新型类肽化合物iQWcF对内皮素受体功能的拮抗作用

目的　评价新型类肽化合物iQWcF对内皮素受体功能的拮抗作用。方法　①在大鼠离体主动脉血管条上 ,先以一定浓度的iQWcF孵育 ,然后累积给予不同浓度的ET 1,以ET 1诱发的血管收缩为指标评价iQWcF对ET受体的拮抗特点。②采用麻醉正常血压大鼠 ,预先静脉给予一定剂量的iQWcF。 5min后静脉注射ET 1(0 9nmol·kg-1) ,观察不同时间点血压的变化 ,以评价iQWcF对ET受体的作用。结果　①化合物iQWcF能浓度依赖地抑制ET 1诱发的大鼠主动脉血管条的收缩。②iQWcF静脉注射 30mg·kg-1能抑制ET 1诱发的升压作用。而对ET 1诱发的降压作用无影响。结论　新结构化合物iQWcF是一选择性的ETA 受体拮抗剂     

新型肽类化合物对内皮素受体的拮抗作用及其心血管药理活性的评价

目的评价新型肽类化合物的内皮素受体拮抗活性及其心血管药理活性。方法离体血管环实验及在体心功能实验。结果该类化合物能剂量依赖性地抑制内皮素诱发的大鼠主动脉血管条的收缩,对正常血压大鼠的血压、心率及心功能无显著影响。在脑卒中易感型自发性高血压大鼠上40,43和44号化合物po引起血压显著下降。结论该类化合物具有拮抗内皮素的药理学作用,对正常血压大鼠的血压、心率及心功能均无显著影响,部分化合物可使脑卒中易感型自发性高血压大鼠血压下降,在心脑血管疾病中可能有潜在的应用价值。     

内皮素系统与心肌肥厚

心肌肥厚是心脏对神经介质和压力超负荷等应激反应的一种代偿性机制。内皮素(ET)作为一种具有强大血管收缩作用的活性多肽,在心血管系统,特别是血管内皮细胞、平滑肌细胞和心肌细胞,ET对正常功能的调节起着重要的生理作用。局部心肌组织中ET过度生成与心肌肥厚的发生密切相关,心肌组织中的ET-1通过与特异性的受体结合,并与局部组织中其它相关的血管活性物质相互作用,介导了心肌肥厚的发生和发展过程。内皮素通过ETA受体诱导心肌细胞的肥厚和心肌成纤维细胞的增生,ETB受体则在心肌肥厚的发生和发展中均起作用。内皮素受体作为新的药物靶点,已经成为人们研究的热点,相应的受体拮抗剂的研究也取得了很大的进展。     

非选择性内皮素受体拮抗剂CPU0213改善感染性休克小鼠/大鼠的血管活性

目的:通过非选择性内皮素受体拮抗剂CPU20213对结扎小鼠和大鼠盲肠并穿孔致感染性休克血管活性的改善,探讨其通过干预内皮素-活性氧(ET-ROS)轴心治疗感染性休克可能的作用机制。方法:结扎小鼠盲肠并穿孔,8 h后按30 mg·kg-1皮下注射(sc)CPU0213,bid×3 d。观察术后该时间段的存活率,计算腹腔渗出液重量,生命器官脏器系数,心肌、肾匀浆和血清丙二醛(MDA),谷胱甘肽过氧化物酶(GSH-PX)含量及胸主动脉血管活性;同样方法结扎大鼠盲肠,检测血浆ET-1浓度和肠系膜血管ETA和ETB受体mRNA表达。结果:模型组小鼠存活率明显降低,生命器官脏器系数明显增加,腹腔渗出液显著增多,GSH-PX活性下降,MDA含量增加,血管收缩和舒张功能及NO生物利用度明显降低;大鼠血浆ET-1浓度显著升高,肠系膜血管ETA和ETB受体mRNA表达上调;CPU20213治疗后,均有不同程度改善。结论:CPU0213通过阻断ET-ROS轴心,改善血管活性,减少腹腔渗出液,提高存活率。     

