吴茱萸次碱的心脏保护作用涉及辣椒素敏感的感觉神经

目的 观察吴茱萸次碱对大鼠心肌缺血再灌注损伤的保护作用是否与激活辣椒素敏感的感觉神经有关。方法 大鼠在实验前10 min静脉注射吴茱萸次碱,然后结扎冠状动脉左前降支60 min,再灌注3 h。测定心肌梗死面积、血清肌酸激酶(CK)活性和血浆降钙素基因相关肽(CGRP)浓度。结果 吴茱萸次碱(100、300μg·kg-1,iv)能显著缩小心肌梗死面积,降低血清CK水平,升高血浆CGRP浓度。这些作用被预先给予竞争性辣椒素受体拮抗药Capsazepine(38 mg·kg-1,s.c.)或选择性感觉神经耗竭剂辣椒素(50 mg·kg-1,s.c.)所完全取消。结论 吴茱萸次碱对大鼠心肌缺血再灌注损伤有保护作用,其保护作用与通过激动辣椒素受体而激活辣椒素敏感的感觉神经有关。     

大鼠灌胃不同纯度吴茱萸提取物后吴茱萸碱及吴茱萸次碱的药动学研究

目的:研究灌胃给予不同纯度吴茱萸提取物后大鼠体内吴茱萸次碱(Rut)和吴茱萸碱(Evo)的药动学特点。方法:以Rut、Evo分别为40、31mg·kg-1的剂量,灌胃给予雌性大鼠高、中、低不同纯度(Rut:45%、28%、9%,Evo:35%、21%、7%)的吴茱萸提取物混悬液(n=6),分别于灌胃后0·25、0·5、0·75、1·0、1·5、2·0、2·5、3·0、4·0h眼底静脉丛采血0·5mL,高效液相色谱法测定血样中Rut和Evo含量,并计算药动学参数cmax、tmax和AUC0～4h。结果:高、中、低纯度组中,cmax:Rut:(215·3±80·4)、(94·5±28·8)、(22·8±4·4)ng·mL-1,Evo:(164·8±65·1)、(78·8±23·5)、(43·4±17·2)ng·mL-1(两两比较P<0·01);tmax:Rut:(0·5±0·0)、(0·6±0·1)、(0·5±0·0)h,Evo:(0·5±0·2)、(0·7±0·2)、(0·5±0·0)h;AUC0～4h:Rut:(117·1±26·5)、(117·4±42·2)、(36·8±5·6)ng·h·mL-1,Evo:(148·9±39·1)、(122·2±23·3)、(80·4±14·3)ng·h·mL-1。3种纯度组中Rut和Evo的cmax具有统计学差异,AUC0～4h随纯度的升高而增加(P<0·01)。结论:吴茱萸提取物的纯度与Rut和Evo的吸收明显有关,在纯度为16%～80%(以二者总含量计)范围内,随着纯度的提高,二者生物利用度均明显增加。     

吴茱萸次碱对高血压大鼠血压的影响及作用机制

目的观察吴茱萸次碱对高血压模型大鼠血压的影响,并初步探讨其作用机制。方法分别采用自发性高血压大鼠(SHR)及两肾一夹(2K1C)高血压大鼠模型,设正常对照组、模型组、卡托普利阳性组及吴茱萸次碱低、中、高剂量组(10,20,40 mg/kg),每日灌胃给药1次,给药4周,每周测定1次血压,末次给药后,腹主动脉取血,分别测定血浆血栓素(TXB2)、6-酮-前列腺-F1α(6-Keto-PGF1α)、肾素活性(PRA)、心房钠肽(ANP)水平。结果在两个模型中吴茱萸次碱均有较好的降压作用,并能使SHR大鼠血浆TXB2水平降低,6-Keto-PGF1α水平升高;使2K1C大鼠血浆PRA、ANP水平升高。结论吴茱萸次碱能明显降低SHR及2K1C大鼠血压,其降压效果可能通过调节PGI2和TXA2水平,改善血管内皮功能及增加舒血管物质ANP水平实现的。     

