氯哌胺对15-甲基前列腺素F_(2α)致泻和兴奋子宫作用的影响

氯哌胺(Loperamide)是一种新型止泻药,能拮抗15-M-PGF_(2α)引起的小鼠小肠内碳粉推进加速和腹泻,作用比吗啡和阿托品强,对离体大鼠回肠的抑制作用也比吗啡、阿托品强。氯哌胺能降低肠平滑肌张力,抑制离体大鼠回肠对15-M-PGF_(2α)的反应性,但却增强子宫平滑肌对15-M-PGF_(2α)的反应性。氯哌胺对离体大鼠子宫自发收缩活动低浓度兴奋、高浓度抑制。氯哌胺对15-M-PGF_(2α)促进大鼠空肠水和钠离子分泌也有拮抗作用,此作用不能被纳洛酮翻转。氯哌胺在小鼠的急性半数致死量为77.9 mg/kg。     

天花粉对妊娠大鼠子宫中孕酮、孕酮受体和前列腺素含量的影响

天花粉对大鼠有抗早孕作用,使妊娠大鼠血浆孕酮浓度,子宫中孕酮和孕酮受体的含量下降,子宫中的PGF_2α含量增高,同时增敏子宫对15-Me-PGR_2α和催产素的反应性,消炎痛能抑制离体妊娠子宫自发收缩活动,但并不抑制天花粉增敏子宫对15-Me-PGF_2α和催产素反应性的作用,实验结果提示天花粉促进子宫PGF_2α的含量增加和增敏子宫对催产物质的反应性是它增加妊娠子宫自发收缩活动的重要机制,而天花粉的上述作用又可能与它使子宫中孕酮和孕酮受体下降有关。     

益母草治疗痛经机制探索

目的　探讨益母草治疗痛经的药理作用及机制。方法　经十二指肠给予益母草水提液,观察豚鼠在体子宫收缩频率及幅度的变化。分别采用由缩宫素及15甲基 PGF_2α所致的子宫痉挛模型,观察小鼠口服益母草提取液后的作用。采用二甲苯致小鼠耳廓肿胀及实验性大鼠子宫炎症模型,分别观察小鼠、大鼠口服益母草提取液的抗炎作用。用放射免疫法及化学分析法分别检测大鼠口服益母草水提液后血液雌、孕激素及子宫平滑肌PGF_2α及PGE₂含量的变化。结果　益母草水提液能增强未孕正常豚鼠在体子宫的收缩。益母草能在一定程度上缓解由15M PGF_2α及缩宫素所致的小鼠子宫痉挛,能减轻二甲苯所致的小鼠耳廓肿胀的程度,改善实验性子宫炎症状况,且能降低子宫炎症时其平滑肌上PGE₂的含量,亦能降低大鼠子宫平滑肌上PGF_2α的含量。益母草水提液能升高血液孕激素的水平,而对雌激素却无明显影响。结论　益母草对子宫具有比较广泛的药理作用,可能通过抑制痉挛子宫的活动、抗炎、降低子宫平滑肌上PGF_2α,PGE₂的含量及升高体内孕激素水平等多种途径缓解痛经症状。     

1-(2,6-二甲氧基)-2-(3,4-二甲基苯乙氨基)丙烷盐酸盐(DDPH)拮抗α1肾上腺素受体的特性

目的　研究DDPH对α₁-肾上腺素受体(α₁-AR)及其亚型的拮抗作用。方法　放射配体结合实验和离体血管收缩功能实验。结果　DDPH对¹²⁵I-BE2254与大鼠脑皮质和脾脏α₁-AR结合呈竞争性拮抗作用。pK_I值在两者间无显著性差别, Hill系数均接近于1.0。在分别稳定表达α_1A,α_1B或α_1D-AR的克隆HEK293细胞中,其拮抗的pK_I值α_1A和α_1D比α_1B-AR高约2倍,Hill系数均接近于1.0。并拮抗去甲肾上腺素(NE)介导大鼠主动脉,肾动脉和脾脏收缩的pA₂值,在三者间无显著差别,斜率接近1.0。结论　DDPH对α₁-AR有竞争性拮抗作用,但其作用对α₁-AR亚型无选择性。     

