醋酸棉酚和15甲基PGF_(2α)甲酯对大鼠子宫胞浆雌激素受体的影响

假孕大鼠口服醋酸棉酚40和80 mg/kg连续5天,平均每个子宫的胞浆蛋白和雌激素受体量明显减少。以每mg蛋白计,雌激素受体浓度同对照组差异不显著。幼大鼠口服醋酸棉酚40mg/kg连续8天,作饱和分析测得对照组和给药组K_d值分别为1.04×10~_(-10)和1.09×10_(-10)mol。最大受体结合数分别为432.0和358.8 fmol/子宫。实验发现棉酚在高浓度时对~3H-雌二醇同其受体的结合有抑制作用。15甲基PGF_(2α)甲酯对假孕大鼠子宫胞浆蛋白水平和雌激素受体均无明显影响。     

四氢异喹啉类生物碱对大鼠脑内α肾上腺素受体的作用

应用放射受体结合法研究了近30种四氢异喹啉类(TIQs)生物碱对大鼠脑内α肾上腺素受体的作用。其中l-CBN,l-THC和l-STP对α₁受体亲和力最高,K_i值为～2.0×10^-7mol/L。其次是DHS,XLP和l-DCT,K_i值分别为4.7×10^-7,6.5×10^-7和7.6×10^-7mol/L。DHS对α₂受体亲和力最高(K_i=1.25×10^-6mol/L),l-REM次之。对α受体亚型亲和力选择比K_i(alpha-2)/Ki(alpha-1)最高的是l-STP(357) 和XLP(154),它们对α₂受体几无亲和力(K_i>10^-4mnl/L)。提示l-STP和XLP对α₁受体有较高的选择性。l-SPD和l-THP对α₁和α₂受体亲和力相近,均为中等强度。THJ,DRC及l-TTD等6种TIQs对α₁和α₂受体均无亲和力(K_i>10^-4mnl/L)。     

某些四氢异喹啉类生物碱对大鼠脑内多巴胺和5-羟色胺受体的作用

本文报道十二种四氢异喹啉类生物碱对大鼠脑内D-2,5-HT₁和5-HT₂受体的结合特性。其中l-千金藤碱(l-STP)对这三种受体均有较高的亲和力,其Ki值分别为1.7×10^-7,9.4×10^-8和1.8×10^-7mol。l-莲碱(l-REM)对5-HT₂受体的亲和力与Z-STP相似(Ki=1.7×10^-7mol)。THB,THC和THJ对D-2受体的亲和力介于l-SPD和l-THP之间。本文报道的多数生物碱能同时影响两种或两种以上受体部位的结合特性,提示它们对单胺神经系统可能有复杂的相互作用。     

醋酸棉酚对大鼠输卵管平滑肌收缩活动的影响

观察了醋酸棉酚水溶性制剂对离体大鼠输卵管平滑肌收缩活动的影响并对其作用机制作了初步探讨。结果表明,醋酸棉酚可提高大鼠输卵管平滑肌收缩张力,但并非为激动α兴奋性肾上腺素能受体,而与促输卵管组织前列腺素(PGs)的生物合成、释放并与促Ca²⁺内流机制有关。棉酚的这种药理作用还与性周期有密切关系,对动情期输卵管的作用明显高于间情期。结果还表明,前列腺索E₁(PGE₁)和前列腺素E₂(PGE₂)均可提高大鼠输卵管平滑肌收缩活性,以PGE₁的作用较强且较持久,此作用可为醋酸棉酚所明显增强。     

7-甲氧基-4′-羟基-3′-二乙胺甲基异黄酮(MHDF)对大鼠血流动力学和主动脉的作用

本实验观察了MHDF对整体大鼠血流动力学和离体大鼠胸主动脉的作用。结果表明iv MHDF(3～12.8 mg/kg)能降低大鼠左心室±dp/dt_max,V_max,V_pm和LVSP,延长T-dp/dt_max,减慢心率。MHDF还能舒张大鼠胸主动脉,ED₅₀为6.5×10^-6mol/L;非竞争拮抗NA和CaCl₂致主脉收缩,pD₂′为3.11±0.21和3.73±0.07;抑制高K⁺致主动脉收缩,IC₅₀为1.76×10^-5mol/L。提示MHDF对血管的作用与α受体阻断剂不同,而可能与钙拮抗有关。     

