Big Endothelin-1 and Nitric Oxide in Hypertensive Elderly Patients with and without Obstructive Sleep Apnea-Hypopnea Syndrome

Background

The role of oxidative stress in hypertensive elderly patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) is unknown.

Objective

The purpose was to evaluate the levels of big endothelin-1 (Big ET-1) and nitric oxide (NO) in elderly hypertensive patients with and without moderate to severe OSAHS.

Methods

Volunteers were hospitalized for 24 h. We obtained the following data: body mass index (BMI); 24-ambulatory blood pressure monitoring; and current medication. Arterial blood was collected at 7pm and 7am for determining plasma NO and Big ET-1 levels. Pulse oximetry was performed during sleep. Pearson''s or Spearman''s correlation and univariate analysis of variance were used for statistical analysis.

Results

We studied 25 subjects with OSAHS (group 1) and 12 without OSAHS (group 2) aged 67.0 ± 6.5 years and 67.8 ± 6.8 years, respectively. No significant differences were observed between the groups in BMI; number of hours of sleep; 24-h systolic and diastolic BPs; awake BP, sleep BP and medications to control BP between groups. No differences were detected in plasma Big ET-1 and NO levels at 19:00 h, but plasma Big ET-1 levels at 7:00 h were higher in group 1 (p = 0.03). In group 1, a negative correlation was also observed between the mean arterial oxyhemoglobin saturation level, 24-h systolic BP (p = 0.03, r = −0.44), and Big ET-1 (p = 0.04, r = −0.41).

Conclusions

On comparing elderly hypertensive patients with and without OSAHS having similar BP and BMI, we observed higher Big ET-1 levels After sleep in the OSAHS group. NO levels did not differ between the hypertensive patients with or without OSAHS.     

慢性肾功能衰竭患者血透前后血浆内皮素-1及血清一氧化氮指标的变化

目的：观察慢性肾功能衰竭（CRF）患者血透前后血浆内皮素-1（ET-1）、及血清-氧化氮（NO）水平的变化。方法：应用放射免疫分析及硝酸还原酶法对50例CRF患者进行血透前后ET-1和NO检测及统计学分析,并与50例正常健康人（对照组）作比较。结果：血透前CRF患者较对照组ET-1明显增高,NO水平显著下降,差异均有统计学意义（P〈0．01）;血透后CRF患者ET-1水平较血透前明显降低（P〈0．01）,但与对照组比较,差异有统计学意义（P〈0．05）;血透后CRF患者NO水平较血透前明显升高（P〈0．05）,与对照组比较差异有统计学意义（P〈0．05）。结论：CRF患者存在高ET血症和低N0血症。血透可以降低CRF患者血浆ET-1水平,升高NO浓度。但血透只能部分替代肾功能,不能彻底纠正CRF患者的血凝亢进和血栓形成,故ET1及NO较对照值仍有较大差异,不能得到正常人水平。     

Sensitivity and Reactivity to Endothelin-1 in Mesenteric Beds and Aortic Rings of 4-Week-Old Spontaneously Hypertensive Rats

The vasoconstrictor effects of endothelin-1 were studied in perfused mesenteric vascular beds (MVB) and aortic rings of 4-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY). Mean blood pressure (124×4 vs. 97×3 mmHg) and initial perfusion pressure in the MVBs (25×2 vs. 19.7×1.2) were significantly higher in SHR. Reactivity to endothelin-1 was increased in MVBs of SHR, as indicated by the maximum perfusion pressure obtained (223 × 8 vs 155 × 7 mmHg, p > 0.001), whereas there was no significant difference in sensitivity between the two strains (EC₅₀ values: 50 × 12 and 80 × 15 pmol, respectively). By contrast, in aortic rings reactivity and sensitivity to endothelin-1 were similar in both strains, (EC₅₀ s: 1.8 × 0.12 and 1.4 × 0.1 nM). Reactivity to norepinephrine was increased in MVBs, but reduced in aortic rings of SHR. The unchanged sensitivity to endothelin-1 and the unspecifically increased reactivity in the MVBs of SHR to endothelin-1 and norepinephrine indicate rather a change in vascular structure and not a functional abnormality. These results suggest that hyperreactivity to endothelin-1 may not be a primary hypertensive mechanism in genetic hypertension.     