滇桂艾纳香提取物促进DUB大鼠子宫收缩机制分析

目的 探讨滇桂艾纳香提取物通过促进子宫平滑肌收缩治疗功能失调性子宫出血(DUB)的作用机制。方法 利用米非司酮联合米索前列醇建立DUB大鼠模型,成模的雌性大鼠40只,随机分5组：正常妊娠组、DUB模型组、益母草颗粒3.125 g•kg^-1组、滇桂艾纳香提取物0.4 g•kg^-1组以及0.2 g•kg^-1组,另取8只未受孕性成熟雌性大鼠作空白对照组,观察滇桂艾纳香提取物对DUB模型大鼠子宫平滑肌收缩的影响,Western Blot法测定大鼠子宫平滑肌中β₂肾上腺素受体(β₂AR)、环磷腺苷效应元件结合蛋白(CREB)及p-CREB蛋白表达水平,并检测大鼠子宫平滑肌中蛋白激酶A(PKA)活性和Ca²⁺离子浓度。结果 与DUB模型组相比,滇桂艾纳香提取物显著提高大鼠子宫收缩频率(P<0.05),增加子宫平滑肌Ca²⁺离子浓度,并且增加p-CREB/CREB蛋白表达(P<0.05);滇桂艾纳香提取物还显著降低了子宫平滑肌PKA活力(P<0.05),但对β₂受体表达没有显著影响。结论 滇桂艾纳香提取物可能是通过抑制β₂受体的活化,间接增强转录调节因子CREB对与子宫平滑肌收缩相关的转录调控,从而促使子宫肌层收缩,产生治疗DUB的作用。     

具有柔性亲电侧链的蒂巴因和奥利文衍生物的合成和生物活性

本文报道了三个新的阿片受体亲和标记配基的合成和初步药理实验的结果,其中化合物7α-双(2-氯乙基)胺基甲基-6,14-内亚乙烯基-四氢奥利文(3),简称α-CMO,在豚鼠回肠纵行肌(GPT),小鼠输精管(MVD)及大鼠脑(去小脑)P₂膜制品中均为阿片受体不可逆结合的激动剂。镇痛试验表明它的活性为吗啡的18倍,镇痛作用持续时间达二天之久。     

高血压大鼠和高血压患者血管平滑肌α肾上腺素受体的反应性增强作用

目的研究高血压状态下血管平滑肌α肾上腺素能受体的反应性增强作用。方法用敏感的离体血管张力描记技术记录大鼠肠系膜动脉和人大网膜动脉的张力，用实时定量的逆转录聚核酶链反应技术测定动脉平滑肌的mRNA水平，用动脉的器官培养方法研究α受体反应性增强的机制。结果自发性高血压大鼠(SHR)的肠系膜动脉环对去甲肾上腺素(NA)的反应性明显强于WKY大鼠，NA对SHR肠系膜动脉平滑肌的最大收缩(E_max)是WKY大鼠E_max的1.82倍；高血压患者大网膜动脉对NA的反应性明显高于非高血压患者，NA的量效曲线显著左移，pD₂值显著高于非高血压患者。SD大鼠肠系膜动脉的器官培养后对NA收缩反应增强，E_max增高，且培养后α₁受体的mRNA水平增高，而α₂受体的mRNA水平无明显变化。结论高血压状态下血管平滑肌α受体的反应性增强，提示α受体上调。     

心喘灵(XC-1)及其衍生物XC-2对肾上腺素受体及动脉平滑肌的作用

本文用放射配基结合法研究了心喘灵(XC-1)及其衍生物XC-2对肾上腺素受体的亲和力,用离体器官方法观察了二者对α受体功能的影响,用酶分析法研究了两药对β受体功能的影响。两药各种作用强度相近,对大鼠脑皮层细胞膜α受体有中等强度亲和力(Ki10^-6mol/L),对兔主动脉和大鼠肛尾肌α₁受体均有中等强度阻断作用,但对大鼠输精管突触前α₂受体只有微弱的阻断作用。二药抑制由ISO激动的腺苷酸环化酶活性的IC₅₀均为3.6×10^-5mol/L。此外,二者都能拮抗CaCl₂,KCl和5-HT引起的主动脉条收缩反应并有直接扩张血管的作用。     