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。     

可乐定镇痛与中枢Ca2+的关系

用大鼠甩尾法和放射配基结合实验,探讨了可乐定镇痛与中枢Ca²⁺的关系。CaCl₂(1μmol/rat,icv)和EGTA(0.2μmol/rat,icv)分别拮抗和增强可乐定(1mg/kg,sc)的镇痛。戊脉安(0.1μmol/rat,icy)对可乐定(1 mg/kg,sc)镇痛无明显影响,但可部分翻转CaCl₂对可乐定镇痛的拮抗。CaCl₂(1×10^-3mol)对[³H]-可乐定结合无明显抑制。结果表明可乐定镇痛与脑室周围组织中Ca²⁺浓度变化密切相关,Ca²⁺至少部分需经对戊脉安敏感的钙通道进入细胞内方可拮抗可乐定镇痛。推沦:可乐定镇痛与神经元内Ca²⁺有关。     

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。     

极谱法研究辅酶Q10与β-环糊精的包结行为

目的研究辅酶Q_{10与β-环糊精(β-CD)的包结行为。方法用极谱法考察主体分子β-CD与电活性客体分子辅酶Q10发生包结反应时，包结物还原波峰电流随时间的变化，峰电位随β-CD浓度的变化，并在自然光照条件下分别考察辅酶Q10和包结物的还原波峰电流随时间的变化。结果在0.1 mol·L^-1 HAc/NaAc (pH 4.7)的乙醇-水(60∶40)介质中，辅酶Q10与β-CD形成1∶1的包结物，测得其包结常数kf为1.26×10⁴ L·mol^-1，包结反应的表观速率常数k为6.64×10^-2 min^-1。并测得辅酶Q10的光降解表观速率常数k为7.77×10^-3 min^-1，辅酶Q10-β-CD包结物的k为3.38×10^-3 min^-1。结论辅酶Q10和β-CD可形成包结物，并在一定程度上提高了辅酶Q10的光稳定性。}     

月橘烯碱抗着床作用及其激素活性的研究

小鼠于妊娠第1～3天,po或sc月橘烯碱(yuehchukene)2mg或4mg/kg·d有明显的抗着床作用。金黄地鼠于妊娠1～3天,sc月橘烯碱4mg/kg·d却无此作用。月橘烯碱有明显的雌激素活性,与雌二醇合用有协同作用。该化合物无雄激素或抗雄激素活性;无孕激素或抗孕激素活性。放射受体竞争实验测得月橘烯碱对[³H]-雌二醇与雌激素受体特异性结合抑制50%的浓度(IC₅₀)为4.2×10^-6mol/L,表观解离常数(KI)为1.24×10^-6mol/L。说明月橘烯碱与雌激素受体有一定的亲和力。     

Synthesis of estradiol haptens

Synthesis of Estradiol Haptens Two estradiol haptens, 4-(3β,17β-dihydroxyestran-7α-yl)butanoic acid ( 9 ) and 7α-(4-aminobutyl)-3β,17β-estradiols ( 13 ), were prepared from 19-nortestosterone by partial synthesis. The binding activity for the cytosol estrogen receptor was determined by competition against [³H]-estradiol; at a concentration of 2×10^?7mol/l, compound 9 displaces 50% of [³H]-estradiol. Attached to AH-Sepharose 4B compound 9 allows the cytosol estrogen receptor from calf uterus to be concentrated 1800-fold by affinity chromatography.     