镇痛经对大鼠离体子宫平滑肌的松弛作用

镇痛经２６．３、３１．５ｍｇ／ｍｌ对大鼠离体子宫平滑肌自发性收缩均有明显抑制作用，剂量５．３、１０．５及１５．８ｍｇ／ｍｌ的镇痛经对缩宫素诱发的大鼠离体子宫平滑肌亦明显抑制，并都呈剂量依赖性，随浴槽内的浓度增加，其抑制作用加强。     

吴茱萸次碱对高血压大鼠胸主动脉血管肽酶C表达的影响研究

目的:研究吴茱萸次碱对高血压大鼠胸主动脉血管肽酶C表达的影响。方法:应用两肾一夹高血压(2K1C)模型大鼠作为研究对象,以夹尾法测量血压。手术后10周分别给予氯沙坦(20mg·kg-1.d-1)和吴茱萸次碱(10、40mg·kg-1.d-1)干预治疗4周,观察每周血压变化。分析主动脉形态学结构变化;通过蛋白印迹法测定主动脉中血管肽酶C的含量。结果:治疗组吴茱萸次碱ig4周后,动脉收缩压显著降低。同模型组比较,治疗组大鼠胸主动脉血管管腔内径显著扩大,膜厚度变薄,血浆和动脉中血管紧张素Ⅱ显著降低,血管肽酶C的表达增强。结论:吴茱萸次碱能够有效降低血压、改善血管重构,其机制可能与表达增强的血管肽酶C介导的血管紧张素Ⅱ的灭活和激肽释放酶的激活有关。     

速激肽受体拮抗剂对豚鼠离体气道平滑肌的作用

速激肽ＮＫ－２受体拮抗剂ＳＲ－４８９６８能抑制抗原诱导的气管和支气管平滑肌收缩；ＮＫ－１受体拮抗剂ＣＰ－９６３４５仅抑制支气管的收缩。两药均抑制辣椒素和Ｐ物质引起的支气管平滑肌收缩；对组胺和氨甲酰胆碱引起气管，支气管收缩作用无明显影响。结果证明速激肽参与抗原诱地的气道平滑肌收缩，速激肽受体拮抗剂具有抗过敏性哮喘的作用。     

蝙蝠葛碱对离体豚鼠气管平滑肌舒张作用的研究

目的:研究蝙蝠葛碱(Dauricine,Dau)对离体豚鼠气管平滑肌的作用及机制。方法:取豚鼠气管制成气管片,运用离体器官实验的方法,记录蝙蝠葛碱对离体豚鼠气管平滑肌的作用和在不同通道及受体阻滞剂孵育的条件下对豚鼠气管平滑肌的作用的变化。结果:蝙蝠葛碱对离体气管平滑肌有明显的舒张作用,在60～120μmol/L的浓度之间舒张效果具有明显的浓度依赖性(P<0.05)。硝苯地平+Dau组在80～160μmol/L浓度下舒张离体豚鼠气管平滑肌的作用较Dau组弱(P<0.05)。普萘洛尔+Dau组在60～120μmol/L浓度下舒张离体豚鼠气管平滑肌的作用较Dau组弱(P<0.05),在120～160μmol/L浓度下舒张离体豚鼠气管平滑肌的作用与Dau组相近(P>0.05)。结论:蝙蝠葛碱对离体豚鼠气管平滑肌有明显的舒张作用,其机制可能是通过阻断Ca2+通道和激动气管平滑肌上的β2受体有关。     