双肾双夹易卒中型肾血管性高血压大鼠重要靶器官小窝蛋白的表达

目的 研究在高血压发展过程中重要靶器官组织信号蛋白小窝蛋白（Caveolin-1）的表达。方法 建立双肾双夹易卒中型肾血管性高血压大鼠动物模型，随机分为高血压组和假手术组，用Western blot的方法检测小窝蛋白在心、脑、肾血管中的表达。结果 2周末高血压组血压明显升高，4周末高血压组心脏体重比明显升高，高血压组重要靶器官心、脑、肾、血管中小窝蛋白的表达随高血压的时程发展明显减少。结论 双肾双夹易卒中型肾血管性高血压大鼠重要靶器官组织小窝蛋白表达减少，提示小窝蛋白信号途径可能参与高血压的发生发展，与高血压靶器官的损害有关。     

黄芪、全蝎、红花、丹参、葛根混合剂抑制自发性高血压大鼠阻力血管肥厚

目的观察黄芪、全蝎、红花、丹参、葛根混合剂(脑心通)对自发性高血压大鼠(SHR)阻力血管结构和血压的影响。方法选择12周龄雄性 SHR 大鼠(二级)32只,随机分成4组,脑心通大剂量组[1.5 g/(kg·d)]、脑心通小剂量组[0.5 g/(kg·d)]、氯沙坦组[30 mg/(kg·d)]和 SHR 组(给等量蒸馏水)。另选周龄、性别相匹配的Wistar Kyoto(WKY,给等量蒸馏水)大鼠8只。各组每日灌胃给药。12周后尾袖法测定动脉血压,称质量后处死。HE 染色,计算机图像分析计算血管壁腔比,以观察各组大鼠肠系膜三级动脉的结构变化。结果 1)大、小剂量脑心通治疗后,两组 SBP 均显著低于 SHR 组[脑心通大剂量:(153.6±12.2)比脑心通小剂量:(159.2±5.8)比 SHR:(178.6±12.0)mmHg,P<0.01];大剂量脑心通组 SHR 治疗后 SBP 较治疗前明显降低[(153.6±12.2)比治疗前(163.6±11.8)mmHg,P<0.01],与小剂量组比较能更进一步降低血压(P<0.05)。2)与 SHR 组相比,小剂量脑心通治疗对肠系膜三级动脉血管的管壁面积/管腔...     

Open-Field Behaviour and Blood Pressure in Spontaneously Hypertensive Rats

The relation between the development of hypertension and changes in behaviour was investigated. Open-field activity of male and female Spontaneously Hypertensive Rats (SHR) and Wistar-Kyoto controls (WKY) was scored at 4, 6 or 10 weeks of age. SHR generally showed higher locomotor activity and exploratory rearing behaviour, but lower grooming activity and defecation. These changes were found for rearing (3–5 fold increase) and grooming scores at all ages, ambulation at 4 weeks and 10 weeks (ambu-lation-inner) and defecation at 6 and 10 weeks of age. Differences were generally more pronounced in female rats. SHR showed less habituation than WKY. Already at the age of 4 and 6 weeks blood pressure was increased in SHR compared with WKY (approximately 120 mm Hg vs. 100 mm Hg). Between 6 and 10 weeks of age blood pressure increased rapidly in SHR, leading to a marked difference at the latter age (about 40 mm Hg), in both male and female rats.

These experiments show that already at a young age, when blood pressure differences with WKY are small, marked behavioural changes are present in SHR. The altered behaviour could play a role in the development of hypertension in SHR.     

