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Enhanced Endothelin Activity Prevents Vasodilation to Insulin in Insulin Resistance 胰岛素抵抗中内皮素活性增强可阻止血管对胰岛素的舒张
Pub Date : 2002-07-01 DOI: 10.1161/01.HYP.0000022806.87281.62
A. W. Miller, C. Tulbert, M. Puskar, D. Busija
Although insulin-mediated vasodilation is impaired in insulin resistance, the mechanisms of this are unknown. We investigated factors mediating vasoactive responses to insulin in control and insulin-resistant rats. Responses to insulin in small mesenteric arteries from control and insulin-resistant rats were investigated after blocking endothelin-A receptors, cyclooxygenase, nitric oxide synthase, and potassium channels. In addition, insulin’s effect on prostacyclin production in small mesenteric blood vessels was assessed by enzyme immunoassay. Insulin induced a concentration-dependent vasodilation in control arteries that was absent in arteries from insulin-resistant rats. However, in the presence of BQ610, an endothelin-A receptor antagonist, the response to insulin was normalized in insulin-resistant arteries. In control arteries, insulin-induced vasodilation was completely inhibited by indomethacin, meclofenamate, glibenclamide, or potassium chloride. In contrast, neither n-nitro-l-arginine nor the combination of charybdotoxin and apamin altered vasodilation to insulin. In insulin-resistant arteries in the presence of BQ610, vasodilation was also inhibited by indomethacin, glibenclamide, and potassium chloride. Insulin increased prostacyclin production in small mesenteric blood vessels from both groups of rats to a similar degree. Insulin-induced vasodilation in small rat mesenteric arteries is mediated through prostacyclin- and ATP-dependent potassium channels. However, insulin-resistant arteries do not vasodilate to insulin unless endothelin-A receptors are blocked. Thus, impaired relaxation to insulin in insulin-resistant rats is due to enhanced vasoconstriction by endothelin, which offsets a normal vasodilatory response to insulin.
虽然胰岛素介导的血管舒张在胰岛素抵抗中受损,但其机制尚不清楚。我们研究了胰岛素抵抗大鼠和对照大鼠对胰岛素的血管活性反应的介导因素。在阻断内皮素- a受体、环氧化酶、一氧化氮合酶和钾通道后,研究了对照组和胰岛素抵抗大鼠肠系膜小动脉对胰岛素的反应。此外,胰岛素对肠系膜小血管生成前列环素的影响通过酶免疫分析法进行了评估。胰岛素诱导对照动脉出现浓度依赖性血管舒张,而胰岛素抵抗大鼠的动脉不存在这种情况。然而,当内皮素a受体拮抗剂BQ610存在时,胰岛素抵抗动脉对胰岛素的反应正常化。在对照动脉中,胰岛素诱导的血管舒张被吲哚美辛、甲氯芬酯、格列苯脲或氯化钾完全抑制。相比之下,n-硝基-l-精氨酸和白藜芦醇毒素和维生素a的组合都没有改变胰岛素的血管舒张。在BQ610存在的胰岛素抵抗动脉中,吲哚美辛、格列本脲和氯化钾也能抑制血管舒张。胰岛素增加了两组大鼠肠系膜小血管中前列环素的产生,其程度相似。胰岛素诱导的大鼠肠系膜动脉血管舒张是通过前列环素和atp依赖的钾通道介导的。然而,除非内皮素- a受体被阻断,否则胰岛素抵抗动脉不会对胰岛素进行血管扩张。因此,胰岛素抵抗大鼠对胰岛素的松弛受损是由于内皮素增强血管收缩,这抵消了对胰岛素的正常血管舒张反应。
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引用次数: 74
Genes and Family Environment Explain Correlations Between Blood Pressure and Body Mass Index 基因和家庭环境解释血压和体重指数的相关性
Pub Date : 2002-07-01 DOI: 10.1161/01.HYP.0000022693.11752.E9
J. Cui, J. Hopper, S. Harrap
The correlations between systolic blood pressure (SBP) and diastolic blood pressure (DBP), and between SBP and body mass index (BMI), might result from genetic or environmental factors that determine variation in 2 or more phenotypes and are shared by family members. In 767 adult nuclear families (n=2912 individuals, including 66 pairs of monozygotic twins and 84 pairs of dizygotic twins), we used a multivariate normal model and the software FISHER to estimate genetic and environmental components of variation and covariation. Mean phenotypes were adjusted for age, gender, and generation, and for antihypertensive treatment. Genetic and shared family environmental factors accounted for 46% and 31% of total variance in SBP, respectively. Adjustment of SBP for DBP reduced considerably both the additive genetic (86.7 to 21.0) and shared environmental (59.7 to 21.0) components of variance. Smaller reductions in genetic (86.7 to 84.9) and shared environmental (59.7 to 51.1) components were observed after adjustment of SBP for BMI. For SBP and DBP, the correlation between the effects of genes was 1.00 and between shared environmental effects was 0.52. For SBP and BMI the correlations were 0.30 for genetic and 0.22 for shared environmental effects. Our findings suggest that the same genes and many of the same family environmental factors determine variation in both SBP and DBP. In contrast, SBP and BMI share genetic and family environmental determinants to a lesser degree. These observations are relevant to multifactorial cardiovascular risk reduction based on genetic and family environmental approaches.