吴茱萸碱对肥胖并发血管肥厚的作用研究

目的研究吴茱萸碱对大鼠肥胖症及并发血管肥厚的预防作用。方法高脂饮食诱导肥胖大鼠模型;形态测量法动态观察大鼠体重、体长和Lee’s指数;ELISA法测定大鼠血清和组织降钙基因相关肽(CGRP)含量;免疫组化测定血管组织和背根神经节(DRG)TRPV1表达;比色法测定大鼠血清总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和甘油三酯含量。结果吴茱萸碱和辣椒素干预大鼠13周后,降低肥胖大鼠体重和Lee’s指数,降低肥胖大鼠内脏脂肪重量和内脏脂肪重量指数,并降低肥胖大鼠血清总胆固醇和甘油三酯含量。吴茱萸碱能逆转肥胖并发的血管肥厚;与正常大鼠相比,肥胖大鼠胸主动脉组织和DRG中TRPV1表达降低,血清和腹主动脉CGRP增加。吴茱萸碱和辣椒素能增加胸主动脉组织和DRG中TRPV1的表达;吴茱萸碱能降低血清和腹主动脉中CGRP含量。结论吴茱萸碱对高脂饮食诱导的肥胖具有良好的预防作用,其作用机制可能与调节血清、血管组织和DRG中CGRP和TRPV1的表达有关,其具体机制值得进一步的深入研究。     

促血管生成素-1蛋白减少大鼠尿激酶溶栓后脑出血转化及机制研究

摘 要 目的：探索促血管生成素-1（Ang-1）蛋白能否减少尿激酶溶栓的大鼠脑梗死模型出血转化率、出血量及其可能的机制。方法: 清洁级SD大鼠按照随机分组法分为4组：假手术组,生理盐水对照组、尿激酶溶栓组、尿激酶+Ang-1组,每组24只。比较各组出血转化率、出血量、脑水肿、血脑屏障破坏情况和紧密连接蛋白occludin,ZO-1的表达。采用脑组织干湿重法评估脑水肿程度,伊文思蓝通透率评估血脑屏障破坏情况,RT-PCR和Western blot检测紧密连接蛋白occludin,ZO-1 mRNA的表达水平。结果: 尿激酶溶栓组的出血量、脑水肿和血脑屏障破坏程度相较于其余各组明显增高（P<0.05）;occludin,ZO-1的表达低于其余各组（P<0.05）;尿激酶+Ang-1组的出血转化率、出血量、脑水肿和血脑屏障破坏程度低于尿激酶溶栓组（P<0.05）。Occludin,ZO-1表达比尿激酶溶栓组增高（P<0.05）。结论:Ang-1蛋白可减少尿激酶溶栓所致的脑出血、血脑屏障损失及脑水肿水平,其机制可能与增加紧密连接蛋白occludin,ZO-1的表达从而保护血脑屏障有关。     

The Relaxant Effect of Propofol on Isolated Rat Intrapulmonary Arteries

Propofol is a widely used anesthetic. Many studies have shown that propofol has direct effects on blood vessels, but the precise mechanism is not fully understood. Secondary intrapulmonary artery rings from male rats were prepared and mounted in a Multi Myograph System. The following constrictors were used to induce contractions in isolated artery rings: high K⁺ solution (60 mmol/L); U46619 solution (100 nmol/L); 5-hydroxytryptamine (5-HT; 3 µmol/L); or phenylephrine (Phe; 1 µmol/L). The relaxation effects of propofol were tested on high K⁺ or U46619 precontracted rings. Propofol also was added to induce relaxation of rings preconstricted by U46619 after pretreatment with the nitric oxide synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME). The effects of propofol on Ca²⁺ influx via the L-type Ca²⁺ channels were evaluated by examining contraction-dependent responses to CaCl₂ in the absence or presence of propofol (10 to 300 µmol/L). High K⁺ solution and U46619 induced remarkable contractions of the rings, whereas contractions induced by 5-HT and Phe were weak. Propofol induced dose-dependent relaxation of artery rings precontracted by the high K⁺ solution. Propofol also induced relaxation of rings precontracted by U46619 in an endothelium-independent way. Propofol at different concentrations significantly inhibited the Ca²⁺-induced contractions of pulmonary rings exposed to high K⁺-containing and Ca²⁺-free solution in a dose-dependent manner. Propofol relaxed vessels precontracted by the high K⁺ solution and U46619 in an endothelium-independent way. The mechanism for this effect may involve inhibition of calcium influx through voltage-operated calcium channels (VOCCs) and receptor-operated calcium channels (ROCCs).     

