高血压病24小时平均脉压与血浆内皮素、一氧化氮关系的探讨

目的　研究 2 4小时平均脉压与血浆内皮素、一氧化氮关系。　方法　对我院住院的原发性高血压病人 70例 ,均在未服药状态下进行动态血压监测。按 2 4小时平均脉压 <6 0mmHg ,6 0mmHg～ 6 9mmHg ,70mmHg～ 79 mmHg,80mmHg～ 89mmHg,90mmHg～ 99mmHg ,>10 0mmHg分成六个组 ,同时测定每个组的血浆内皮素、一氧化氮。　结果　随着 2 4小时平均脉压增加 ,血浆内皮素浓度增加 ,而血浆一氧化氮浓度降低。　结论　高血压患者 2 4小时平均脉压与血浆内皮素成正相关 ,与血浆一氧化氮成负相关     

糖尿病大鼠血、睾丸和脑组织内皮素水平的初步研究

目的　探讨糖尿病大鼠以及用银杏叶提取物 (EGb)治疗后血浆、睾丸和脑组织中内皮素的变化及意义。方法　将SD大鼠分为正常对照组、糖尿病模型组、EGb治疗组三组 ,在EGb治疗 5周后 ,用放射免疫法同时测定各组大鼠血浆、睾丸和脑组织中内皮素 (ET)的含量。结果　脑组织及血浆中ET含量正常对照组与糖尿病组比较无显著性差异 (P >0 0 5 ) ,睾丸组织中ET含量糖尿病组明显高于正常对照组 ,两者有显著性差异 (P <0 0 5 ) ;糖尿病组与EGb治疗组比较各种组织ET含量有下降倾向 ,但无显著性差异 (P >0 0 5 )。结论　糖尿病大鼠睾丸组织中ET含量增高 ,可能造成睾丸组织损害 ;EGb治疗可能有利于降低大鼠血液、睾丸和脑组织中的ET含量 ,但需进一步试验证实。     

普伐他汀早期应用对急性冠状动脉综合征血管炎症反应及内皮功能的影响

目的观察普伐他汀在急性冠状动脉综合征患者早期(发病48h以内)应用对患者血浆一氧化氮、内皮素及C反应蛋白的影响。方法60例急性冠状动脉综合征患者随机分为两组。普伐他汀组30例,常规治疗组(未服用他汀类调脂药物)30例,疗程2周,分别于治疗前后测定血浆一氧化氮、内皮素及C反应蛋白水平。结果普伐他汀组血浆C反应蛋白(32.7±10.8μg/L)及内皮素(50.3±17.2μg/L)水平明显下降、血浆一氧化氮(50.3±10.2μmol/L)水平明显上升,与常规治疗组血浆C反应蛋白(44.3±9.7μg/L)、内皮素(72.4±16.4μg/L)及血浆一氧化氮(42.8±8.7μmol/L)水平比较有显著性差异(P<0.01)。结论普伐他汀在急性冠状动脉综合征患者中早期应用能够抑制血管内皮的炎症反应,稳定粥样斑块,改善血管内皮功能,解除冠状动脉痉挛。     

氨氯地平并苯那普利对高血压患者血浆一氧化氮与内皮素的影响

目的:评价氨氯地平、苯那普利单独和联合治疗对高血压患者血浆一氧化氮(NO)和内皮素(ET)的影响。方法:选择126例高血压患者随机分为3组,氨氯地平组(A组,41例,接受氨氯地平治疗);苯那普利组(B组,45例,接受苯那普利治疗);联合治疗组(C组,40例,接受氨氯地平和苯那普利治疗)。于治疗前、后行血压及血浆NO、ET测定,并与40例正常对照组血浆NO、ET水平对照。结果:较之对照组,三组高血压患者NO水平显著降低(P<0.01),ET水平显著升高(P<0.01)。三组治疗后血压、ET水平均有显著下降(P均<0.01),A组及B组下降幅度无显著差异,C组下降幅度明显高于A组和B组的(P<0.05);三组血浆NO水平均有显著升高(P均<0.01);A组及B组血浆NO水平升高无显著差异(P>0.05),C组NO升高幅度明显高于A组和B组的(P<0.05)。结论:氨氯地平和苯那普利单独治疗均可明显降低血压和血浆ET水平,同时升高血浆NO水平,而两药联用疗效更佳。     