收缩压(SBP)和舒张压(DBP)之间以及收缩压(SBP)和体重指数(BMI)之间的相关性可能是由遗传或环境因素决定的,这些因素决定了2种或更多表型的变异,并由家庭成员共享。在767个成人核心家庭(n=2912个人,包括66对同卵双胞胎和84对异卵双胞胎)中,我们使用多元正态模型和FISHER软件来估计变异和协变的遗传和环境因素。平均表型根据年龄、性别、世代和抗高血压治疗进行调整。遗传和共有的家庭环境因素分别占SBP总方差的46%和31%。舒张压对舒张压的调整大大降低了加性遗传(86.7 - 21.0)和共享环境(59.7 - 21.0)方差成分。根据BMI调整收缩压后,遗传因子(86.7 - 84.9)和共同环境因子(59.7 - 51.1)的降低幅度较小。对于收缩压和舒张压,基因效应之间的相关系数为1.00,共同环境效应之间的相关系数为0.52。SBP和BMI的遗传相关性为0.30,共同环境影响相关性为0.22。我们的研究结果表明,相同的基因和许多相同的家庭环境因素决定了收缩压和舒张压的变化。相比之下,收缩压和BMI在较小程度上具有遗传和家庭环境决定因素。这些观察结果与基于遗传和家庭环境方法的多因素心血管风险降低有关。
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引用次数: 102
Long-Term Adrenomedullin Infusion Improves Survival in Malignant Hypertensive Rats 长期输注肾上腺髓质素提高恶性高血压大鼠的存活率
Pub Date : 2002-07-01 DOI: 10.1161/01.HYP.0000023226.50264.42
Yosuke Mori, T. Nishikimi, N. Kobayashi, H. Ono, K. Kangawa, H. Matsuoka
Previous studies have demonstrated that adrenomedullin has inhibitory effects on the proliferation and DNA synthesis of mesangial cells and vascular smooth muscle cells in vitro and that plasma adrenomedullin levels are markedly elevated in malignant hypertension. This study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in malignant hypertensive rats. We studied the following 3 groups: control Wistar Kyoto rats, deoxycorticosterone acetate–salt spontaneously hypertensive rats, and adrenomedullin-treated deoxycorticosterone acetate–salt spontaneously hypertensive rats. Chronic adrenomedullin infusion using an osmotic minipump was started simultaneously with deoxycorticosterone acetate–salt treatment. After 3 weeks of the treatment, malignant hypertensive rats were characterized by higher blood pressure, kidney weight, urinary protein excretion, glomerular injury score, plasma renin concentration, aldosterone level, endogenous rat plasma adrenomedullin level, renal cortical tissue angiotensin II level, angiotensin-converting enzyme mRNA level, and transforming growth factor-&bgr;1 mRNA level in the renal cortex, and by lower creatinine clearance, compared with the control rats. Chronic adrenomedullin infusion significantly improved these parameters (kidney weight −6.5%, urinary protein excretion −63.8%, glomerular injury score −38.3%, plasma renin concentration −52.4%, aldosterone −23.2%, rat adrenomedullin −28.6%, renal angiotensin II −28.1%, renal angiotensin-converting enzyme mRNA −38.3%, renal transforming growth factor-&bgr;1 mRNA −56.2%, and creatinine clearance +20.5%) without significant reduction of mean arterial pressure (−4%). Kaplan-Meier survival analysis showed that adrenomedullin infusion significantly prolonged survival time. These results suggest that subdepressor dose of chronic adrenomedullin infusion has renoprotective effects in this malignant hypertension model, at least in part, via inhibition of the circulating and intrarenal renin-angiotensin system.