Relaxant Effect of Foeniculum vulgare on Isolated Guinea Pig Tracheal Chains

Foeniculum vulgare is a grassy plant which is believed to have several therapeutic effects including anti-asthmatic uses. We have therefore studied the relaxant (bronchodilatory) effect of this plant on isolated guinea pig tracheal chains and its possible mechanism(s). The bronchodilatory effects of aqueous and ethanol extracts, essential oil, and 1µM theophylline in comparison with controls were examined by their relaxant effects on precontracted isolated tracheal chains of guinea pig in two different conditions including: non-incubated tissues (group 1) and incubated tissues with 1µM propranolol and 1µM chlorpheniramine (group 2). In addition, the anticholinergic effects of essential oil and 10 nM atropine were tested by performing the cumulative log-concentrationresponse curves of methacholine induced contraction of tracheal chains compared with that of saline (for all experimental conditions n = 8). In group 1 and 2 experiments, essential oil and theophylline and, in group 1, ethanol extract showed significant relaxant effects compared to those of saline and ethanol, respectively. Although bronchodilatory effects of essential oil was lower than theophylline in group 1 (p &lt; 0.01), there was no significant difference between the effect of ethanol extract in both groups and the effect of essential oil in group 2 experiments with that of theophylline. The relaxant effect obtained in group 2 for essential oil was significantly greater (p &lt; 0.05) and for ethanol extract nonsignificantly lower than those of group 1 experiments. The results also showed non-parallel rightward shift of methacholine-response curves and nonsignificant difference of EC 50 (the effective concentration of methacholine, causing 50% of maximum response) obtained in the presence of essential oil compared to those of saline. These results indicated bronchodilatory effects of ethanol extract and essential oil from Foeniculum vulgare which is not due to inhibitory properties of the plant on muscarinic and histamine H 1 and/or an stimulatory effect on ß 2 -adrenergic receptors.     

Mechanisms Underlying the Vecuronium-Induced Tetanic Fade in the Isolated Rat Muscle

Abstract The cellular mechanisms underlying the effects of vecuronium on the tetanic contraction were studied in vitro with a combination of myographic and electrophysiologic techniques. We used the isolated sciatic nerve extensor digitorum longus muscle preparation of the rat. Indirect twitches were evoked at 0.1 Hz pulses and tetani at 50 Hz pulses. Trains of end-plate potentials were generated at 50 Hz. The electrophysiological variables used in the analysis of the end-plate potentials were: amplitude, tetanic run-down, quantal size and quantal content. The myographic study demonstrated that vecuronium at 0.4 μM caused tetanic fade, but left the twitch unaffected. Regarding electrophysiology, vecuronium (0.4 μM) decreased the amplitude of end-plate potentials and increased their tetanic run-down. These changes were due to significant reductions in both the quantal content of the end-plate potentials and the quantal size. It is concluded that vecuronium has both pre- and postsynaptic effects at the neuromuscular junction, and that it induces fade of the tetanic contraction via a summation of these effects.     

环维黄杨星D对大鼠心肌肥厚的保护作用及机制研究

目的:探讨环维黄杨星D(Cvb-D)对甲状腺素诱导大鼠心肌肥厚的保护作用及机制.方法:除正常对照组外,各组每日均腹腔注射左旋甲状腺素(L-Thy)1 mg·kg-1,连续14 d,制备大鼠心肌肥厚模型.末次给药24 h后处死大鼠,计算大鼠心脏质量指数(全心质量/体质量,HW/BW)和左心室质量指数(左心室质量/体质量,LVW/BW),观察心肌组织病理形态学改变,并测定心肌组织中一氧化氮(NO)、一氧化氮合成酶(NOS)、超氧化物歧化酶(SOD)、丙二醛(MDA)的含量,评价Cvb-D对大鼠心肌肥厚的影响及可能机制.结果:与对照组比较,L-Thy模型组大鼠心脏质量指数明显升高,病理切片可见心肌肥厚改变,心肌NO、NOS和SOD含量显著降低,MDA显著增加.与模型组相比,Cvb-D中、高剂量组(12,24 mg·kg-1)均能明显降低小鼠HW/BW和LVW/BW,病理切片可见损害较模型组减轻,心肌NO、NOS、SOD含量显著升高(P<0.05),MDA含量显著下降(P<0.01).结论:环维黄杨星D对L-Thy诱导的大鼠心肌肥厚具有一定的保护作用,其作用机制可能与其抗心肌氧化损伤有关.     