扩张型心肌病大鼠心脏左室内皮素受体及其亚型分析

目的 观察扩张型心肌病大鼠左室ETR及其亚型的变化.方法用125I-ET-1建立内皮素受体及其亚型的放射配基分析法,进行饱和结合试验,对扩张型心肌病大鼠左室心肌ETR及其亚型的含量进行分析.结果(1) 放射配基分析法检测ETR的基本实验条件为37 ℃孵育 60 min,膜蛋白投放量以20～40 μg 为佳; (2) ET-1及非选择性拮抗剂bosentan、选择性拮抗剂BQ123、BQ788等均能竞争抑制125I-ET-1与内皮素受体的结合,而去甲肾上腺素则不能抑制; (3) 正常大鼠左室内皮素受体数量为 (92.21±34.34) nmol·     

内皮素受体拮抗剂临床研究进展

内皮素（endothclin,ET）是由血管内皮细胞、心肌、平滑肌等合成及分泌的一种含有21个氨基酸的活性多肽,基因克隆证实ET、有三个异构体为ET-1、ET-2和ET-3,其中ET-1既有强烈而持久的血管收缩作用,又具有促进细胞生长和有丝分裂特性,是引起多种疾病的炎性因子。已经上市的内皮素受体拮抗剂有波生坦、替唑生坦、恩拉生坦、西他生坦、阿曲生坦及安贝生坦,在治疗高血压、肺动脉高压、肿瘤、糖尿病并发症、心肌梗死及脑血管痉挛等方面取得很好效果。     

新的非肽类内皮素拮抗剂:咖啡酸、阿魏酸

目的:研究桂皮酸类化合物咖啡酸和阿魏酸对内皮素(endothelin 1,ET-1) 生物效应的拮抗作用。方法:体内ET 1iv 致小鼠急性死亡、体外血管平滑肌细胞培养、主动脉条收缩试验和ET 受体结合试验。结果:咖啡酸和阿魏酸(ip) 能剂量依赖性地显著延长ET-1 致小鼠急性死亡时间,在离体器官可观察到咖啡酸与阿魏酸能拮抗ET-1的缩血管效应;放射性受体 配体结合实验表明,咖啡酸和阿魏酸可竞争性地抑制ET-1 与其受体的结合。结论:咖啡酸和阿魏酸为新的非肽类ET 拮抗剂。     

内皮素系统在慢性心力衰竭中作用的研究进展

内皮素（EF）既有强烈而持久的血管收缩作用，又具有促细胞生长和促有丝分裂特性，ET受体属G蛋白偶联家族，ET及其受体结合后通过一系列的信号传导而发挥作用，引起多种心血管疾病，如高血压，冠脉疾病，原发性肺动脉高压和慢性心力衰竭（CHF）等。ET受体拮抗剂在CHF的实验研究和初步临床应用中有明显的效果，血中ET-1水平降低，血液动力学得到改善，心脏指数增加，心肌重构和心室肥大被抑制，同时提高了生存率。     

达芦生坦对大鼠心肌内皮素受体结合的影响及一次给药对肺动脉高压的治疗作用

目的:研究内皮素受体(ETR)拮抗剂达芦生坦(DR)对大鼠心肌ETR的选择性,及一次给药对肺动脉高压大鼠的治疗作用。方法:放射受体结合方法测定DR对125I-ET与大鼠左室膜ETR竞争结合。对低氧肺动脉高压大鼠静脉注射DR后右室血流动力学的改善作用。结果:DR(0.1μmol.L-1)竞争125I-ET1与心肌ET受体的总结合率降为31.5%±7.7%。抑制125I-ET1与ETAR和ETBR结合的IC50值为1.93±0.21和147±20 nmol.L-1,比值为76。DR输注后20 min明显改善血流动力学。结论:DR是有较高亲和力与选择性的ETAR拮抗剂。急性一次给药对肺动脉高压大鼠血流动力学有明显改善作用。     