L-和DL-正丁基东莨菪碱对大鼠子宫作用的比较

用放射配基结合法测定L-正丁基东莨菪碱，DL-正丁基东莨菪碱与阿托品对大鼠子宫M 胆碱受体的亲和力。结果表明，L-与DL-正丁基东莨菪碱对大鼠子宫M胆碱受体的亲和力十分相近，但都比阿托品弱。比较L-正丁基东莨菪碱、DL-正丁基东莨菪碱和阿托品对离体大鼠子宫的影响及对抗乙酰胆碱所致的子宫收缩作用，表明两种正丁基东莨菪碱对离体大鼠子宫无影响，而能对抗乙酰胆碱所致的子宫收缩，且作用相近，但都比阿托品弱。说明生物效应与其受体亲和力的大小相关。     

抗孕唑对妊娠大鼠子宫蜕膜、前列腺素含量和宫缩的影响

目的　研究抗孕唑对妊娠大鼠子宫蜕膜组织形态,PGF_2α和PGE₂含量及对离体大鼠子宫收缩幅度的影响。方法　用HE染色,放射免疫法和离体子宫收缩记录等方法。结果　抗孕唑使妊娠大鼠子宫蜕膜细胞受损、剥离,并使子宫和血清中PGE₂和PGF_2α的含量升高;　对离体妊娠大鼠子宫有收缩作用,其效价为米索前列醇的0.6倍。结论　抗孕唑损伤蜕膜细胞,刺激释放前列腺素,并可提高早孕子宫对催产素和米索前列醇的敏感性。     

Potentiating effect of d-INPEA on prostaglandin (PGF 2 and PGE 2 )-evoked contractions of the isolated rat uterus

The effect of d-INPEA on prostaglandin (PGF_2α and PGE₂)-evoked contractions was studied on the isolated rat uterus. Addition of d-INPEA (1 × 10⁻⁵ g/ml) to the organ bath produced a pronounced increase in the amplitude of the prostaglandin-evoked responses. The increase was 4- and 10-fold for PGF_2α and PGE₂ respectively. This potentiating action of d-INPEA, if confirmed in in vivo studies, may enable the clinicians to use a smaller dose of prostaglandins for the induction of labour or for the termination of pregnancy, thereby reducing incidence and severity of their side effects.     

Hypotensive and spasmolytic activities of crude extract ofCyperus scariosus

Intravenous administration of hydro-methanolic extract ofCyperus scarious (3–10 mg/kg) produced hypotensive and bradycardiac effects. These effects remained unaltered in atropinized animals indicating that cardiovascular effects of the plant extract are not mediated through activation of muscarinic receptors. In thein vitro studies, it suppressed the spontaneous contractions of guinea-pig paired atria, rat uterus and rabbit jejunum in a concentration-dependent (0.1–1 mg/ml) manner. It also inhibited histamine or acetylcholine-induced contractions of guinea-pig ileum indicating non-specific spasmolytic action. In rabbit aorta, it inhibited norepinephrine (10 μM) as well as K⁺ (80 mM)-induced contractions at similar concentrations (0.1–1mg/ml). These data indicate thatCyperus scariosus contains Ca²⁺ channel blocker-like constituent(s) which may explain hypotensive effect observedin vivo and the general spasmolytic activity of plant may explain its folkloric use in diarrhoea.     

山莨菪碱对乙酰胆碱和去甲肾上腺素引起的兔虹膜释放前列腺素的影响

本文研究了654-2对Ach及NE引起的兔虹膜释放PGE₂及6-keto-PGF_1α作用的影响。Ach及NE使虹膜释放PGs增加,654-2对Ach释放PGs的作用呈剂量依赖性抑制,当654-2浓度为3×10^-5mol/L时,Ach(5x10^-5mol/L)引起的PGE₂及6-keto-PGF_1α的释放量分别降低31%及30%。654-2浓度高于6x10^-5mol/L时显著抑制NE(5x10^-5mol/L)释放虹膜PGs的作用,当654-2浓度为3x10^-4mol/L时,使NE增加虹膜释放PGE:及6-keto-PGF_1α的量分别从62%及34%降至7.5%及4%(p<0.01)。654-2抑制PGs释放对其抗感染性休克等作用可能是有利的。     

STUDIES ON THE SPASMOLYTIC AND UTERINE RELAXANT ACTIONS OF N -ETHYL AND N -BENZYL-1,2-DIPHENYL ETHANOLAMINES: ELUCIDATION OF THE MECHANISMS OF ACTION

