就上述结果产生的可能机制及其与高血压、卒中发病的关系进行了讨论。     

Angiotensin-converting enzyme (kinase II) in pituitary gland of spontaneously hypertensive rats

Angiotensin-converting enzyme (ACE) (kinase II; dipeptidyl carboxypeptidase, EC 3.4.15.1) activity was measured in pituitary gland of young (4-week-old) and adult (18-week-old) male, spontaneously hypertensive rats (SHR) and in age-matched normotensive male Wistar-Kyoto (WKY) control rats. In the three lobes of the pituitary gland ACE activity was significantly higher in young than in adult animals, in both SH and WKY rats. In the anterior lobe, ACE activity was lower in SHR when compared to age-matched Wistar-Kyoto controls. In contrast, ACE activity in the intermediate lobe of the pituitary gland was higher in SHR, and in particular in young animals. The observed differences between young WKY and SH rats in both the intermediate and anterior lobes did not appear to be due to a modified affinity of ACE for the substrate hippuryl-His-Leu, but to alterations in ACE maximal velocity or number of available molecules. No differences in ACE activity were detected between SHR and WKY rats in the posterior lobe. Total protein content was higher in the intermediate lobe and lower in the posterior lobe of young SHR when compared to normotensive controls. The present results suggest the possibility for a role of pituitary ACE in spontaneous (genetic) hypertension in rats.