API0134对血管平滑肌细胞增殖和血小板源生长因子B链、碱性纤维母细胞生长因子及相关癌基因表达的影响

为探讨API0134防治冠状动脉粥样硬化和腔内成形术后再狭窄的作用机制，采用内皮素诱导建立培养的血管平滑肌细胞增殖模型，用氚标胸腺嘧啶脱氧核苷掺入法、流式细胞术、免疫细胞化学检测及Northernblot方法，观察了API0134对血管平滑肌细胞增殖的作用及对血小板源生长因子B链、碱性纤维母细胞生长因子及其相关癌基因C－sis和C－mpc表达的影响。结果发现，API0134能逆转内皮素所致的氚标胸腺嘧啶脱氧核苷掺入量增多（对照组为499±92，内皮素组为617±98，API0134组为506±102），阻止血管平滑肌细胞由静止期（G0／G1期；对照组为72％，内皮素组为50％，API0134组为60％）进入DNA合成期（S期；三组分别为26％、36％和30％）和有丝分裂期（G2／M期，三组分别为2％、14％和4％），并能逆转内皮素引起的血小板源生长因子B链、碱性纤维母细胞生长因子抗原、c－sis和c－mpc的mRNA表达增强。提示API0134有抑制血管平滑肌细胞增殖的作用，这种作用与生长因子及癌基因调控的分子生物学机制有关。     

Endogenous urocortins reduce vascular tone and renin-aldosterone/endothelin activity in experimental heart failure.

AIMS: To investigate the role of the endogenous urocortin peptides in heart failure (HF) through blockade of the corticotropin-releasing factor receptor 2 (CRF-R2). METHODS AND RESULTS: Eight sheep were administered the CRF-R2 antagonist CRF(9-41) (1.5 mg bolus) before (Normal) and after development of pacing-induced HF. Compared with controls, CRF(9-41) in HF significantly increased mean arterial pressure (MAP) (71+/-2 vs. 75+/-2 mmHg, P=0.0024) and calculated total peripheral resistance (CTPR) (33.3+/-5.2 vs. 39.4+/-5.9 mmHg/L/min, P=0.0455). Similar trends were observed in the Normal state (MAP 87+/-1 vs. 89+/-2 mmHg, P=0.0689; CTPR 21.9+/-2.0 vs. 24.4+/-2.4 mmHg/L/min, P=0.0731). Left atrial pressure was elevated similarly in both states (Normal P=0.0013; HF P=0.0298), whereas cardiac output tended to be reduced (Normal P=0.0614). CRF(9-41) increased plasma urocortin-I (Normal 10.3+/-0.8 vs. 19.8+/-1.3 pmol/L, P<0.001; HF 14.4+/-0.9 vs. 25.3+/-0.8 pmol/L, P<0.001), renin (Normal 0.34+/-0.06 vs. 0.41+/-0.02 nmol/L/hr, P=0.013; HF 1.14+/-0.29 vs. 1.57+/-0.36 nmol/L/hr, P=0.0326), aldosterone (Normal 370+/-62 vs. 563+/-99 pmol/L, P=0.0813; HF 662+/-141 vs. 1024+/-209 pmol/L, P=0.095), and endothelin-1 (HF 3.18+/-0.18 vs. 4.74+/-1.04 pmol/L, P=0.0087). MAP, CTPR, renin, and endothelin-1 responses to CRF-R2 antagonism were significantly greater in HF than in the Normal state (P=0.049, 0.0427, 0.0311, and 0.0412, respectively). CONCLUSION: These data suggest that the endogenous urocortin peptides contribute to the suppression of vascular tone and renin-angiotensin-aldosterone/endothelin activation in HF and thus, play a protective compensatory role in this disorder.     