Possible Mechanisms Underlying Statin-Induced Skeletal Muscle Toxicity in L6 Fibroblasts and in Rats

3-Hydroxy-3-methylglutaryl CoA reductase inhibitors (statins) are safe and well-tolerated therapeutic drugs. However, they occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Here, we investigated the mechanism of statin-induced myotoxicity in L6 fibroblasts and in rats in vivo. L6 fibroblasts were differentiated and then treated with pravastatin, simvastatin, or fluvastatin for 72 h. Hydrophobic simvastatin and fluvastatin decreased cell viability in a dose-dependent manner via apoptosis characterized by typical nuclear fragmentation and condensation and caspase-3 activation. Both hydrophobic statins transferred RhoA localization from the cell membrane to the cytosol. These changes induced by both hydrophobic statins were completely abolished by the co-application of geranylgeranylpyrophosphate (GGPP). Y27632, a Rho-kinase inhibitor, mimicked the hydrophobic statin-induced apoptosis. Hydrophilic pravastatin did not affect the viability of the cells. Fluvastatin was continuously infused (2.08 mg/kg at an infusion rate of 0.5 mL/h) into the right internal jugular vein of the rats in vivo for 72 h. Fluvastatin infusion significantly elevated the plasma CPK level and transferred RhoA localization in the skeletal muscle from the cell membrane to the cytosol. In conclusion, RhoA dysfunction due to loss of lipid modification with GGPP is involved in the mechanisms of statin-induced skeletal muscle toxicity.     

西地那非对大鼠输精管的舒张作用及其机制

目的 观察西地那非（Sil）对体外大鼠输精管平滑肌的舒张效应及其机制.方法 ①取Wistar成年雄性大鼠16只,随机分为电刺激收缩组和高浓度氯化钾收缩组各8只,将大鼠颈椎脱臼处死,剖取输精管分成两段,其中一组分别以0.1～100.0 μmol&#8226;L^-1Sil直接作用于输精管;另一组给予L-NAME后再以0.1～100.0 μmol&#8226;L^-1Sil直接作用于输精管,采用台式平衡记录仪检测Sil对输精管平滑肌张力的影响;②将成熟雄性大鼠颈椎脱臼处死,剖取输精管分成两段,取附睾端输精管称重,用作cGMP测定;其他部分分为空白对照组、基础释放组、cGMP激发组（给予0.1 mmol&#8226;L^-1SNP激发）和L-NAME（0.1 mmol&#8226;L^-1）预孵育组,各组均给予3,10,100 μmol&#8226;L^-1Sil孵育.提取各组cGMP采用125I放射免疫法测定.结果 ①Sil使电刺激和高浓度氯化钾（80 mmol&#8226;L^-1）刺激体外大鼠输精管平滑肌收缩标本呈浓度依赖性舒张（均P＜0.05）,EC50分别为9.82和46.9 μmol&#8226;L^-1;②当L-NAME存在时,Sil对电刺激引起的收缩和高浓度氯化钾刺激引起的收缩的舒张量-效曲线右移,最大效应分别由（87.27±1.91）%降到（68.02±2.29）%（P＜0.05）,和（87.46±3.87）%降到（72.99±4.23）%（P＜0.05）, EC50分别增加到45.7和63.2 μmol&#8226;L-1（均P＜0.05）;③Sil可浓度依赖性升高cGMP含量（P＜0.05）,而且该作用能被L-NAME完全抑制;在硝普钠存在时,Sil能更进一步提高大鼠附睾端输精管平滑肌组织中的cGMP浓度（P＜0.05）.结论 Sil呈浓度依赖性舒张输精管,该作用可能与NO-cGMP途径和NO-cGMP非依赖性途径有关.     