丁咯地尔对大鼠外周离体血管的药理作用

目的 :分析丁咯地尔对大鼠外周血管的药理作用及机制。方法 :采用离体血管平滑肌张力实验 ,研究其对多种因素引起大鼠尾动脉、胸主动脉收缩作用的影响。结果 :丁咯地尔可浓度依赖性地使去甲肾上腺素、去氧肾上腺素、可乐定和 5 羟色胺引起的大鼠尾动脉收缩的累积对数浓度 反应曲线平行右移 ,最大反应不降低 ,其pA2 分别为 5.4 5,7.2 5,5.97和 6.58。使去甲肾上腺素致大鼠胸主动脉 ;氯化钾、氯化钙致大鼠尾动脉、胸主动脉收缩的累积对数浓度 反应曲线右移 ,最大反应降低 ,其pD′2 分别为 3.88,3.76,3.33,4 .0 3和 3.60。结论 :丁咯地尔可竞争性拮抗大鼠尾动脉的肾上腺素α受体(α1,α2 受体 )和 5 羟色胺受体 ,还可非竞争性拮抗氯化钾、氯化钙致大鼠尾动脉、胸主动脉的收缩     

Antihypertensive effect of an endothelin receptor antagonist in DOCA-salt spontaneously hypertensive rats.

1. Endothelin-1 gene expression is enhanced in aorta and mesenteric arteries, and possibly other vessels, of deoxycorticosterone acetate (DOCA)-salt hypertensive rats but is normal or reduced in spontaneously hypertensive rats (SHR). Bosentan, a mixed ETA/ETB endothelin receptor antagonist, blunts the development of elevated blood pressure of DOCA-salt hypertensive rats but not in SHR. In this study we investigated whether treatment of DOCA-salt SHR with bosentan would result in blunted rise in blood pressure. 2. SHR, aged 13 weeks, were implanted with silastic containing DOCA and offered 1% saline to drink. Systolic blood pressure was measured by the tail-cuff method. Endothelin-1 mRNA abundance in aorta and mesenteric arteries was measured by Northern blot analysis. Content of immunoreactive endothelin in blood vessels was measured by radioimmunoassay. 3. Systolic blood pressure rose less in bosentan-treated DOCA-salt SHR (to 223 +/- 2 mmHg) in comparison to the untreated rats (241 +/- 1), a small but significant difference (P < 0.001). However, blood pressure of bosentan-treated DOCA-salt SHR was still higher than in age-matched SHR. Endothelin-1 mRNA abundance and content of immunoreactive endothelin were increased in the aorta and the mesenteric arterial bed of DOCA-salt SHR, and were unaffected by treatment with bosentan. 4. These data support the hypothesis of a role of endothelin-1 in blood pressure elevation in this hypertensive model with malignant hypertension. They also support the hypothesis that an antihypertensive effect of the mixed ETA/ETB endothelin receptor antagonist, bosentan, is found when experimental hypertensive animals exhibit enhanced endothelin-1 gene expression in blood vessels.     

盐酸埃他卡林对内皮素系统的影响

目的　研究新型抗高血压药物盐酸埃他卡林 (iptakaimhydrochloride,Ipt)对内皮素 (ET)系统的作用。方法　以放射免疫法测定大鼠血浆内皮素水平和培养的血管内皮细胞释放的内皮素量;以RT PCR技术,测定内皮素及其转化酶(ECE)基因表达的变化;在离体血管标本上,观察内皮素对血管平滑肌张力的影响;在麻醉大鼠上,插入肺内动脉导管测定肺动脉压。结果　①在SHRsp上,Ipt0 25 ~4 0m·kg-1,po, 1次 /d, 3个月,可对抗血浆中内皮素水平的病理性增高;②在培养的新生小牛主动脉内皮细胞 (BAEC)上Ipt在 1~1000μmol·L-1浓度范围内,能剂量依赖性地抑制培养的新生小牛主动脉内皮细胞分泌内皮素;③并能抑制培养的新生小牛主动脉内皮细胞内皮素和内皮素转化酶基因的表达;④在离体大鼠主动脉标本上,Ipt0 5 ~100μm·L-1可浓度依赖性地对抗ET 1的缩血管作用,此作用在无钙营养液中明显减弱;⑤在麻醉的SD大鼠上,经肺内动脉注入ET 1可以诱发肺动脉收缩,肺动脉压增高。Ipt0 5和1 0mg·kg-1可对抗肺动脉内注射ET 1诱发的肺动脉高压,但对正常肺动脉压无明显影响。结论　盐酸埃他卡林可对抗内皮素系统的功能,其特征包括抑制血管内皮细胞内皮素转化酶和内皮素基因的表达,抑制内皮素的释放,对抗高血压状态下血浆内皮素水平的病理性增?     