Plasma Endothelin-1 Levels in Patients with Aldosterone-Producing Adenoma and Pheochromocytoma

The aim of the study was to evaluate possible changes of plasma endothelin-1 levels (ET-1) in patients with hypertension secondary to primary aldosteronism and pheochromocytoma. We enrolled in the study: 12 patients affected by aldosterone-producing adenoma (5 M and 7 W; mean age 42.1 ± 17.2 years); 8 patients with pheochromocytoma (5 M, 3 W; mean age 36.2 ± 17.1 years); 15 patients with essential hypertension (9 M, 6 W; mean age 48.5±10 years). We also enrolled a normal control group (8 M, 12 W; mean age 34.2 ± 11 years). The mean plasma ET-1 concentrations in patients with pheochromocytoma were significantly higher (23.9 ± 5.2 pg/ml) than those in normal subjects (7.3 ± 1.9 pg/ml), in patients with primary aldosteronism (12.1 ± 3.8 pg/ml) and in patients with essential hypertension (9.2 ± 3 pg/ml); p < 0.001, respectively. The present investigation demonstrates that in human adrenal hypertension patients with pheochromocytoma have increased circulating ET-1 levels respect to patients with aldosterone-producing adenoma.     

一平苏对糖尿病大鼠血管反应性的影响

目的　观察一平苏 (西拉普利 )对糖尿病大鼠血管反应性的影响。方法　建立STZ所致的糖尿病大鼠血管体外灌流模型 ,以八道生理记录仪检测大鼠肠系膜血管反应持续时间及灌注压的变化。结果　糖尿病大鼠肠系膜血管对去甲肾上腺素的反应持续时间 (9.4± 3.1vs 5 .2± 2 .1,P <0 0 1) ,最高灌压显著降低 (5 .12± 0 87vs 7.81±0 92kPa ,P <0 0 1) ;口服一平苏 8周的糖尿病组大鼠血管反应性无明显改变。     

一平苏对糖尿病大鼠血管反应性的影响

目的观察一平苏(西拉普利)对糖尿病大鼠血管反应性的影响。方法建立STZ所致的糖尿病大鼠血管体外灌流模型,以八道生理记录仪检测大鼠肠系膜血管反应持续时间及灌注压的变化。结果糖尿病大鼠肠系膜血管对去甲肾上腺素的反应持续时间(9.4±3.1vs5.2±2.1,P<0.01),最高灌压显著降低(5.12±0.87vs7.81±0.92kPa,P<0.01);口服一平苏8周的糖尿病组大鼠血管反应性无明显改变。     

Plasma and Gastric Mucosal Endothelin-1 Concentrations in Patients with Peptic Ulcer

Peptic ulcer in the human stomach causeslocalized destruction of the gastric wall, which may beassociated with focal vascular insufficiency.Endothelin-1, an extremely potent vasoconstrictorpeptide, modulates regional blood flow in thevasculature of stomach, suggesting a role forendothelin-1 in peptic ulcer. We examined therelationship among endogenous plasma and mucosalendothelin-1 concentrations and the severity and area of ulcer in 19patients with gastric ulcers and eight healthy adults.Endothelin-1 concentrations were measured by enzymeimmunoassay in plasma and gastric mucosal specimens from ulcer margins, corpus, and antrum. The severityand area of ulcer were assessed endoscopically. Plasmaendothelin-1 concentrations in active (P < 0.01compared with normal) and healing (P < 0.05) stagesof ulcer were significantly greater than those innormal subjects. Plasma endothelin-1 concentrations, butnot mucosal endothelin-1 concentrations in the ulcermargin, were significantly associated with the severity of the ulcer. There was a significantpositive correlation between plasma endothelin-1concentration and area of ulcer (r = 0.70, P < 0.01).In conclusion, locally increased endothelin-1 may be an important mediator contributing to thepathogenesis of peptic ulcer.     