雌激素促进人的类成骨细胞TE85成骨作用的受体机制

目的：研究雌激素促进人的类成骨细胞株TE85细胞骨形成的作用。方法：用³H-胸腺嘧啶、³H-脯氨酸参入法分别测定细胞的增殖和胶原合成; 紫外分光光度法测定细胞内骨碱性磷酸酶（ALP）活性; 放免法测定细胞内骨钙素（BGP）含量; 放射配基法测定细胞核雌激素受体结合。结果：雌激素（E₂, 0.01～1.0 nmol.L^-1）可浓度依赖地刺激TE85细胞的³H-胸腺嘧啶和³H-脯氨酸的参入量; 在相同的时间点和剂量下,可增加成骨细胞内ALP活性和BGP的含量。结论：E₂通过增加成骨细胞数量、促进细胞胶原蛋白及ALP和BGP的合成而促进成骨作用,这些作用是通过雌激素受体介导的。     

Influence of hormonal status in relaxant effect of diethylstilbestrol and nifedipine on isolated rat uterus contraction

• 1.1. The effects of diethylstilbestrol (DES, 10⁻⁷-10⁻⁵ M) and nifedipine (10⁻¹⁰-10⁻⁷ M) on KCl (60 mM)-induced tonic contraction in the uterus of ovariectomized and 17β-estradiol (0.1 mg/kg/day, s.c.)-, 17α-estradiol (0.1 mg/kg/day, s.c.)-, or progesterone (2 mg/kg/day, s.c.)-treated rats have been assayed.
• 2.2. The dose-dependent relaxation produced by nifedipine in ovariectomized rats (EC₅₀ = 5.59 ± 1.25 × 10⁻⁹ M) is potentiated in uterus of rats treated with 17β-estradiol and progesterone (EC₅₀ = 0.59 ± 0.1 and 0.49 ± 0.1 × 10⁻⁹ M, respectively) but not in the 17α-estradiol-treated rats (3.01 ± 0.6 × 10⁻⁹ M).
• 3.3. The relaxation produced by DES on ovariectomized rats (EC₅₀ = 0.84 ± 0.14 × 10⁻⁶ M) is reduced when the rats are treated with 17β-estradiol (EC₅₀ = 2.22 ± 0.2 × 10⁻⁶ M) or progesterone (EC₅₀ = 1.24 ± 0.08 × 10⁻⁶ M), but unmodified by 17α-estradiol (EC₅₀ = 0.58 ± 0.01 × 10⁻⁶ M).
• 4.4. The nifedipine-induced relaxation is reversed with Bay K 8644 (10⁻¹⁰-10⁻⁶ M) in all experimental conditions. However, Bay K 8644 counteracted the relaxation of DES at 45.7% on ovariectomized rats but this was lower than 30% in the other groups.
• 5.5. Our results suggest that in ovariectomized rats the effects of both nifedipine and DES are similar, but 17β-estradiol and progesterone produce a contrary effect on the relaxation induced by nifedipine and DES (by increasing the nifedipine and decreasing the DES effects).
• 6.6. The modifications produced by 17α-estradiol are similar to those produced by the ovariectomy and this suggests that 17α-estradiol is a drug lacking estrogenic activity.

     

Antagonizing bradykinin (BK) obliterates the cardioprotective effects of bradykinin and angiotensin-converting enzyme (ACE) Inhibitors in ischemic hearts

Bradykinin (BK) (1 × 10 ^?12?1 × 10^?8 mol/l) and the ACE inhibitor ramiprilat (2.58 × 10 ^?9?2.58 × 10^?5 mol/l) markedly reduced the incidence and duration of reperfusion arrhythmias in the isolated ischemic rat heart. Pretreatment with ramipril (1 mg/kg p.o.), enalapril (10 mg/kg p.o.), but not captopril (50 mg/kg p.o.) had similar effects. Active compounds also improved cardiodynamics and reduced lactate dehydrogenase (LDH) and creatine kinase (CK) activities, as lactate formation in coronary venous effluent. Cardiac tissue levels of glycogen, adenosine triphosphate (ATP), and creatine phosphate (CP) were preserved. The BK antagonist D-Arg-[Hyp², Thi^5,8, D-Phe⁷]BK abolished the beneficial effects of BK, ramipril, and ramiprilat in a competitive way. Increased concentrations of BK or ramiprilat were able to reverse the antagonism. In anesthetized dogs an infusion of BK, at the dose of 1 ng/kg/min during coronary occlusion and reperfusion was devoid of cardiovascular effects but reduced mortality and the decrease of LDH activity and lactate concentration in coronary sinus blood and preserved tissue levels of glycogen and energy-rich phosphates in the ischemic myocardium.     