Pharmacological characterization of YM598, an orally active and highly potent selective endothelin ET(A) receptor antagonist

We describe here the pharmacology of (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), a novel selective endothelin ET(A) receptor antagonist synthesized through the modification of the ET(A)/ET(B) non-selective antagonist, bosentan. YM598 inhibited [125I]endothelin-1 binding to cloned human endothelin ET(A) and ET(B) receptor, with K(i) of 0.697 and 569 nM, and inhibited endothelin-1-induced increases in intracellular Ca(2+) concentration in human and rat endothelin ET(A) receptor. YM598 also inhibited endothelin-1-induced vasoconstriction in isolated rat aorta with a pA(2) value of 7.6. In vivo, YM598 inhibited the pressor response to big endothelin-1, a precursor peptide of endothelin-1. DR(2) values of YM598 in pithed rats were 0.53 mg/kg, i.v. and 0.77 mg/kg, p.o., and its antagonism in conscious rats was maintained for more than 6.5 h at 1 mg/kg, p.o. In contrast, YM598 had no effect on the sarafotoxin S6c-induced depressor or pressor responses. YM598 showed not only superior antagonistic activity and higher-selectivity for endothelin ET(A) receptor in vitro, but at least a 30-fold higher potency in vivo than bosentan. In conclusion, YM598 is a potent and orally active selective endothelin ET(A) receptor antagonist.     

Renal and depressor effects of SQ 29,072, a neutral endopeptidase inhibitor, in conscious hypertensive rats.

The depressor and renal responses to the neutral endopeptidase (NEP) inhibitor, SQ 29,072, were characterized in both the conscious spontaneously hypertensive rat (SHR) and the conscious deoxycorticosterone acetate (DOCA)/salt hypertensive rat. Inhibition of tissue NEP activity by pharmacologically active doses was also ascertained in both hypertensive models. Intravenous administration of 300 mumol/kg of SQ 29,072 significantly reduced mean arterial pressure (MAP), produced modest natriuretic and diuretic responses, and inhibited renal NEP activity by approximately 40% in conscious SHR. Doses of 100 and 300 mumol/kg of SQ 29,072 elicited greater depressor responses (-36 +/- 7 and -41 +/- 8 mm Hg, respectively) in DOCA/salt hypertensive rats than in SHR (-11 +/- 24 and -31 +/- 5 mm Hg, respectively). SQ 29,072 (300 mumol/kg, i.v.) also inhibited renal NEP activity to a greater extent (70%) in DOCA/salt hypertensive rats. Similarly, the depressor responses to exogenous ANP 99-126 (1, 3, and 10 nmol/kg, i.v.) were greater in DOCA/salt hypertensive rats (-16 +/- 4, -38 +/- 6, and -73 +/- 6 mm Hg, respectively) than in the SHR (0 +/- 6, -17 +/- 3, and -24 +/- 3 mm Hg, respectively). Finally, equidepressor doses of SQ 29,072 and ANP 99-126 both increased urine volume as well as sodium and cyclic GMP excretion in conscious DOCA/salt hypertensive rats. In conclusion, the profile of depressor and renal activities produced by SQ 29,072 was consistent with potentiation of endogenous ANP by inhibition of NEP in conscious SHR and DOCA/salt hypertensive rats.     

Sildenafil improves diabetic vascular activity through suppressing endothelin receptor A, iNOS and NADPH oxidase which is comparable with the endothelin receptor antagonist CPU0213 in STZ-injected rats

Objectives Abnormal vascular activity in diabetes is related not only to impaired nitric oxide bioavailability but also to inflammatory cytokines, endothelin A receptor (ET_A) activation and NADPH oxidase in the vasculature. The potential role of sildenafil in improving vascular function was investigated. Its action was likely blocking upregulated ET_A and NADPH oxidase, and was compared with the endothelin receptor antagonist CPU0213. Methods Diabetes was induced by single‐dose administration of streptozotocin (65 mg/kg, i.p.) to rats and the vascular activity of the thoracic aorta was measured. Key findings An increase in contractile tone to phenylephrine and a decrease in relaxant tone to acetylcholine was found in the thoracic aorta. Oxidative stress was evident by increased malondialdehyde and reduced glutathione peroxidase levels in serum and upregulation of ET_A, MMP‐9 (matrix metalloproteinase‐9), inducible nitric oxide synthase and NADPH oxidase p67^phox were found in the vascular wall. The vascular abnormalities and abnormal biomarkers were attenuated significantly by either sildenafil or CPU0213 along with an improvement of nitric oxide bioavailability and vascular activity. Conclusions Improvement of diabetic vascular abnormal activity by sildenafil results from its suppression of activation of ET_A and NADPH oxidase in the vasculature, and these actions are comparable with those of the endothelin receptor antagonist CPU0213.     