The influence of N -ethyl- and N -benzyl-1,2-diphenyl ethanolamines (compounds E and B, respectively) was examined on the spontaneously contracting rabbit jejunum and the rat uterus together with their influence on the contractions induced by some spasmogens in the guinea-pig ileum and oxytocics and CaCl₂in the pregnant rat uterus. Both E and B inhibited the spontaneous contractions of the rabbit jejunum with ID₅₀values of 0.13 and 0.03 μmol ml⁻¹. Their inhibitory activities were not antagonized by α- or β-adrenoceptor blockers but significantly reversed by CaCl₂(0.015 μmol ml⁻¹). The compounds also antagonized nicotine, ACh-, histamine-, 5-HT- and CaCl₂-induced contractions by 44–100%. Compound E seemed to be several times more potent than B in inhibiting the spontaneous uterine contractions with an ID₅₀of (7 nmol ml⁻¹). Their inhibitory effects were not antagonized by β₂-adrenoceptor or H₂-receptor blocking drugs. Both compounds (40 nmol ml⁻¹) antagonized in a competitive manner CaCl₂-induced contractions in the K⁺-depolarised uterus and PGE₂and oxytocin-induced uterine contractions. The ID₅₀values were in the range of 1.6–10.7 nmol ml⁻¹. The results suggest that E and B compounds may be considered as putative L-Ca²⁺channel blockers with certain selectivities. The E compound seemed to be more selective against uterine L-Ca²⁺channels and the B compound against intestinal smooth muscles. Thus, the compounds may be of potential value in treatment of some colics, the irritant bowel syndrome, dysmenorrhoea and premature deliveries. 1999 Academic Press@p$hr     

消旋15(R)-15-甲基PGE2甲酯的合成

d,l-15(R)-15-Methyl-PGF_2α methyl ester 11-trimethylsilyl ether(II)wasprepared from selective monosilylation of d,l-15(R)-15-methyl-PGF_2αmethyl ester(I) withtrimethylsilyldiethylamine in acetone. Oxidation of(II ) with Collin's reagent gave d,l-15(R)-15-methyl-PGE₂ methyl ester 11-trimethylsilyl ether(III)which,without purification,was converted to d,l-15(R)-15-methyl-PGE₂ methyl ester(IV)under mild acidic conditions.     

7α-和7β-甲基-10β,17β-二乙酰氧基-△4-雌甾烯-3酮的抗早孕作用

7α-和7β-甲基-10β,17β-二乙酰氧基-△⁴-雌甾烯-3酮(简称7α-和7β-甲-乙氧雌酮)对小鼠抗早孕ED₅₀分别为1.6和5.5 mg/kg。7α-甲-乙氧雌酮在大鼠也有抗早孕作用并使血浆孕酮浓度降低,应用10 μg/ml浓度能抑制离体妊娠大鼠卵巢孕酮合成。7α-和7β-甲-乙氧雌酮与兔子宫胞浆雌二醇受体的相对结合亲和力(RBA)分别为10.8和1.5,与孕酮受体的RBA均<1.7α-和7β-甲-乙氧雌酮都有较弱的雌激素和抗雌激素活性。     

Leucocyte recruitment induced by type II phospholipases A2 into the rat pleural cavity