既往研究表明肾上腺髓质素对体外培养的系膜细胞和血管平滑肌细胞的增殖和DNA合成有抑制作用,恶性高血压患者血浆肾上腺髓质素水平明显升高。本研究旨在探讨慢性肾上腺髓质素输注对恶性高血压大鼠的肾保护作用。我们研究了Wistar京都大鼠、醋酸去氧皮质酮盐自发性高血压大鼠和肾上腺髓质素处理的醋酸去氧皮质酮盐自发性高血压大鼠。使用渗透性微型泵慢性肾上腺髓质素输注与脱氧皮质酮醋酸盐治疗同时开始。治疗3周后,与对照大鼠相比,恶性高血压大鼠血压、肾重、尿蛋白排泄、肾小球损伤评分、血浆肾素浓度、醛固酮水平、内源性大鼠血浆肾上腺髓质素水平、肾皮质组织血管紧张素II水平、血管紧张素转换酶mRNA水平、肾皮质转化生长因子- 1 mRNA水平升高,肌酐清除率降低。慢性肾上腺髓质素输注显著改善了这些参数(肾重- 6.5%,尿蛋白排泄- 63.8%,肾小球损伤评分- 38.3%,血浆肾素浓度- 52.4%,醛固酮- 23.2%,大鼠肾上腺髓质素- 28.6%,肾血管紧张素II - 28.1%,肾血管紧张素转换酶mRNA - 38.3%,肾转化生长因子- bgr; 1mrna - 56.2%,肌酐清除率+20.5%),但平均动脉压(- 4%)未显著降低。Kaplan-Meier生存分析显示,肾上腺髓质素输注可显著延长存活时间。这些结果表明,在这种恶性高血压模型中,亚抑制剂量的慢性肾上腺髓质素输注至少在一定程度上通过抑制循环和肾内肾素-血管紧张素系统具有肾保护作用。
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引用次数: 40
Insulin Sensitivity and Blood Pressure in Black and White Children 黑人和白人儿童的胰岛素敏感性和血压
Pub Date : 2002-07-01 DOI: 10.1161/01.HYP.0000019972.37690.EF
M. Cruz, Terry T Huang, Maria S. Johnson, B. Gower, M. Goran
Although insulin sensitivity is correlated with high blood pressure in adults, it is unclear whether such a relationship exists in children across ethnic groups. Therefore, the aims of the study were to establish (1) if body composition and insulin sensitivity were related to blood pressure in children, and (2) if any differences in blood pressure between white and black children were explained by body composition and/or insulin sensitivity. Insulin sensitivity and the acute insulin response were established by the minimal model and body composition by dual-energy X-ray absorptiometry. Blood pressure was recorded in the supine position. Body composition, fasting insulin (P <0.01), and the acute insulin response (P <0.05) were positively related to systolic blood pressure but not to diastolic blood pressure, and insulin sensitivity (P <0.001) was negatively related to systolic blood pressure but not to diastolic blood pressure. Insulin sensitivity was negatively associated with systolic and diastolic blood pressure after adjustment for body composition (P <0.01). Black children had higher systolic (110±9.2 versus 105±8.5 mm Hg, P =0.01) and diastolic (59±7.0 versus 54±8.0 mm Hg, P <0.01) blood pressure than did white children. The ethnic difference in blood pressure was not explained by body composition, fasting insulin, acute insulin response, or insulin sensitivity. In conclusion, the relationship between insulin sensitivity and systolic blood pressure is evident early in life. Black ethnicity and low insulin sensitivity contribute independently to higher blood pressure in children.
