芹菜甲素和乙素的抗惊厥作用

1-芹菜甲素(1-3-丁基苯酞)和1-芹菜乙素(1-3-丁基-4,5二氢苯酞)是从芹菜籽分离出的抗惊厥有效成分。在小于TD₅₀剂量下,对最大电休克(MES),最小电休克(MET),戊四唑(MST)和原发听源性惊厥(MAS)等四种动物模型有效,可认为有广泛的抗惊作用。其人工合成的dl-芹菜甲素(dl-3-丁基苯酞)更有抗惊作用强,毒性小和便于推广应用的优点。     

蛇床子素对豚鼠离体回肠和结肠带的作用

以豚鼠离体回肠和结肠带为标本,观察蛇床子素(Ost)的作用与Ca²⁺)的关系。结果表明:Ost和钙拮抗剂Ver产生剂量依赖性抑制乙酰胆碱(ACh)、组胺及KCl所致回肠条或结肠带的收缩;非竞争性拮抗CaCl₂累积量—效曲线,pD₂分别为4.41±0.15,7.0±0.2。Ost 100μmol/L和Ver 1μmol/L均能对抗小剂量Ca²⁺所致结肠带收缩,但被加入较大量Ca²⁺所取消。Ost和Ver均能抑制ACh诱导的依内钙性收缩,不影响依外钙性收缩。结果提示Ost具有钙拮抗作用,其作用方式与Ver类似。     

新化合物三环哌酯的抗N和M胆碱受体作用

三环哌酯盐酸盐（ＴＣＰＮ·ＨＣｌ）和碘甲烷盐（ＴＣＰＮ·ＣＨ₃Ｉ）为新化学实体。本文以烟碱诱发小鼠惊厥，豚鼠回肠收缩为评价中枢和外周神经元性Ｎ受体功能的指标，以槟榔碱诱发小鼠震颤为评价中枢Ｍ受体功能的指标，并在肌细胞上进一步观察药物对Ｎ受体离子通道的影响。结果表明，ＴＣＰＮ·ＨＣｌ使烟碱诱发小鼠惊厥的量效曲线平行右移；并对抗槟榔碱诱发小鼠震颤的作用，也可对抗烟碱诱发回肠收缩，阻断神经肌肉接头处自发微终板电流，并优先阻断开放时间长、电流强度大的Ｎ受体离子通道。提示ＴＣＰＮ·ＨＣｌ有强效抗中枢Ｎ和Ｍ受体作用。     

盐酸关附甲素注射液对实验性心律失常的作用

关附甲素是从关白附子块根中提取的一种新生物碱。实验表明IGFAH(50　g/ml)对大鼠离体心脏结扎冠脉诱发的室性心律失常有明显的保护作用,IGFAH3、6、12mg/kgiv能显著提高电刺激麻醉兔心室致颤阈值,IGPAH13.4,16.8,21.0mg/kgiv能明显对抗Cal₂-Ach液诱发小鼠房扑(颤),其ED₂为12.4±1.5mg/kg。IGFAH10,25,40mg/kgiv对乌头碱诱发的大鼠室性心律失常有明显的保护作用。IGFAH小鼠iv的LD₅₀为163.9mg/kg,其96%可信限为151.9—176.7mg/kg。     

芫花主要黄酮成分对肝微粒体UGTs及UGT1A1活性的体外抑制作用

目的 考察芫花主要黄酮成分芫花素和芹菜素对尿苷二磷酸葡萄糖醛酸转移酶（UGTs）及UGT1A1活性的影响。方法 采用体外肝微粒体孵育模型,以4-硝基酚（4-nitrophenol,4-NP）为底物检测UGTs活性,胆红素为底物检测UGT1A1活性;利用UV及UPLC-MS/MS测定底物或代谢产物的含量。结果 对UGTs,在大鼠肝微粒体、小鼠肝微粒体以及人肝微粒体孵育体系中,芫花素和芹菜素均能不同程度地抑制UTGs活性;抑制强弱顺序：在大鼠肝微粒体温孵体系中,芫花素>芹菜素;在小鼠肝微粒体以及人肝微粒体温孵体系中,芹菜素>芫花素。对UGT1A1,在人肝微粒体孵育体系中,芫花素和芹菜素均表现为中等强度的竞争性抑制作用,抑制强弱顺序：芹菜素（IC₅₀=12.40 μmol·L^-1）>芫花素（IC₅₀=23.21 μmol·L^-1）。结论 芫花素和芹菜素对不同肝微粒体孵育体系中UGTs及UGT1A1均可产生显著抑制作用且存在种属差异。芫花素及芹菜素可能存在基于UGT酶的药物相互作用。     

