抗蛇毒中草药红背丝绸对内皮素-1的拮抗作用

目的：研究我国广西抗蛇毒中草药红背丝绸〖Ｃｉｓｓｕｓ ａｓｓａｍｉｃａ （Ｌａｗｓ．）Ｃｒａｉｂ〗对内皮素－１（ｅｎｄｏｔｈｊｅｌｉｎ,１ＥＴ－１）的拮抗作用。方法：对红背丝绸进行提取分离,用不同提取物拮抗ＥＴ＝１引起的小鼠急性死亡、大鼠离体血管条收缩人和整体大鼠升压作用。结果：红背丝绸乙醇提取物、乙醇提取物之乙酸乙酸萃取物以及从乙酸乙酯苯取物中分离得到的白ｒｅｓｖｅｒａｔｒｏｌ）在整体和离体水平     

白藜芦醇的提取分离及其对内皮素-1的拮抗作用

目的：研究草药红背丝绸化学成分的提取分离及其活性成分白藜芦醇对内皮素的拮抗作用。：用不同剂量白藜芦醇拮抗ＥＴ－１引起的小鼠急性死亡,大鼠离体血管条收缩,整体大鼠升压作用,致平滑肌细胞增殖效应,以及白藜芦醇拮抗「＾１２５Ｉ」ＥＴ－１与血管平滑肌成纤维细胞结合实验。结果：白藜芦醇对ＥＴ－１致小鼠急性死亡有明显的保护作用;可明显地拮抗由ＥＴ－１引起的离体大鼠主动脉条的收缩作用。     

红鱼眼醇提物镇痛抗炎作用的实验研究

目的:研究红鱼眼醇提物镇痛、抗炎的作用。方法:采用热板法和醋酸扭体法观察红鱼眼醇提物对小鼠的镇痛作用;采用二甲苯致小鼠耳廓肿胀法和角叉菜胶诱导大鼠足趾肿胀法观察红鱼眼醇提物的抗炎作用。结果:高、中、低剂量红鱼眼醇提物(30、20、10g·kg-1)均能在不同程度上提高小鼠的痛阈值,并能显著抑制小鼠耳廓肿胀和足趾肿胀反应;高剂量红鱼眼醇提物能显著减少大鼠角叉菜胶性炎性渗出液中前列腺素E2含量。结论:红鱼眼醇提物具有一定的镇痛、抗炎作用。     

47种中草药提取物的体外抗菌活性筛选研究

目的:测定47种中草药的80 %乙醇提取物的体外抗菌活性。方法:对大肠埃希菌、铜绿假单胞菌进行抗生素药敏试验;制备47种中草药醇提物,采用常规琼脂扩散法进行体外抑菌试验。结果:47种中草药的醇提物中有11种对大肠埃希菌、铜绿假单胞菌和白色念珠菌有不同程度的抑制活性;其中尤以赤芍和石榴皮的醇提物抗耐药菌活性最高,赤芍醇提物对上述3种菌特别是耐药菌的抑制活性均较高,其最低抑菌浓度(MIC)分别为1 3、1 1、1 8mg/ml;石榴皮醇提物对上述3种菌的抑制活性也较高,其MIC分别为8 3、3 6、2 3mg/ml。结论:赤芍和石榴皮醇提物呈现广谱抗菌特性,且具有抗耐药菌作用。     