BQ‐788, A Selective Endothelin ETB Receptor Antagonist

We describe characteristics of a selective endothelin (ET) ET_B receptor antagonist, BQ‐788 [N‐cis‐2,6‐dimethylpiperidinocarbonyl‐L‐γ‐methylleucyl‐D‐1‐methoxycarbonyltryptophanyl‐D‐norleucine], which is widely used to demonstrate the role of endogenous or exogenous ETs in vitro and in vivo. In vitro, BQ‐788 potently and competitively inhibited ¹²⁵I‐labeled ET‐1 binding to ET_B receptors in human Girrardi heart cells (hGH) with an IC₅₀ of 1.2 nM, but only poorly inhibited the binding to ET_A receptors in human neuroblastoma cell line SK‐N‐MC cells (IC₅₀, 1300 nM). In isolated rabbit pulmonary arteries, BQ‐788 showed no agonistic activity up to 10 μ and competitively inhibited the vasoconstriction induced by an ET_B‐selective agonist (pA₂, 8.4). BQ‐788 also inhibited several bioactivities of ET‐1, such as bronchoconstriction, cell proliferation, and clearance of perfused ET‐1. Thus, it is confirmed that BQ‐788 is a potent, selective ET_B receptor antagonist. In vivo, in conscious rats, BQ‐788, 3 mg/kg/h, i.v., completely inhibited a pharmacological dose of ET‐1‐ or sarafotoxin6c (S6c) (0.5 nmol/kg, i.v.)‐induced ET_B receptor‐mediated depressor, but not pressor responses. Furthermore, BQ‐788 markedly increased the plasma concentration of ET‐1, which is considered an index of potential ET_B receptor blockade in vivo. In Dahl salt‐sensitive hypertensive (DS) rats, BQ‐788, 3 mg/kg/h, i.v., increased blood pressure by about 20 mm Hg. It is reported that BQ‐788 also inhibited ET‐1‐induced bronchoconstriction, tumor growth and lipopolysaccharide‐induced organ failure. These data suggest that BQ‐788 is a good tool for demonstrating the role of ET‐1 and ET_B receptor subtypes in physiological and/or pathophysiological conditions.     

Ethanol Stimulates Immunoreactive Endothelin-1 and -2 Release from Cultured Human Umbilical Vein Endothelial Cells

The present study employed enzyme-immunoassay to examine the effect of ethanol on endothelin-1 and/or -2(ET1 + 2) release from human umbilical vein endothelial cells. Thirty minutes of exposure to ethanol increased the release of immunoreactive ET1 + 2 from cultured endothelial cells in a dose-dependent manner. However, ethanol at concentrations of less than 400 mM did not induce any LDH release from the endothelial cells. Trypan blue exclusion test revealed that 400 mM solution of ethanol decreased the cell viability to 7.7%. Thus, ethanol was found to directly stimulate ET1 + 2 release from cultured human umbilical vein endothelial cells. This reaction of vascular endothelial cells against ethanol may be related to ethanol-induced cardiovascular diseases such as hypertension, myocardial infarction and stroke, as well as fatal alcohol syndrome.     

A review of the profile of endothelin axis in cancer and its management

The endothelins and their associated receptors are important controllers of vascular growth, inflammation and vascular tone. In cancer, they have roles in the control of numerous factors in cancer development and progression, including angiogenesis, stromal reaction, epithelial mesenchymal transitions, apoptosis, invasion, metastases and drug resistance. Also, we consider current information on the role of this signalling system in cancer and examine the state of the current cell, animal and clinical trials utilizing endothelin targeted drugs for cancer management. Although targeting the endothelin axis in cell lines and xenografts show some promise in retarding cellular growth, results from limited clinical trials in prostatic cancer are less encouraging and did not offer significant survival benefit. The ability to target both cancer cells and vasculature via endothelin is an important consideration that necessitates the further refining of therapeutic strategies as we continue to explore the possibilities of the endothelin axis in cancer treatment.     

Pretreatment of Donors with Endothelin Receptor Antagonist TAK-044 Improves Cardiac Functional Recovery Following Preservation with University of Wisconsin Solution

Objective : Previous studies suggest that endothelin-1 (ET-1) plays a role in myocardial ischemia/reperfusion injury. Although administration of an endothelin receptor antagonist to the recipient has been shown to improve myocardial function after ischemia/reperfusion in a rat heart transplantation model, the effect of administering an endothelin receptor antagonist to the donor has not yet been examined. This study was designed to investigate the effects of pretreating donors with an ET A /ET B endothelin receptor antagonist (TAK-044) on myocardial function after cold preservation of a rat heart. Design : Male rats were pretreated with normal saline (control group, n = 8), TAK-044 (TAK group, n = 8, 1 mg/kg). Following cardiac arrest using cardioplegia, we washed out the coronary vascular beds with cold University of Wisconsin solution followed by 6-h preservation. After preservation, the hearts were mounted on a Langendorff apparatus to estimate aortic flow (AF), coronary flow (CF), cardiac output (CO), systolic pressure (SP), heart rate (HR), and rate-pressure product (RPP: HR &#50 SP). The concentration of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) within the coronary perfusate during reperfusion was measured. Results : AF, SP, and CO were significantly greater in the TAK group than in the control group ( p = 0.0045, 0.004, and 0.0295, respectively). Conclusion : Pretreatment of donors with a nonselective endothelin receptor antagonist (TAK-044) improved cardiac functional recovery following preservation and may be beneficial for prolonged myocardial preservation.