关附甲素对实验性心律失常和心肌收缩性的影响

关附甲素(GFA)浓度为20～3oμg·ml^-1时,可以降低无K⁺高Ca²⁺液灌流离体大鼠心脏诱发VT和VF的发生率。清醒大鼠ivGFA2.5～10mg·kg^-1,可依剂量性显著增加北草乌头碱引起室性早搏的用量。清醒犬ivGFA10mg·kg^-1,可逆转哇巴因引起VT,并对麻醉犬(10～20mg·kg^-1),由ACh诱发房颤有明显的抑制作用。GFA10mg·kg^-1iv可明显减慢麻醉犬或清醒犬心率,对心肌收缩性(V_max和V_pm)只有轻度而短暂的抑制,但对左室收缩压,心搏量和心输出量无明显影响。     

秦艽生物碱的薄层色谱扫描测定

用CS-930型双波长薄层扫描仪探讨适合秦艽生物碱定量测定条件。以乙醚—丙酮为展开剂,在硅胶GF₂₅₄板上分离了秦艽甲素和丙素,分别用荧光熄灭和荧光法检出斑点后扫描测定。扫描参数:秦艽甲素λ_s255nm,λ_R280nm;秦艽丙素λ_s300nm,λ_R330nm;反射法锯齿扫描;SX=7;外标一点法;△y=0.2。得到两条通过原点直线。秦艽甲素及丙素的回收率分别为102.75%及100.42%,变异系数分別为2.48%及0.22%。用此法测定了中药秦艽中甲素和丙素的含量;对比了不同产地、同一产地野生和种植、地上和地下部分药材的生物碱含量,为开发秦艽资源提供信息。     

关附甲素的结构简化物及抗心律失常活性

为寻找活性高、毒副作用小的抗心律失常新药,以关附甲素为先导物进行结构简化,共设计合成了1-苯基-3-烷胺基-1,2-丙二醇类化合物14个和吲哚嗪类化合物9个。对抗氯仿诱发小鼠心律失常试验表明,Ⅰ₁,Ⅰ₂,Ⅰ₃,Ⅰ₇,Ⅰ₈,Ⅰ₁₄和Ⅱ27个化合物有较显著的抗心律失常活性,其中Ⅰ₂,Ⅰ₃,Ⅰ₇和Ⅰ₈抗心律失常活性优于关附甲素。     

基于细胞膜色谱技术的人参皂苷及五味子木脂素与血管内皮生长因子受体的作用分析

目的 运用细胞膜色谱（CMC）技术检测分析人参皂苷与五味子木脂素中15种成分与血管内皮生长因子（VEGF）受体的作用。方法 运用Western blotting法检测筛选VEGF受体高表达细胞株;构建VEGF受体CMC,并建立ECV304/CMC online-LC检测方法,以索拉菲尼作为阳性药,对人参皂苷Rb₁、Rb₂、Rb₃、Rc、Rd、Rg₁、Rg₂、Rg₃、Rh₁、Ro、F₂,五味子甲素,五味子乙素,五味子醇甲,五味子醇乙进行VEGF受体结合强度的检测分析;CCK-8法检测筛选出的成分（5、10 μg/mL）对ECV304细胞的促增殖作用。结果 Western blotting结果显示,ECV304细胞中VEGF受体高表达;人参皂苷Rb₁、Rb₂、Rb₃、Rc、Rd、Rg₃、Rh₁、F₂、五味子甲素、五味子乙素与VEGF受体CMC柱有结合作用;CCK-8法检测以上成分对ECV304细胞的活力影响发现,人参皂苷Rb₂能促进细胞的增殖。结论 人参皂苷Rb₂能与VEGF受体结合,且显著促进ECV304细胞增殖。     