尽管胰岛素敏感性与成人高血压相关,但尚不清楚这种关系是否存在于不同种族的儿童中。因此,本研究的目的是确定(1)身体成分和胰岛素敏感性是否与儿童血压有关,以及(2)白人和黑人儿童之间的血压差异是否可以用身体成分和/或胰岛素敏感性来解释。通过最小模型和双能x线吸收仪建立胰岛素敏感性和急性胰岛素反应。在仰卧位记录血压。体成分、空腹胰岛素(P <0.01)、急性胰岛素反应(P <0.05)与收缩压呈正相关,与舒张压无相关;胰岛素敏感性(P <0.001)与收缩压呈负相关,与舒张压无相关。调整体成分后,胰岛素敏感性与收缩压和舒张压呈负相关(P <0.01)。黑人儿童的收缩压(110±9.2比105±8.5 mm Hg, P =0.01)和舒张压(59±7.0比54±8.0 mm Hg, P <0.01)高于白人儿童。血压的种族差异不能用身体成分、空腹胰岛素、急性胰岛素反应或胰岛素敏感性来解释。总之,胰岛素敏感性和收缩压之间的关系在生命早期就很明显。黑人和低胰岛素敏感性是儿童高血压的独立诱因。
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引用次数: 76
Excess ldosterone Is Associated With Alterations of Myocardial Texture in Primary Aldosteronism 原发性醛固酮增多症中过量的醛固酮与心肌结构改变有关
Pub Date : 2002-07-01 DOI: 10.1161/01.HYP.0000023182.68420.EB
G. Rossi, V. Di Bello, C. Ganzaroli, A. Sacchetto, M. Cesari, A. Bertini, D. Giorgi, R. Scognamiglio, M. Mariani, A. Pessina
Hyperaldosteronism has been causally linked to myocardial interstitial fibrosis experimentally, but it remains unclear if this link also applies to humans. Thus, we investigated the effects of excess aldosterone due to primary aldosteronism (PA) on collagen deposition in the heart. We used echocardiography to estimate left ventricular (LV) wall thickness and dimensions and for videodensitometric analysis of myocardial texture in 17 consecutive patients with PA and 10 patients with primary (essential) hypertension who were matched for demographics, casual blood pressure, and known duration of hypertension. The groups differed in serum K+, ECG PQ interval duration, plasma renin activity, and aldosterone levels (all P ≤0.002) but not for casual blood pressure values, demographics, and duration of hypertension. Compared with hypertensive patients, PA patients showed a higher LV mass index (53.7±1.8 versus 45.5±2.0 g/m2.7;P =0.008) and lower values of the cyclic variation index of the myocardial mean gray level of septum (CVIs; −12.02±5.84% versus 6.06±3.08%;P =0.012) and posterior wall (−11.13±6.42% versus 8.63±9.62%;P =0.012). A regression analysis showed that CVIs was predicted by the PQ duration, supine plasma renin activity, plasma aldosterone, and age, which collectively accounted for ≈36% of CVIs variance. PA is associated with alterations of myocardial textures that suggest increased collagen deposition and that can explain both the dependence of LV diastolic filling from presystole and the prolongation of the PQ interval.