活血逐瘀方浸膏的舒张血管作用及其作用机制

目的观察活血逐瘀方浸膏的舒张血管作用，并探讨其作用机制。方法采用豚鼠肠系膜微血管和大鼠体外主动脉环研究活血逐瘀方浸膏舒张血管作用;硝酸还原酶法测定血浆一氧化氮(NO)和血管NO、一氧化氮合酶(NOS)、原生型一氧化氮合酶（cNOS）及诱生型一氧化氮合酶（iNOS）的活性。结果活血逐瘀方浸膏有抗去甲肾上腺素致豚鼠肠系膜微血管收缩的作用;松弛苯肾上腺素引起体外大鼠胸主动脉环收缩的作用，预加格列本脲或普萘洛尔后仍然有松弛作用，而去内皮后引起收缩作用;高剂量的活血逐瘀方浸膏非常显著性地升高血浆NO及主动脉NO含量、提高NOS和cNOS的活性;低剂量活血逐瘀方浸膏显著性提高血管cNOS的活性。结论活血逐瘀方浸膏有舒张血管的作用，其作用机制可能与其激活血管NOS、cNOS活性和促进血管内皮NO释放有关。     

吴茱萸碱对心肌细胞缺血损伤的研究

摘 要 目的：探讨吴茱萸碱对心肌细胞缺血损伤的保护作用。方法: 培养H9c2心肌细胞,缺氧24 h造成心肌细胞损伤模型,给予不同浓度（0.1,1,5,10 μmol·L^-1 ）吴茱萸预处理细胞12 h,CCK 8检测心肌细胞的活性,RT PCR检测心肌细胞炎症因子的转录,Tunel染色检测心肌细胞凋亡,免疫印迹检测信号通路的改变。结果:4种浓度的吴茱萸碱在基础状态下并未影响心肌细胞活性（P＞0.05）;缺氧24 h后,心肌细胞活性显著降低,给予1,5,10 μmol·L^-1 的吴茱萸与对照组相比差异有统计学意义（P＜0.05）,且其效果呈现剂量依耐性;细胞促炎症因子肿瘤坏死因子α（TNF α）、白细胞介素 1（IL 1）和白细胞介素 6（IL 6）的转录明显增加,心肌细胞凋亡增多,吴茱萸碱可以增加缺氧损伤的细胞活性,减少细胞炎症因子的转录,减少细胞凋亡数量,给予1 μmol·L^-1 和10 μmol·L^-1 的吴茱萸与对照组相比差异有统计学意义（P＜0.05）。免疫印迹结果显示,吴茱萸碱通过增加蛋白激酶B（AKT）和AMP依赖蛋白激酶α（AMPKα）的活性,抑制核因子 κB（NF κB）的活性发挥其心肌保护作用,给予1 μmol·L^-1 和10 μmol·L^-1 的吴茱萸与对照组相比差异有统计学意义（P＜0.05）。结论:吴茱萸碱能保护心肌细胞缺血损伤,可能成为新的抗心肌缺血药物。     

Muscle Relaxant Action of MS-322, a New Centrally Acting Muscle Relaxant,in Rats

• 1.The pharmacological properties of (R)-(+)-3-phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole hydrochloride (MS-322) were investigated and compared with those of other muscle relaxants.
• 2.MS-322 (3–12 mg/kg, IV) reduced spinal reflex potentials in acutely spinalized rats dose dependently. Its inhibitory effects on polysynaptic and dorsal root reflexes were more marked than those on the monosynaptic reflex.
• 3.MS-322 (1.5–12.0 mg/kg, IV) depressed the afferent discharges of de-efferented muscle spindles in anesthetized rats dose dependently.
• 4.The inhibitory effect of MS-322 on this afferent activity was considered to be due to its membrane stabilizing action.
• 5.In addition to the central effects of MS-322, its effect on muscle spindles may contribute to its muscle relaxant activity.