Clinical Outcome in Three Patients with Postpartum Hemolytic Uremic Syndrome Treated with Frequent Plasma Exchange

Abstract: This study reviewed 3 cases of postpartum hemolytic uremic syndrome (HUS) at our hospital over a 3 year period. The 3 patients had clinical and laboratory abnormalities similar to those of 12 patients with other causes of thrombotic microangiopathy presenting during the same time span. Both groups were treated with 4–7 plasma exchange treatments/week and prednisone, 60 mg/ day or its intravenous equivalent, until remission. The postpartum HUS patients had a more complicated, prolonged course; 3 of 3 required dialysis compared to 4 of 12 in the nonpostpartum group (p > 0.05), and they required more plasma exchange treatments (49 ± 17 vs. 10 ± 8, p = 0.0001) and a longer duration of therapy (70 ± 31 vs. 19 ± 17 days, p > 0.01) before remission. All postpartum HUS patients discontinued dialysis and survived whereas 4/12 nonpostpartum patients died before attaining remission. Compared to other variants of thrombotic microangiopathy, postpartum HUS requires a longer duration of therapy, but with aggressive therapy, renal and overall prognoses may be better.     

原发性高血压患者血浆肾上腺髓质素、内皮素-1的改变

目的 :观察高血压患者血浆肾上腺髓质素 (ADM)和内皮素 - 1(ET- 1)的改变。　　方法 :用特异性的放射免疫法测定 5 2例原发性高血压患者 [其中高血压 期 (高血压 期组 ) 2 5例 , 期 (高血压 期组 ) 16例 , 期 (高血压 期组 ) 11例 ]血浆 ADM、ET- 1水平并与正常对照组相比较。　　结果 :高血压 期组血浆 ADM、ET- 1水平显著高于高血压 期组、高血压 期组 (P<0 .0 1) ,高血压 期组、高血压 期组两者水平高于正常对照组 (P<0 .0 1) ,而高血压 期组与高血压 期组之间没有显著差异。　　结论 :高血压时血管细胞为抵消或减轻 ET- 1等缩血管物质的过度分泌而代偿性的合成和分泌 ADM增多。     

卡维地洛对压力负荷性大鼠心室重构及ET-1 mRNA表达的影响

目的　研究第三代 β受体阻滞剂卡维地洛对压力负荷性大鼠心室重构及心肌ET 1mRNA表达的影响。 方法　 2 0只Wistar大鼠行腹主动脉缩窄术造成后负荷增高型大鼠模型 ,随机分为肥厚组和卡维地洛组 ,4周药物干预后测定血流动力学指标和心室重量指数 ,心肌ET 1mRNA的表达水平。结果　肥厚组MBP和LVSP升高 (P <0 0 5 ) ,LVMI和RVMI升高 18 1% ,2 7 7% (P <0 0 5 ) ,ET 1mRNA表达增加 2 0 9% (P <0 0 1) ;卡维地洛改善血液动力学指标 (P <0 0 1～0 0 5 ) ,降低LVMI和RVMI(P <0 0 5 ) ,下调心肌ET 1mRNA的表达 (P <0 0 5 )。结论　压力负荷性大鼠表达上调的ET 1参与心室重构。卡维地洛下调ET 1的过度表达可能是其防治心室重构的机制之一     

Lack of Influence of Circulating Adrenaline on Blood Pressure in Normotensive and Hypertensive Rats