Bothropstoxin-I (BthTX-I) and bothropstoxin-II (BthTX-II) are Lys-49 and Asp-49 phospholipases A₂ (PLA₂s), respectively, isolated from Bothrops jararacussu venom. Piratoxin-I (PrTX-I) is a Lys-49 PLA₂ isolated from Bothrops pirajai venom. In this study, the ability of BthTX-I, BthTX-II and PrTX-I to recruit leucocytes into the rat pleural cavity and potential mechanisms underlying this effect were investigated. Intrapleural injection of either BthTX-I or PrTX-I (10–100 μg/cavity each) caused a significant leucocyte infiltration at 12 h after injection. The maximal cell migration was observed with the dose of 30 μg/cavity (14.9±15.5 and 17.6±1.6×10⁶ cells/cavity, respectively). Leucocyte counts consisted mainly of mononuclear cells, but significant amounts of neutrophils and eosinophils were also observed. Intrapleural injection of BthTX-II (10–100 μg/cavity) caused a marked leucocyte infiltration at 6 and 12 h after injection. The maximal response was observed with the dose of 100 μg/cavity (57.3±3.4×10⁶ cells/cavity, 6 h). The leucocyte counts were mainly composed of neutrophils and mononuclear cells. The treatment of either BthTX-I (30 μg/cavity, 12 h) or BthTX-II (30 μg/cavity, 6 h) with the PLA₂ inhibitor p-bromophenacyl bromide (p-BPB) had no effect on the total and differential leucocyte counts induced by these proteins. The same treatment partially reduced the PrTX-I-induced pleural leucocyte infiltration. In rats depleted of the histamine and 5-hydroxytryptamine (5-HT) stores by chronic treatment with compound 48/80, the total leucocyte counts in response to BthTX-I, BthTX-II and PrTX-I was not significantly affected compared to control animals. In addition, BthTX-I, BthTX-II and PrTX-I (100 μg/ml each) significantly degranulated pleural mast cells in vitro leading to the release of [¹⁴C]5-hydroxytryptamine ([¹⁴C]5-HT). p-BPB and heparin (50 IU/ml) significantly reduced the [¹⁴C]5-HT release induced by these PLA₂s. Our results demonstrate that BthTX-I, BthTX-II and PrTX-I recruit leucocyte into the pleural cavity of the rat by mechanisms unrelated to enzymatic activity and pleural mast cell degranulation.     

Endothelium-derived nitric oxide partially mediates salbutamol-induced vasodilatations

This study examined the ability of salbutamol (selective β₂-adrenoceptor agonist) to cause endothelium-dependent relaxation in rat aortic rings and depressor response in conscious rats. Salbutamol (0.01–100 μM) concentration dependently relaxed preconstricted aortic rings. The relaxant response was partially attenuated by either mechanical removal of the endothelium or treatment with N^G-nitro-l-arginine methyl ester (L-NAME, 100 μM). In conscious rats, either i.v. infused phenylephrine (5 μg/kg per min) or i.v. bolus injected L-NAME (12.8 mg/kg), but not the vehicle, caused similar sustained increases in mean arterial pressure (MAP). I.v. infused salbutamol (2–128 μg/kg per min, each dose for 5 min) dose dependently decreased MAP in vehicle-treated rats; the depressor responses were potentiated by hypertension induced by phenylephrine. In contrast, the magnitudes of the depressor response to salbutamol in L-NAME-treated rats were less than those in rats pretreated with phenylephrine or the vehicle. I.v. bolus injections of salbutamol (0.25–16 μg/kg) also caused dose-dependent and transient decreases in MAP in vehicle-treated rats. The magnitude but not the duration of the depressor response to salbutamol was less in rats treated with L-NAME, compared to those in rats given phenylephrine or the vehicle. These results suggest that endothelium-derived nitric oxide is partially involved in β₂-adrenoceptor-mediated vasodilatation.     

Dermal penetration of propylene glycols: Measured absorption across human abdominal skin in vitro and comparison with a QSAR model

The dermal penetration of undiluted monopropylene glycol (MPG) and dipropylene glycol (DPG) has been measured in vitro using human abdominal skin under conditions of infinite dose application, and the results compared with predictions from the SKINPERM QSAR model (ten Berge, 2009). The measured steady-state penetration rates (J_ss) for MPG and DPG were 97.6 and 39.3 μg/cm²/h, respectively, and the permeability coefficients (K_p) were 9.48 × 10⁻⁵ cm/h for MPG and 3.85 × 10⁻⁵ cm/h for DPG. In comparison, the SKINPERM model slightly over-predicted J_ss and K_p for MPG and DPG by between 2.6- and 5.1-fold, respectively. The model predictions of 254 μg/cm²/h and 24.6 × 10⁻⁵ cm/h for MPG, and 202 μg/cm²/h and 19.8 × 10⁻⁵ cm/h for DPG were in fairly good agreement with the measured values. Further, the model predicted a J_ss of 101 μg/cm²/h and a K_p of 9.9 × 10⁻⁵ cm/h for the homologue tripropylene glycol. Assuming that the measured J_ss was the same under conditions of finite dose application (taken to be 10 μL/cm²) and was maintained over a 24-h period (both conservative assumptions), the relative dermal absorption of the applied dose was estimated to be 23% (0.96%/h) for MPG and 9% (0.39%/h) for DPG. However, the extrapolation for MPG may be further overestimated due to possible residence in the stratum corneum under infinite conditions of exposure that would not be applicable to a finite loading dose.