杜仲提取物直接或内皮依赖性地引起大鼠血管舒张

目的研究杜仲不同溶剂提取物的舒血管作用并探讨其乙醇提取物的血管舒张机制。方法大鼠胸主动脉环张力测定法。结果在内皮完整血管，杜仲水提物（AQEO）及醇提物（ALEO）均可显著降低PE诱发的血管张力，但醇提物作用显著大于水提物，醇提物的血管舒张活性显著高于其不同溶剂萃取物。杜仲醇提物对去内皮血管的舒张作用显著低于对内皮完整血管。L-N-硝基精氨酸甲酯（L-NAME）、1H-[1，2，4]草酸重氮[4，3-a]喹噁啉（ODQ）、吲哚美辛（INDO）可以显著降低ALEO的舒血管作用（P〈0.05）;四乙氨（TEA）、4-氨基吡啶（4-AP）对ALEO的作用无显著影响，但格列苯脲（glibenclamide）可以明显削弱（P〈0.05）ALEO的血管舒张作用。ALEO对无钙环境下肾上腺素（PE）引起的收缩有显著影响（P〈0.01）。结论杜仲乙醇提取物可以直接或内皮依赖性地引起血管舒张，其机制既与NO，PGI2介导的途径有关，也与其抑制电压依从性钙通道和激活ATP敏感钾通道有关。     

老年冠心病血瘀型与血浆内皮素浓度的关系

内皮素（endothelin，ET）是一种首先由猪的血管内皮细胞中分离纯化出的对个氨基酸的生物活性多肽，人的内皮素有3种基因表达，即ET－1、EY－2、ET－3，其中以ET－1活性最强。内皮素具有强烈的收缩冠状动脉作用，内皮素的大量释放，可能是机体在某些病理状态下的一种内源性致病因素。在正常生理状态下，血浆中ET－1含量较低，某些病理情况下可达数倍或数十倍。笔者用放射免疫分析法（RIA）对36例老年冠心病血瘀型患者血浆内皮素（ET-1）进行研究，以探讨ET－1血浆浓度的变化与冠心病血瘀型的辨证关系。本研究证实：老年冠心病血瘀型…     

内皮素与肺动脉高压

内皮素（Endothelin，ETs）为血管内皮细胞产生的肽类家族，由21个氨基酸残基组成，具有强烈银血管作用。依克分子强度看，其最适链长度为21个氨基酸残基。内皮京前体bigET－1（1－39）和bigET－1（1－25）由ET转化酶水解生成21个氨基酸残基，才能充分表达其编血管作用。可以认为ET－1（1-21）为此种肽类之成熟形式．hgET－1是在内皮细胞内或在内皮细胞外转化为ET－1的尚未确定。但内皮细胞具有使大部分bigET－l转化为ET一正的酶，因为在猪的主动脉内皮细胞培养上清液中，只能测出少量的bigET－1‘”。ETs在已知的缩血管物质中作…     

葛根醇提物对糖尿病模型大鼠血脂与血管的保护作用

目的：研究葛根醇提物对糖尿病模型大鼠血脂与血管的保护作用。方法：以高糖高脂饮食联合一次性腹腔注射链脲霉素以复制大鼠糖尿病模型。实验分为正常对照（等容生理盐水）组、模型（等容生理盐水）组与葛根醇提物高、中、低剂量（300、150、75mg／kg）组。灌胃给药,每天1次,连续2个月。测定大鼠体质量、日饮水量,自动生化仪测定空腹血糖（FBG）、总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）含量;硝酸还原酶法测定一氧化氮（NO）含量;双抗体夹心固相酶免疫法测定内皮素（ET）1含量。结果：与正常对照组比较,模型组大鼠体质量显著减少,饮水量显著增加,FBG显著升高,TC、TG、LDL-C含量显著增加,HDL含量显著减少,ET-1含量显著增加,N0含量显著减少（P〈0．01）;与模型组比较,葛根醇提物高、中剂量组大鼠体质量显著增加,饮水量显著减少,FBG显著降低,TC、TG、LDL-C含量减少,HDL-C含量增加,ET-1含量减少,NO含量增加（P〈0．01或P〈0．05）。结论：葛根醇提物对糖尿病模型大鼠血脂、血管有一定改善作用,其机制可能与调节血脂平衡,维持血管活性物质动态稳定有关。     