实验表明,高醛固酮增多症与心肌间质纤维化有因果关系,但尚不清楚这种联系是否也适用于人类。因此,我们研究了原发性醛固酮增多症(PA)引起的过量醛固酮对心脏胶原沉积的影响。我们使用超声心动图估计左心室(LV)壁厚度和尺寸,并对17例连续的PA患者和10例原发性(原发性)高血压患者的心肌质地进行视频密度分析,这些患者在人口统计学、随意血压和已知高血压持续时间方面相匹配。两组在血清K+、心电图PQ间隔时间、血浆肾素活性和醛固酮水平方面存在差异(P均≤0.002),但在随意血压值、人口统计学和高血压持续时间方面没有差异。与高血压患者相比,PA患者的左室质量指数(53.7±1.8)高于高血压患者(45.5±2.0 g/m2.7, P =0.008),心肌间隔平均灰度循环变异指数(CVIs;- 12.02±5.84%比6.06±3.08%,P =0.012)和后壁(- 11.13±6.42%比8.63±9.62%,P =0.012)。回归分析显示,PQ持续时间、仰卧位血浆肾素活性、血浆醛固酮和年龄可以预测CVIs,这些因素合计占CVIs方差的约36%。PA与心肌结构改变有关,表明胶原沉积增加,这可以解释左室舒张充盈依赖于收缩前和PQ间期延长。
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引用次数: 228
Von Willebrand Factor, Soluble P-Selectin, and Target Organ Damage in Hypertension: A Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) 血管性血血病因子、可溶性p选择素和高血压靶器官损伤:盎格鲁-斯堪的纳维亚心脏结局试验(ASCOT)的一项亚研究
Pub Date : 2002-07-01 DOI: 10.1161/01.HYP.0000022061.12297.2E
C. C. Spencer, D. Gurney, A. Blann, D. Beevers, G. Y. Lip
To investigate the relationship between soluble markers of platelet, endothelial and rheological function, and target organ damage and their response to intensified management in a population of middle-age hypertensive patients at high risk of cardiovascular complications, we studied 382 consecutive patients (308 men; mean age, 63 years, SD 8) along with 60 normotensive controls free of cardiovascular disease. Patients were divided into those with target organ damage (TOD; n=107) and those free of end-organ damage. Plasma levels of soluble P-selectin (sP-sel), a marker of platelet activation, and von Willebrand factor (vWF), an index of endothelial damage/dysfunction (both enzyme-linked immunosorbent assay), and the rheological indices fibrinogen, plasma viscosity, hematocrit, platelet, and white cell count were measured. In 53 patients, variables were further measured after 6 months of intensified cardiovascular risk management. Patients with TOD had significantly higher vWF, 137 (SD 33) versus 125 (SD 33) IU/dL (P =0.002,) and a greater proportion of smokers, 31% versus 16% (P =0.002). There were no statistically significant differences in plasma viscosity, fibrinogen, hematocrit, white blood cell count, platelet count, or sP-sel between the 2 subgroups. In multivariate analysis, vWF was a significant independent predictor for TOD. After 6 months of intensified management in 53 patients who entered the trial, there were significant reductions in systolic blood pressure, total cholesterol, hematocrit, plasma viscosity, sP-sel, and vWF (all P <0.01) but no significant change in fibrinogen. In conclusion, there is a relationship between TOD and endothelial damage/dysfunction in hypertension. Intensified management results in improvements in hemorheology, endothelial and platelet function.
为了研究血小板可溶性标志物、内皮和流变功能与靶器官损伤的关系及其对心血管并发症高危中年高血压患者强化治疗的反应,我们研究了382例连续患者(308例男性;平均年龄63岁,SD 8),血压正常且无心血管疾病的对照组60例。患者分为靶器官损伤组(TOD);N =107)和无终末器官损伤者。测定血浆可溶性p选择素(sP-sel)(血小板活化标志物)和血管性血友病因子(vWF)(内皮损伤/功能障碍指标)的水平(均采用酶联免疫吸附法),以及流变学指标纤维蛋白原、血浆粘度、红细胞压积、血小板和白细胞计数。在53例患者中,在加强心血管风险管理6个月后,进一步测量了变量。TOD患者的vWF明显更高,分别为137 (SD 33)和125 (SD 33) IU/dL (P =0.002),吸烟者的比例更高,分别为31%和16% (P =0.002)。两组患者血浆黏度、纤维蛋白原、红细胞压积、白细胞计数、血小板计数、sP-sel均无统计学差异。在多变量分析中,vWF是TOD的显著独立预测因子。53例入组患者经过6个月的强化治疗后,收缩压、总胆固醇、红细胞压积、血浆粘度、sP-sel和vWF均显著降低(P <0.01),但纤维蛋白原无显著变化。综上所述,高血压患者TOD与内皮损伤/功能障碍有关。强化治疗可改善血液流变学、内皮和血小板功能。
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引用次数: 85
Cardiovascular Effects of Nasal and Transdermal Nicotine and Cigarette Smoking 鼻腔和透皮尼古丁与吸烟对心血管的影响
Pub Date : 2002-06-01 DOI: 10.1161/01.HYP.0000018825.76673.EA
N. Benowitz, Anna Hansson, P. Jacob
The purpose of this study was to compare circadian blood pressure and heart rate patterns and other cardiovascular effects of nicotine delivered rapidly (via nasal spray, NNS), slowly (transdermal nicotine, TDN), by cigarette smoking (rapid delivery of nicotine plus other smoke toxins), and placebo NNS. Twelve healthy cigarette smokers were studied on a research ward when they smoked cigarettes (16 per day) or used TDN (15 mg/16 h), NNS (24 1-mg doses per day), or placebo NNS, each for 5 days. There were no significant differences in systolic blood pressure, but diastolic blood pressure was slightly increased during cigarette smoking. Plasma epinephrine, &bgr;-thromboglobulin, and fibrinogen levels were higher during cigarette smoking than with TDN. For most measurements, NNS values were intermediate between and not significantly different from those of cigarette smoking and TDN. We conclude that, at recommended doses, TDN and NNS have fewer effects on biomarkers of cardiovascular risk than does cigarette smoking.