Some neurochemical properties of a new antidepressant,bupropion hydrochloride (Wellbutrin™)

Bupropion is a novel antidepressant agent. In the present study, an attempt was made to gain some insight into the mechanism of the drug's antidepressant activity. In vitro studies revealed that bupropion was a weak, competitive inhibitor of norepinephrine (NE) uptake into rat hypothalamic synaptosomes and of dopamine (DM) uptake into rat striatal synaptosomes, having IC50 values of 6.5 ± 0.6 × 10^?6 M and 3.4 ± 0.4 × 10^?6 M, respectively. At 1 × 10^?5 M, the drug produced a 20 ± 3% inhibition of serotonin (5-HT) uptake into rat hypothalamic synaptosomes. The drug was also a weak inhibitor of the ATP-Mg⁺² stimulated uptake of NE and DM into synaptic vesicles of whole rat brain, having IC50 values of 3.3 × 10^?5 M and 6.0 × 10^?5 M, respectively. Bupropion had no dose-dependent effect on the spontaneous release of NE, DM, and 5-HT from these synaptosomal preparations in concentrations as high as 1 × 10^?4 M. Brain monoamine oxidase (MAO) activity in vitro was not affected by concentrations of the drug ranging from 10^?7 M to 10^?5 M. Bupropion was also without effect on brain MAO, 1 hr after i.p. doses in rats as high as 100 mg/kg. The ED50 value for bupropion necessary to inhibit the uptake of ³H-catecholamines by 50% into synaptosomes incubated in the serum from rats treated with the drug was 40 mg/kg i.p., while its ED50 value for antidepressant activity, as judged by the ability of bupropion to reverse the immobile posture of “helpless” rats, was 8 mg/kg i.p. These neurochemical properties of bupropion on uptake of biogenic amines and on MAO activity serve to distinguish it from other antidepressant drugs of the tricyclic and MAO inhibitor classes.     

Estradiol-chlordecone (Kepone) interactions: Additive effect of combinations for uterotropic and embryo implantation functions

Chlordecone (Kepone) is a polychlorinated hydrocarbon that has a low affinity for the estrogen receptor. Although the compound has been shown to be an estrogen antagonist for some responses within the central nervous system, and in hypophyseal gonadotrophic cells, such an action for other responses has not been reported. In the present study ovariectomized immature rats were used to determine the uterotropic effects of chlordecone in the presence or absence of estradiol. Administration of 30 mg/kg chlordecone per day for 3 days increased the response to 0.01, 0.1 and 1 μg/kg per day of estradiol benzoate (EB). No additive or inhibitory effect was found with chlordecone plus 10 μg/kg EB. Likewise, the uterine response to 15 or 30, but not 45, mg/kg chlordecone was enhanced by the co-administration of 0.1 μg/kg EB. A second response, initiation of embryo implantation in hypophysectomized, progesterone-primed, delayed implanting pregnant rats was tested. Subliminal doses of estradiol or chlordecone were additive for initiating normal implantation in more than 80% of the animals. The results indicate that chlordecone is not an estrogen antagonist for functions that require the action of the estrogen receptor in the uterus. The mechanism(s) involved in the additive action have not been determined but emphasize the need to consider xenoestrogen-natural estrogen interactions when assessing risks for reproductive toxi.     

白三烯C4（LTC4）放射受体结合方法的建立及二苯乙烯低聚体和LTC4受体结合特性

目的：建立LTC₄放射受体结合实验方法,并比较二苯乙烯低聚体（Gn-3）和LTC₄受体的结合特性。方法：以豚鼠肺膜为实验材料,采用³H-LTC₄为放射配体,以FPL₅₅₇₁₂作阳性对照药物,Gn-3为实验药物,进行药物竞争结合实验。采用离体器官生物检测法鉴定Gn-3对LTC₄受体的拮抗作用。结果：3H-LTC₄与其相应受体呈现单一结合位点,Gn-3可明显取代3H-LTC₄与其受体结合。生物学检定法证实Gn-3可抑制LTC₄引起的生物学效应。 结论：豚鼠肺膜LTC₄受体为单一结合位点受体,Gn-3为高活性的LTC₄受体拮抗剂。     