内皮素受体拮抗剂在心血管病临床应用的可能性

内皮素（ETs）是Yanagisawa和Collesgues在1988年首次发现的，它包括3种异构体（ET－1，ET－2和ET－3），每种异构体均由21个氨基酸和连接一对半脱氨酸残基的2个二硫键组成。1988年以来，它们在许多心血管疾病中可能的病理生理作用已成为研究的中心。ET-1是哺乳动物中作用最强的血管收缩物质，在体内外其对静脉的作用比对动脉的作用强3～10倍。ET—1也是血管内皮细胞（VEC）产生的一类主要的异构体。由212个氨基酸组成的前原ET－1，首先被酶解成含有38个氨基酸的前体和大ET－1两段。大ET－1可进一步经内皮素转化酶（ECE）作用而…     

豨莶草的小鼠急性毒性及抗小鼠急性痛风性关节炎作用

目的 研究豨莶草醇提物和水提物的小鼠急性毒性及抗小鼠急性痛风性关节炎作用。方法 Bliss法计算豨莶草醇提物和水提物的LD50;以尿酸钠诱导建立小鼠急性痛风性关节炎模型,观察豨莶草醇提物和水提物的抗关节肿胀作用。结果 以豨莶草生药计,豨莶草醇提物的LD50为267.00 g·kg^-1,豨莶草水提物的LD50为147.91 g·kg^-1;小鼠急性痛风性关节炎模型组、给药24 h后豨莶草醇提物组和豨莶草水提物组的关节肿胀度分别为（0.134 8±0.049 3）,（0.098 0±0.034 0）和（0.117 2±0.024 0）mL。结论 豨莶草醇提物的急性毒性显著低于豨莶草水提物;豨莶草醇提物的抗尿酸钠诱导的小鼠急性痛风性关节肿胀作用优于豨莶草水提物。     

咖啡酸、阿魏酸：新的非肽类内皮素拮抗剂

目的评价桂皮酸类化合物咖啡酸和阿魏酸对内皮素(ET_1)生物效应的拮抗作用并初步探讨其拮抗ET_1的作用机理。方法用咖啡酸与阿魏酸腹腔注射及静脉注射给药后观察其对ET_1致小鼠急性死亡以及对大鼠升压效应、对离体主动脉条的收缩效应的拮抗作用 ;口服给药后考察其对醋酸去氧皮质酮(DOCA)_盐高血压大鼠ET_1的作用 ,并对DOCA_盐高血压动物模型ET_1血浆浓度、血压和动物体重变化及心血管组织增生的影响 ;对ET_1、c_fos、热休克蛋白(HSP70)mRNA基因表达的影响。结果咖啡酸和阿魏酸腹腔注射给药后能显著延长ET_1致小鼠急性死亡时间 ,与对照组相比该作用具剂量依赖性 ;静脉注射给药后能拮抗ET_1引起的正常大鼠升压效应 ;在离体器官上可观察到咖啡酸与阿魏酸能拮抗ET_1的缩血管效应 ;咖啡酸和阿魏酸长期口服给药能降低DOCA_盐高血压模型大鼠的血压、对心脏和血管的组织增生有明显的抑制作用 ;可降低血浆中ET_1的浓度并可减少ET_1引起的c_fos、HSP70mRNA基因表达的增加 ;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与其受体结合。结论咖啡酸和阿魏酸为新的非肽类ET_1拮抗剂。     

Effect of magnesium on mRNA expression and production of endothelin-1 in DOCA-salt hypertensive rats

The aim of this study was to investigate whether or not the decrease in blood pressure induced by dietary magnesium supplementation in DOCA-salt hypertensive rats is associated with modifications in expression and tissular production of endothelin-1. DOCA-salt treatment increased blood pressure, induced renal and cardiac hypertrophy, and increased endothelin-1 expression and production in the kidney, heart, and aorta. Mg supplementation for 8 weeks lowered blood pressure in DOCA-salt hypertensive rats and prevented hypertrophies and the increase of endothelin-1 expression and production in the heart, aorta, and kidney. Treatment with a receptor ETA antagonist, ABT-627, was used to clarify the relationship between the lowering effect of Mg supplementation on blood pressure and endothelin-1 production. When DOCA-salt rats were treated with ABT-627 for 8 weeks, Mg supplementation failed to lower blood pressure. In conclusion, these findings suggest that the lowering effect of Mg supplementation on blood pressure requires an inhibitory effect on endothelin-1 activity and/or endothelin-1 production in DOCA-salt hypertensive rats.     