本研究的目的是比较快速(通过鼻腔喷雾剂,NNS)、缓慢(透皮尼古丁,TDN)、吸烟(快速传递尼古丁和其他烟雾毒素)和安慰剂NNS的昼夜节律血压和心率模式以及其他心血管影响。研究人员对12名健康吸烟者进行了研究,他们分别吸烟(每天16支)或使用TDN(15毫克/16小时)、NNS(每天24剂1毫克剂量)或安慰剂NNS,各持续5天。两组的收缩压无显著差异,但吸烟时舒张压略有升高。吸烟时血浆肾上腺素、血栓球蛋白和纤维蛋白原水平高于TDN。对于大多数测量,NNS值介于吸烟和TDN之间,没有显著差异。我们的结论是,在推荐剂量下,TDN和NNS对心血管风险的生物标志物的影响小于吸烟。
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引用次数: 118
Losartan Reduces Central and Peripheral Sympathetic Nerve Activity in a Rat Model of Neurogenic Hypertension 氯沙坦降低神经源性高血压大鼠模型中枢性和外周交感神经活动
Pub Date : 2002-06-01 DOI: 10.1161/01.HYP.0000018590.26853.C7
S. Ye, Huiquin Zhong, V. Duong, V. Campese
We have developed a new model of neurogenic hypertension in the rat, in which hypertension is caused by injecting 50 &mgr;L of 10% phenol in the lower pole of one kidney. Administration of phenol in the kidney causes an immediate and persistent rise in blood pressure (BP), norepinephrine (NE) secretion from the posterior hypothalamic nuclei (PH), and renal sympathetic nerve activity (RSNA). Because angiotensin II (Ang II) is known to stimulate central and peripheral sympathetic nervous system (SNS) activity, we have tested the hypothesis that losartan, a specific Ang II AT1 receptor antagonist, may lower BP, at least in part, by SNS inhibition. To this end, we studied the effects of losartan on BP and SNS activity following intrarenal phenol injection. Central SNS activity was measured by NE secretion from the PH using a microdialysis technique, and peripheral SNS activity was measured by direct recording of renal nerve activity. At the end of the experiments, brains were isolated and interleukin (IL)-1&bgr; and nitric oxide synthase (NOS) mRNA gene expression was measured by RT-PCR in the PH, paraventricular nuclei (PVN), and locus ceruleus (LC). The intrarenal injection of phenol raised BP, as well as central and renal SNS activity, but reduced the abundance of IL-1&bgr; and neuronal NOS (nNOS) mRNA in the PH, PVN, and LC. Whether injected intravenously or in the lateral ventricle, losartan caused a significant (P <0.01) and dose-dependent inhibition of the effects of phenol on BP, NE secretion from the PH, and RSNA. Losartan also caused a significant (P <0.01) and dose-dependent rise in IL-1&bgr; and nNOS-mRNA gene expression in the PH, PVN, and LC of phenol-injected rats. In conclusion, these studies have shown that the intrarenal injection of phenol causes a rise in central and renal SNS activity and a decrease in IL-1&bgr; and nNOS-mRNA in the PH, PVN, and LC. Losartan prevented the rise in BP and SNS activity, as well as the decrease in IL-1&bgr; and nNOS mRNA abundance caused by phenol. These studies have demonstrated that the antihypertensive action of losartan in the phenol renal injury model is largely mediated by inhibition of central and peripheral SNS activity and suggest that activation of IL-1&bgr; and nNOS, 2 important modulators of central SNS activity, mediates the inhibitory action of losartan on SNS activity.