The relationship between circulating adrenaline and blood pressure was examined by manipulating plasma adrenaline levels in both normotensive and hypertensive rats: bilateral adrenalmedullectomy was performed in spontaneously hypertensive rats and stroke-prone spontaneously hypertensive rats; adrenaline bitartrate was infused chronically (25-32 μg/kg/h s.c.) into Wistar Kyoto, Sprague Dawley and stroke-prone rats via osmotic minipumps. Arterial and venous catheters were subsequently implanted for direct measurement of mean arterial pressure, blood sampling and drug administration in conscious rats. Adrenaline infusion for 5-6 weeks in Wistar Kyoto rats did not affect resting blood pressure (118 ± 3 versus 119 ± 1 mmHg in controls) even though plasma adrenaline was elevated 12-fold. Plasma noradrenaline was marginally elevated. Blood pressure was also unaffected by adrenaline infusion in Sprague Dawley or stroke-prone hypertensive rats. One week after adrenal medullectomy, plasma adrenaline was reduced 89% in spontaneously hypertensive rats, but blood pressure was unaffected. Ten weeks after adrenal medullectomy in young stroke-prone rats, resting blood pressure was slightly higher (167 ± 2 mmHg) than in control rats (157 ± 2 mmHg), although adrenaline was reduced by 34% in plasma and 67% in adrenal glands. Nitroprusside was infused acutely to lower blood pressure and reflexly elevate plasma noradrenaline. Neither of these responses were affected by chronic adrenaline infusion or adrenal medullectomy. In both adrenaline-infused Wistar Kyoto and medullectomised stroke-prone rats, autonomic blockade reduced blood pressure to a similar extent as in controls, indicating that the degree of sympathetic vasoconstriction was not altered by either treatment. Moreover, pressor responses to i.v. phenylephrine were similar in all groups, indicating that changes in plasma adrenaline did not affect post-synaptic receptor sensitivity. We conclude that elevated plasma adrenaline seen in spontaneous hypertensive rats is unlikely to contribute to their hypertension.     

Comparison of Endothelin-1 and Noradrenaline Stimulated Inositol Phosphate Formation in Cultured Aortic Smooth Muscle Cells from Spontaneously Hypertensive and Wistar Kyoto Rats

Total [³H]-inositol phosphate formation was measured in cultured aortic smooth muscle cells from 6 and 14 week spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) normotensive rats. Basal inositol phosphate formation was significantly increased in cells cultured from SHR compared to WKY at both 6 and 14 weeks as was basal phosphatidylinositol formation. This difference in basal values was apparent after 9 h or more incubation with [³H]-myoinositol. Both endothelin-1 and noradrenaline stimulated inositol phosphate formation was unchanged in cultured smooth muscle cells from 6-week SHR compared to WKY. In cultured smooth muscle cells from 14-week SHR a decrease was observed in endothelin-1 stimulated inositol phosphate formation compared to controls. Noradrenaline stimulated inositol phosphate formation was increased in cultured cells from 14 week SHR. Endothelin-1 and noradrenaline stimulated inositol phosphate formation does not appear to be involved in the development (at 6 weeks) of hypertension in this model. However, in established hypertension (14 weeks) cells from SHR have altered total [³H] inositol phosphate formation in response to stimulation with noradrenaline and endothelin-1 although these changes are in opposite directions. Therefore, in cultured smooth muscle cells from 14-week rats noradrenaline and endothelin-1 appear to be regulated independently with regard to their effects on the phosphatidylinositol cycle.     

Immunohistological Study of Endothelin-1 and Endothelin-A and B Receptors in Two Patients with Scleroderma Renal Crisis

Scleroderma renal crisis (SRC) developed in two patients with systemic sclerosis (SSc) and they died from respiratory failure. Findings on autopsy revealed congestion and oedema in both lungs and intimal thickening of the small renal arteries in both patients. Immunohistological investigations showed positive staining of anti-human endothelin (ET)-1 in the media of the small renal arteries and ET-B receptor in the medial smooth muscle of the small renal arteries. This observation suggests an important pathophysiological role of ET-1 in the development of SRC in some patients with SSc. Received: 17 April 1998 / Accepted: 11 March 1999     

Evaluation of the Relationship Between Arterial Blood Pressure,Aortic Stiffness and Serum Endothelin-1 Levels in Patients with Essential Hypertension