内皮素受体拮抗剂用于肺动脉高压的治疗进展

肺动脉高压（PAH）是一类以肺血管阻力进行性升高为主要特征的心肺血管疾病,最终可导致右心衰竭甚至死亡。早期发现PAH患者中内皮素明显高于正常,可引起肺血管的持续收缩及重构。内皮素受体拮抗剂可阻断该通路进而起到降低肺高压的作用。但目前国内临床上对于该类药物了解甚少。本文参考国内外文献对内皮素受体拮抗剂在PAH中的作用机制及临床应用作简要综述,旨在指导临床用药,使更多患者获益。     

孤束核微注射内皮素-1对高血压大鼠心血管活动的影响

目的研究内皮素－１（ＥＴ－１）在孤束核对高血压大鼠心血管活动的作用。方法乌拉坦麻醉大鼠单侧孤束核微注射ＥＴ－１或ＥＴ受体拮抗剂后，观察血压、心率、左室收缩压和±ｄｐ／ｄｔｍａｘ的变化。结果在乌拉坦麻醉的ＷＫＹ大鼠和自发性高血压大鼠（ＳＨＲ），单侧孤束核微注射１．０ｐｍｏｌ或３．３ｐｍｏｌ的ＥＴ－１均可引起血压、左室收缩压和±ｄｐ／ｄｔｍａｘ升高，呈剂量依赖性；心率轻度减慢，与剂量不相关。血压持续升高９０ｍｉｎ以上。ＳＨＲ的心血管反应强度与ＷＫＹ大鼠无显著差异。孤束核微注射非选择性ＥＴＡ／ＥＴＢ受体拮抗剂ＰＤ１４２８９３对ＳＨＲ和ＷＫＹ大鼠的血压和心率均无明显影响。结论孤束核ＥＴ－１与ＳＨＲ的血压增高无关     

Different activation of vascular mitogen-activated protein kinases in spontaneously and DOCA-salt hypertensive rats

Regulation mechanisms of the activity of vascular mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, may be altered in hypertension. To examine whether vascular MAP kinase activation mechanisms are altered in hypertension, we measured the activity of MAP kinases in rat aorta strips from spontaneously hypertensive rats (SHR) and from deoxycorticosterone acetate (DOCA)-salt hypertensive rats, and examined whether vascular angiotensin and endothelin systems are responsible for the alteration of MAP kinase activation in these hypertensive models. Endothelium-denuded aorta strips were incubated at 37 degrees C in medium. MAP kinase activity after incubation was increased in rat aorta strips. The MAP kinase activation was greater in 9- and 15-week-old SHR aorta strips than in age-matched Wistar Kyoto rats (WKY) aorta strips. Similarly, MAP kinase activation was enhanced in aorta strips from DOCA-salt hypertensive rats. In aorta strips from these kinds of rats, the angiotensin receptor antagonist, losartan, and the endothelin receptor antagonist, cyclo (D-alpha-aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl) (BQ123), inhibited the MAP kinase activation. The losartan-induced, but not BQ123-induced, inhibition of MAP kinase activation was enhanced in 15-week-old SHR aorta strips, whereas the BQ123-induced, but not losartan-induced, inhibition of MAP kinase activation was enhanced in DOCA-salt hypertensive rat aorta strips. Angiotensin II-induced MAP kinase activation was enhanced in 15-week-old SHR aorta strips, whereas it was depressed in DOCA-salt hypertensive rat aorta strips. These results indicate that MAP kinase activation function is enhanced in aorta strips from both kinds of hypertensive rats. It appears that the enhancement of MAP kinase activation results partly from enhanced vascular angiotensin system in SHR and from enhanced vascular endothelin system in DOCA-salt hypertensive rats.