我们建立了一种新的大鼠神经源性高血压模型,在一个肾的下极注射50 μ L 10%的苯酚引起高血压。在肾脏中使用苯酚会引起血压(BP)、下丘脑后核(PH)分泌去甲肾上腺素(NE)和肾交感神经活动(RSNA)的立即和持续升高。由于已知血管紧张素II (Ang II)能刺激中枢和周围交感神经系统(SNS)的活性,我们已经验证了氯沙坦(一种特异性的Ang II AT1受体拮抗剂)可能通过抑制SNS降低血压的假设。为此,我们研究了氯沙坦对静脉注射苯酚后血压和SNS活性的影响。中枢SNS活动通过微透析技术从PH分泌NE来测量,外周SNS活动通过直接记录肾神经活动来测量。在实验结束时,分离脑,白细胞介素(IL)-1&bgr;采用RT-PCR法检测PH、室旁核(PVN)和蓝核座(LC)中一氧化氮合酶(NOS) mRNA基因的表达。肾内注射苯酚使血压升高,中央和肾脏SNS活性升高,但IL-1&bgr丰度降低;PH、PVN和LC中神经元NOS mRNA的表达。无论是静脉注射还是侧脑室注射,氯沙坦对苯酚对BP、PH分泌NE和RSNA的影响均有显著(P <0.01)且剂量依赖性的抑制作用。氯沙坦也引起IL-1&bgr显著升高(P <0.01),且呈剂量依赖性;苯酚注射大鼠PH、PVN和LC中nNOS-mRNA基因表达的变化。总之,这些研究表明,肾内注射苯酚导致中央和肾脏SNS活性升高,il -1和bgr降低;PH、PVN和LC中nNOS-mRNA的表达。氯沙坦抑制了BP和SNS活性的升高,抑制了il -1和bgr的降低;苯酚引起的nNOS mRNA丰度。这些研究表明氯沙坦在酚性肾损伤模型中的降压作用主要是通过抑制中枢和外周SNS活性介导的,并提示il -1的激活;2种重要的中枢SNS活性调节剂nNOS介导氯沙坦对SNS活性的抑制作用。
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引用次数: 99
KDR (VEGF Receptor 2) Is the Major Mediator for the Hypotensive Effect of VEGF 血管内皮生长因子受体2 (KDR)是血管内皮生长因子降压作用的主要调节因子
Pub Date : 2002-06-01 DOI: 10.1161/01.HYP.0000018588.56950.7A
Bing Li, A. Ogasawara, Renhui Yang, Wei Wei, G. He, T. F. Zioncheck, S. Bunting, A. D. de Vos, Hongkui Jin
Vascular endothelial growth factor (VEGF) exerts vasodilation-induced hypotension as a major side effect for treatment of ischemic diseases. VEGF has 2 receptor tyrosine kinases, KDR and Flt-1. Little is known about which receptor mediates VEGF-induced hypotension. To elucidate the role of each receptor in mediating hypotension, KDR-selective and Flt-1–selective mutants were used for in vitro and in vivo studies. The KDR-selective mutant induced vascular endothelial cell proliferation comparable to VEGF, whereas the Flt-1– selective mutant had no effect on proliferation. Intravenous injection of KDR-selective mutant, Flt-selective mutant, or VEGF caused a dose-related decrease in mean arterial pressure in conscious rats. The hypotensive response to KDR-selective mutant was significantly less than that to VEGF (P <0.01) but was greater than that to Flt-selective mutant (P <0.01). Similarly, VEGF and KDR-selective mutant induced more potent vasorelaxation than Flt-selective mutant or placenta growth factor that binds Flt-1 only (P <0.01), and the vasorelaxation to KDR-selective mutant was not significantly different at low concentrations but less than that to VEGF at high concentrations. The results indicate that the vasodilation and hypotensive effect of VEGF may involve both receptors, but KDR is the predominant receptor mediating this effect. Because KDR-selective mutant induced proliferation and angiogenesis similar to VEGF but was associated with 36% attenuation in hypotension, the data suggest that the KDR-selective mutant may represent an alternative treatment for ischemic diseases.