Effect of long-term ouabain treatment on contractile responses of rat aortae

Male Sprague-Dawley rats were infused with 50 microg/kg/day of ouabain for 4 weeks to address the question whether prolonged exposure to the drug affects blood pressure, the in vitro contractile responses to agonists and high K+ of their aortae, and the influence of endothelium on these responses. Systolic blood pressure was not affected by ouabain treatment. The responsiveness of endothelium-intact aortae from ouabain-treated rats to endothelin-1 increased, that to phenylephrine decreased, and that to high K+ was unchanged, as compared with control. The responses of endothelium-free aortae to endothelin-1, phenylephrine, and high K+ were lower in ouabain-treated than in control rats. The removal of endothelium increased the response to phenylephrine and decreased that to high K+ in either control or ouabain-treated rat aortae, whereas it did not affect the response to endothelin-1 in control rat aortae and decreased it in ouabain-treated rat aortae. The response to caffeine was unaffected by either ouabain treatment or endothelium removal. Thus rat ouabain long-term treatment induces opposing effects on the responsiveness of their intact aortae to an alpha-adrenergic agonist and endothelin-1. If these effects observed in the ex vivo experiments occur also in vivo on rat microvasculature, they could balance out and contribute to the lack of effect on systolic blood pressure of prolonged ouabain treatment.     

Effects of AT1 receptor antagonist and spironolactone on cardiac expression of ET-1 mRNA in SHR-SP/Izm

Angiotensin II stimulates and angiotensin-converting enzyme inhibitor decreases endothelin-1 expression. Effects of the angiotensin-type 1 antagonist (angiotensin receptor blocker) on tissue expression of endothelin-1 in hypertension remained unknown. We investigated the effects of angiotensin-type 1 antagonist with and without co-administration of the aldosterone receptor antagonist spironolactone on cardiac expression of endothelin-1 mRNA. Angiotensin receptor blocker (candesartan, 1.0 mg/kg per day) was orally administered to male spontaneously hypertensive stroke-prone rats/Izm from 4 weeks of age for 4 weeks, 12 weeks and 28 weeks (angiotensin receptor blocker group). Lowdose spironolactone (10 mg/kg per day, s.c.), which does not affect blood pressure, was co-administered with angiotensin-type 1 antagonist for 28 weeks (angiotensin-type 1 antagonist + spironolactone group). Cardiac expression of endothelin-1 mRNA was determined. In the angiotensin receptor blocker group, although cardiac expression of endothelin-1 mRNA was significantly decreased after 4 weeks of treatment, it was significantly increased after 12 weeks and 28 weeks of treatment. In the angiotensin receptor blocker + spironolactone group, while systolic blood pressure did not show a further decrease from that in the angiotensin receptor blocker group, cardiac expression of endothelin-1 mRNA was decreased to the level in the untreated group. These results suggest that effects on endothelin-1 expression could modify the cardioprotective effects of angiotensin receptor blocker. Coadministration of angiotensin receptor blocker with low-dose spironolactone is recommended for further cardioprotection via suppression of endothelin-1 expression.     