芹菜甲素的药理作用

本文以合成的dl-芹菜甲素为代表,观察芹菜甲素的系统药理作用。在小于TD₅₀剂量下,芹菜甲素能对抗ⅳ戊四唑所致的全身强直性惊厥,但不能防止EEG癫痫样放电,芹菜甲素对抗脑室注射谷氨酸诱发惊厥、ACh诱发震颤和ip震颤素震颤。芹菜有较强的解除ACh和BaCl₂离体回肠痉挛作用。芹菜甲素对动物呼吸、循环和泌尿系统无明显作用。局部和全身给药也不影响瞳孔和对光反射。     

Effects of Cholinoceptor Blocking Drugs,Adrenoceptor Stimulants,and Calcium Antagonists on the Transmurally Stimulated Guinea-pig Urinary Bladder in Vitro and in Vivo

Abstract The effects of different drugs on the response to transmural electrical stimulation of the guinea-pig urinary bladder were studied in vitro and in vivo. In vitro, atropine (3.0 × 10^-8-5.9 × 10^-4M) did not influence the contractions. When used in high concentrations (>5.2 × 10^-5M), PR 197, another anticholinergic compound, reduced the responses by 25-40%, probably by a non-specific action. Noradrenaline (2.0×10^-6-2.0 × 10^-4M) and isoprenaline (2.0 × 10^-8-2.0 × 10^-4M) had concentration-related inhibitory effects that could be blocked by propranolol (5.2 × 10^-6M). Adenosine (2.0 × 10^-2M) inhibited the response by 27±3% (mean±S.E.M., n = 9). Theophylline (2.0 × 10^-3-6.0 × 10^-4M) had no consistent effects. The calcium antagonist nifedipine (1.2 × 10^-6-1.7 × 10^-5M) reduced the contractions by 25-50%; verapamil (2.2 × 10^-5-4.4 × 10^-4M) was little effective. In vivo, atropine (10 mg/kg) reduced the contractions by 55±5 % (n= 10), whereas PR 197 (5 mg/kg) almost completely suppressed the responses. Noradrenaline (20-100 μg/kg) and isoprenaline (20-300 μg/kg) also caused a marked inhibition that could be blocked by propranolol (0.25-2.0 mg/kg). Theophylline (5 and 10 mg/kg) had a weak (10-20%) inhibitory effect. Adenosine (3.0 mg/kg) reduced the contractions by 47±4% (n= 14); in guinea-pigs pretreated with atropine (10 mg/kg), adenosine produced a further 10 to 20% decrease of the responses. Verapamil (0.5-2.0 mg/kg) had no consistent effect, whereas nifedipine (0.1-0.2 mg/kg) caused an inhibition of 20-50%. The results suggest that β-adrenoceptor stimulants, and drugs with a combined anticholinergic and non-specific action, can effectively suppress the electrically evoked contractions in the guinea-pig urinary bladder.     

Cadmium alteration of hexobarbital action: Sex-related differences in the rat

Three days after ip administration of a single cadmium dose (0.84 mg of Cd/kg), duration of hexobarbital hypnosis was significantly potentiated in male but not in female rats. Cadmium in larger doses of 2, 4, and 6 mg/kg, ip, did not alter duration of hexobarbital hypnosis in female rats, although lethality was observed 24 hr after administration of the two higher cadmium doses. Hepatic microsomal metabolism of hexobarbital was significantly decreased in male rats but not in females when measured 72 hr after cadmium administration (2 mg/kg, ip). Addition of cadmium in concentrations ranging from 5 × 10^?6m to 5 × 10^?3m to microsomes isolated from untreated male and female rats produced a dose-dependent inhibition of hexobarbital metabolism at all Cd concentrations in males. In female-derived microsomes a significant inhibition of hexobarbital metabolism was observed only at higher cadmium concentrations (5 × 10^?4m and 5 × 10^?3m). These data suggest that a sex-related difference exists in the ability of cadmium to alter response to hexobarbital in the rat which appears to be mediated through differences in hepatic microsomal metabolism.