血管内皮生长因子(VEGF)发挥血管舒张诱导的低血压是缺血性疾病治疗的主要副作用。VEGF有2种受体酪氨酸激酶,KDR和Flt-1。对于哪种受体介导vegf诱导的低血压知之甚少。为了阐明每种受体在介导低血压中的作用,kdr选择性和flt -1选择性突变体被用于体外和体内研究。kdr选择性突变体诱导血管内皮细胞增殖与VEGF相当,而Flt-1选择性突变体对增殖没有影响。静脉注射kdr选择性突变体、flt选择性突变体或VEGF导致有意识大鼠平均动脉压的剂量相关降低。kdr -选择性突变体的降压效果显著低于VEGF (P <0.01),而高于flt -选择性突变体(P <0.01)。同样,VEGF和kdr -选择性突变体诱导的血管舒张作用强于flt -选择性突变体或仅结合Flt-1的胎盘生长因子(P <0.01),且kdr -选择性突变体的血管舒张作用在低浓度下无显著差异,而在高浓度下则小于VEGF。结果表明,VEGF的血管扩张和降压作用可能涉及两种受体,但KDR是介导这种作用的主要受体。由于kdr选择性突变体诱导的增殖和血管生成与VEGF相似,但与低血压降低36%相关,数据表明kdr选择性突变体可能代表缺血性疾病的替代治疗方法。
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引用次数: 120
Heart Rate: An Important Confounder of Pulse Wave Velocity Assessment 心率:脉搏波速度评估的重要混杂因素
Pub Date : 2002-06-01 DOI: 10.1161/01.HYP.0000019132.41066.95
P. Lantelme, C. Mestre, M. Lièvre, A. Gressard, H. Milon
Arterial stiffness is a strong determinant of cardiovascular risk. Pulse wave velocity (PWV) is an index of arterial stiffness, and its prognostic value has been repeatedly emphasized. The purpose of the present study was to assess the effect of heart rate (HR) on PWV. Twenty-two subjects with a mean age of 77.8±8.4 (SD) years and permanent cardiac pacing were studied. In each subject, PWV was measured at 5 different pacing frequencies in the same session (60, 70, 80, 90, 100 bpm), the order of the various frequencies being randomly determined. Furthermore, to test the reproducibility, a repeat measurement of PWV was obtained in one randomly selected frequency. Blood pressure (BP) was measured by conventional means at each pacing frequency. PWV appeared fairly reproducible because no significant difference was disclosed between the 2 measurements obtained at the same HR level (P =0.5) and both measurements were strongly correlated (r =0.87, P <0.001). No significant BP variation was observed during pacing. There was a highly significant effect of HR on PWV estimated by a one-way, within-subjects analysis of variance (P =0.01). This study demonstrates that HR is an important factor in the intraindividual variation of PWV in elderly subjects. This raises methodological concern about the measurement of this parameter. Standardizing PWV for HR level seems mandatory if one wants to interpret PWV changes in clinical trials or in the follow-up of patients.
动脉僵硬度是心血管风险的重要决定因素。脉搏波速度(PWV)是动脉硬度的一项指标,其预后价值已被反复强调。本研究的目的是评估心率(HR)对PWV的影响。研究对象22例,平均年龄77.8±8.4 (SD)岁,永久性心脏起搏。每个受试者在同一时段内以5个不同的起搏频率(60,70,80,90,100bpm)测量PWV,各频率的顺序随机确定。此外,为了测试再现性,在一个随机选择的频率上获得了PWV的重复测量。采用常规方法测量各起搏频率的血压(BP)。PWV具有相当的可重复性,因为在相同HR水平下获得的两个测量值之间没有显着差异(P =0.5),并且两个测量值都具有强相关性(r =0.87, P <0.001)。起搏期间未观察到明显的血压变化。通过单因素、受试者内方差分析估计,HR对PWV的影响非常显著(P =0.01)。本研究表明,HR是导致老年人PWV个体差异的重要因素。这引起了对该参数测量方法的关注。如果想要在临床试验或患者随访中解释PWV的变化,标准化PWV的HR水平似乎是强制性的。
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引用次数: 358
期刊
Hypertension: Journal of the American Heart Association
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