The effect of taurine on the salt-dependent blood pressure increase in the voltage-dependent calcium channel beta 3-subunit-deficient mouse

To examine the anti-hypertensive effect of taurine, we studied the effects of taurine on the salt-dependent blood pressure elevation, the electrocardiogram, and plasma catecholamine levels in the voltage-dependent calcium channel beta3-subunit-deficient mouse. In the wild-type mice, chronic high-salt loading (8% NaCl in chow) did not increase the blood pressure, whereas there was a significant increase in the systolic blood pressure in the beta3-subunit-deficient mice given a high-salt diet. Oral supplementation of taurine (3% in drinking water) could attenuate the increase in the blood pressure elicited by the high-salt diet. Plasma catecholamine levels were significantly decreased by the high-salt diet, and supplementation of taurine prevented those decreases in beta3-subunit-deficient mice. It is suggested, therefore, that chronic supplementation of taurine has an anti-hypertensive action in salt-dependent blood pressure elevation.     

Differential inhibition by TAK-044 of the inotropic effects of endothelin-1 and endothelin-3

The influence of a nonselective antagonist of endothelin receptors, TAK-044 (cyclo-[d-alpha-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-l-alanyl-l-alpha-aspartyl-d-2-(2-thienyl)glycyl-l-leucyl-d-tryptophyl] disodium), on the positive inotropic effect of endothelin-1 and endothelin-3 was investigated in isolated rabbit myocardium. While TAK-044 produced a concentration-dependent rightward shift of the concentration-response curve for endothelin-1 and endothelin-3, the effect of endothelin-3 was hundred times more sensitive to TAK-044 than that of endothelin-1. The combination of FR139317 ([2-(R)-[2(R)-[2(S)-[[1-(hexahydro-1H-azepinyl)]carbonyl]amino-4-methylpentanoyl]amino-3-[3-(1-methyl-1H-indolyl)]propionyl] amino-3-(2-pyridyl)propionic acid]) and BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-l-gamma-methylleucyl-d-1-methoxycarbonyltryptophanyl-d-norleucine) mimicked the inhibitory action of TAK-044 on the positive inotropic effect of endothelin-3 but enhanced the effect of endothelin-1. In a receptor-binding assay, TAK-044 was four times more potent in antagonizing the specific binding of endothelin-1 than that of endothelin-3. Endothelin-1 may activate receptor subtypes that trigger both positive and negative inotropic effects, the latter being more susceptible to the antagonistic action of TAK-044, which may explain in part the differential antagonistic action of TAK-044 on the inotropic effect of endothelin-1 and endothelin-3.     

The effects of endothelin-1 on ischaemia-induced ventricular arrhythmias in rat isolated hearts

We have shown previously that a small bolus dose of endothelin-1, given intravenously before coronary occlusion, exerts a marked antiarrhythmic effect in anaesthetised rats. The aim of the current study was to determine whether or not this is due to a direct effect of endothelin-1 on the heart by assessing the antiarrhythmic effect of endothelin-1 against occlusion-induced arrhythmias in rat isolated hearts. Rat isolated hearts were perfused in Langendorff mode (constant flow) and subjected to coronary artery occlusion for 30 min. Coronary perfusion pressure and a surface electrocardiogram (ECG) were monitored throughout the experiment. In the first series of studies, the effects of three 5-min infusions of endothelin-1 (0.1-10 nM), given prior to coronary occlusion, were assessed. A second series of hearts was given a single bolus dose of endothelin-1 (10 pmol) 5 min prior to ischaemia. A third series of experiments was performed using a modified (low K+) Krebs Henseleit solution to increase the incidence of ischaemia-induced ventricular fibrillation (VF). In these hearts, endothelin-1 (0.1 or 2 pmol) was administered as a bolus injection 5 min before ischaemia. Infusion of endothelin-1 prior to ischaemia did not modify the incidence or severity of arrhythmias at any of the concentrations used. Bolus administration of endothelin-1 (10 pmol) in hearts perfused with Kreb's Henseleit solution containing normal K+ (4.4 mM) was found to cause a small rise in coronary perfusion pressure, with no preceding depressor response. Under these conditions, endothelin-1 exerted only a very moderate reduction in arrhythmias, by reducing the arrhythmia count in the 21-30-min post-occlusion period. Furthermore, in hearts perfused with low K+ solution, bolus injection of endothelin-1, in a dose that either had no effect on coronary perfusion pressure (0.1 pmol) or produced a significant vasodilator effect with no significant pressor effect (2 pmol), had no effect on ventricular fibrillation. Thus, in concentrations that are sufficient to exert effects on the coronary vasculature, endothelin-1 fails to modify arrhythmias in an isolated heart preparation. These results suggest that the antiarrhythmic effects of endothelin-1 previously observed in vivo are not due to a direct effect on either the myocardium or the coronary blood vessels.     