This study has attempted to evaluate the relationship between aortic stiffness, blood pressure (BP) and serum endothelin-1 (ET-1) levels in patients with essential HT. Totally 152 subjects, consisting of 103 patients diagnosed with HT at least 1 year previously and 49 healthy individuals, were enrolled in this study. They were subdivided, on the basis of BP measurements made at home, into three groups as the hypertensives with dysregulated BP (n = 56), the hypertensives with regulated BP (n = 47) and the normotensive controls (n = 49). Statistically significant differences were observed between the three groups with respect to aortic elasticity parameters (p < 0.01 for aortic strain, aortic distensibility and aortic stiffness). Serum ET-1 levels in the three groups were similar (p = 0.101), but a significant correlation was observed between the ET-1 values and the aortic elasticity parameters (p = 0.004). Alteration of the aortic elasticity parameters in patients with HT not only correlates with the serum ET-1 levels indicating endothelial dysfunction but also gives direct clues about status of BP regulation.     

Endothelin-1 and Adrenomedullin Plasma Levels After Exposure to Fludrocortisone,Dexamethasone, and Spironolactone

We asked whether plasma concentrations of endothelin-1 (ET-1) or adrenomedullin (ADM) are altered by different activity states of the renin–angiotensin–aldosterone system (RAAS). Levels of ET-1 and ADM were studied in patients with primary aldosteronism (n = 15), essential hypertension (n = 15), and adrenal insufficiency (n = 7). Effects of fludrocortisone, dexamethasone, or spironolactone treatment on ET-1 and ADM levels were also analyzed. Plasma ET-1 and ADM concentrations did not differ significantly between the patient groups. After fludrocortisone, dexamethasone, or spironolactone treatment, both ET-1 and ADM did not change significantly. The data support the hypothesis that the RAAS is not directly linked with the ET-1/ADM system.     

Blood Pressure Changes in Spontaneously Hypertensive and Normotensive Rats with Neonatal Streptozotocin Induced Type 2 Diabetes

ABSTRACT

We examined the blood pressure changes in hypertensive and normotensive rats with Type 2 diabetes induced by neonatal streptozotocin (STZ) treatment. STZ was intraperitoneally injected at 2 days of age with the dose of 25, 50 and 75 mg/kg for male spontaneously hypertensive rats (SHR) and with 75, 100, 125 and 150 mg/kg for male normotensive Wistar Kyoto rats (WKY). Blood pressure was measured by indirect tail-cuff method until 12 weeks of age. STZ-treated SHR, of which plasma glucose and glycosylated hemoglobin increased and body weight decreased with the dose of STZ, developed and maintained hypertension, same as did the vehicle- treated control SHR. On the other hand, STZ-treated WKY which developed only mild hyperglycemia lost body weight with the dose of STZ but the blood pressures rose slightly, these changes being correlated with the glycemic levels. The explanation for these differences between SHR and WKY remained to be elucidated.     

复方丹参饮对胰岛素抵抗型大鼠血管内皮细胞一氧化氮及内皮素的影响

目的探讨复方丹参饮对胰岛素抵抗（IR）型大鼠血管内皮细胞一氧化氮（NO）及内皮素（ET-1）的影响。方法将60只健康雄性Wistar大鼠随机分为空白对照组、模型对照组、罗格列酮组、复方丹参饮治疗组（中药治疗组）、复方丹参饮预防组（中药预防组）,每组12只。采用高脂高糖饮食建立大鼠IR模型,各组大鼠灌胃给药。16周后采用酶联免疫法检测各组大鼠血中N0、ET-1的含量。结果与空白对照组相比,除复方丹参饮预防组差异无统计学意义外,其余各组NO含量减少、ET-1含量增加（P〈0．05或P〈0．01）;与模型对照组相比,罗格列酮组及中药预防组与治疗组均能增加NO及减少ET-1的含量（P〈0．05或P〈0．01）。结论复方丹参饮具有保护血管内皮细胞的功能,其机制与升高血清NO及降低血浆ET-1水平有关。