In vitro and in vivo effects of endothelin-1 and YM598, a selective endothelin ET A receptor antagonist, on the lower urinary tract

We investigated the contractile response of the lower urinary tract to endothelin-1 in vitro (rabbits) and in vivo (dogs). We also assessed the effects of a selective endothelin ET_A receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2, 2′-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on endothelin-1-induced contractile responses. In the in vitro study, endothelin-1 induced contractile responses in isolated rabbit bladder base, urethra, and prostate tissues. YM598 (10^− 7–10^− 5 M) antagonized these endothelin-1-induced contractile responses without affecting the maximal responses. In the in vivo study, endothelin-1 induced the elevation of non-prostatic urethral pressure as well as prostatic urethral pressure even in the presence of tamsulosin (10 μg/kg, i.v.) in anesthetized male dogs. YM598 (0.1–3 mg/kg, i.v.) inhibited these endothelin-1-induced contractile responses in a dose-dependent fashion. These results suggest that endothelin ET_A receptors play an important role in the lower urinary tract contraction, and that the selective endothelin ET_A receptor antagonist YM598 has ameliorating effects on various urinary dysfunctions, including benign prostatic hyperplasia.     

Effects of endothelin-1 on systemic and renal hemodynamics in hypertensive-diabetic rats (CRDH), diabetic rats (CDR), and hypertensive rats (SHR)

The Cohen-Rosenthal diabetic hypertensive rat is a unique animal model in which genetic hypertension and diabetes developed after crossbreeding of a sensitive substrain of Cohen diabetic rats and spontaneously hypertensive rats (SHR) and feeding them a copper-poor sucrose diet. This study examined the acute effects of endothelin-1 on the systemic and renal hemodynamics in Cohen-Rosenthal diabetic hypertensive rats, Cohen diabetic rats and spontaneously hypertensive rats. Intravenous injection of endothelin- 1 (1.0 nmol/kg) into anesthetized SHR resulted in a significant immediate depressor response in mean arterial pressure [from 165 +/- 3 mmHg to 124 +/- 12 mmHg (P < 0.0001)] followed by a minor hypertensive phase (mean arterial pressure increased to 170 +/- 2 mmHg). Simultaneously, the administration of endothelin-1 caused a significant decrease in renal blood flow from 5.8 +/- 0.9 mL/minute to 3.2 +/- 0.5 mL/minute (P = 0.026). These responses were blunted in Cohen-Rosenthal diabetic hypertensive rats and Cohen diabetic rats. Analysis of intrarenal blood flow by laser-Doppler in Cohen-Rosenthal diabetic hypertensive rats revealed that endothelin-1 injection caused a decrease in cortical blood flow (Delta = -12 +/- 2.9%). However, in contrast to its well known renal medullary vasodilatory effect, endothelin-1 produced a significant decline in the medulla blood flow (Delta = -17.5 +/- 3.4%) (P = 0.0125). These findings suggest that Cohen diabetic rats and Cohen-Rosenthal diabetic hypertensive rats have reduced sensitivity to the vascular and renal action of endothelin-1. Furthermore, in the Cohen-Rosenthal diabetic hypertensive rats the expected endothelin- 1-induced medullary vasodilation was abolished and even reversed into prolonged vasoconstrictor response.