高纯度单体制备及结构鉴定芹菜籽中3种苯酞成分

目的 分离和鉴定芹菜籽中苯酞类化合物。方法 采用硅胶柱色谱、制备薄层色谱方法分离纯化苯酞类化学成分,用波谱分析技术鉴定化合物结构。结果 从芹菜籽中分离制备得到3种主要的苯酞类化合物,分别鉴定为芹菜甲素、芹菜乙素和新蛇床内酯。结论 采用该法制备的样品纯度大于98%,可作为对照品使用。     

Antihistaminic effect of terfenadine: A new piperidine-type antihistamine

The antihistaminic effect of terfenadine was studied in the isolated guinea pig ileum, histamine skin wheals in guinea pigs and monkeys, and i.v. histamine-induced death in guinea pigs. In the guinea pig ileum, terfenadine, 1 × 10^?7 M, shifted the histamine dose-response curve to the right in a parallel fashion without affecting the dose-response curve of acetylcholine and barium chloride. However, as the dose of terfenadine was increased (3.16 × 10^?7 and 1 × 10^?6 M) the histamine dose-response curves were displaced to the right with a depression of the maximum response and a reduction of the slope. Thus an unsurmountable type of antagonism was observed. Acetylcholine was also antagonized in a similar fashion by these two concentrations. In contrast, terfenadine appeared to displace the barium chloride dose-response curve to the right in a parallel fashion. At 0.4 and 0.8 mg/kg p.o., terfenadine shifted the histamine skin wheal dose-response curves to the right in a parallel fashion, but at 1.6 to 6.4 mg/kg, terfenadine antagonized the histamine wheal dose-response curves with a depression of the maximum and the slope of the curve. These results were also similar to those of cyproheptadine but were different from those of chlorpheniramine, which produced parallel shifts. In monkeys, terfenadine produced a substantially greater effect on the histamine wheal than did chlorpheniramine (both administered at 30 mg/kg p.o.). Terfenadine also completely protected against i.v. histamine-induced death in guinea pigs. Terfenadine produced no atropine-like effect against pilocarpine-induced salivation in rabbits, no demonstrable histamine H₂ antagonism, no antiserotonin activity, no α or β antagonism, and no untoward cardiovascular effects. Most significantly, terfenadine had no overt central nervous system (CNS) effects in mice, rats, guinea pigs, or monkeys; whereas chlorpheniramine produced tremors and convulsions in mice and monkeys when tested at much lower doses than those used for terfenadine. It is concluded that terfenadine is an effective and specific antihistaminic compound with the potential advantage of a lack of CNS sedative effects.     

Effect of 4-aminopyridine and 3,4-diaminopyridine on guinea-pig isolated ileum

1 4-Aminopyridine and 3,4-diaminopyridine produced concentration-dependent contraction on guinea-pig isolated ileum incubated in Tyrode solution. The EC₅₀ values were 1.14 × 10^?4 and 1.39 × 10^?4M , respectively. 2 Calcium channel blockers such as verapamil, diltiazem, nifedipine, flunarizine, and lanthanum chloride antagonized the contracting effect induced by 4-aminopyridine and 3,4-diaminopyridine in guinea-pig isolated ileum. 3 Diazoxide and atropine sulphate behaved similarly as antagonists of the contracting effect induced by 4-aminopyridine and 3,4-diaminopyridine in guinea-pig isolated ileum. 4 It is concluded that the aminopyridines exert their effects through the release of acetylcholine from parasympathetic nerve terminals.     

吡喹酮对神经肌肉接头传递的作用

吡喹酮可使电刺激腓总神经所引起的胫前肌收缩反应明显加强。如给腓总神经施加超强刺激,静脉注射筒箭毒碱可减弱肌肉收缩反应,吡喹酮却能加强筒箭毒碱的抑制作用,使神经肌肉传递迅即完全阻断。采用微电极细胞内记录技术研究吡喹酮对离体大鼠膈神经隔肌的作用,发现吡喹酮不明显影响膈肌细胞的静息膜电位。低浓度吡喹酮(2×10^-4M)可使微终板电位(mepp)频率明显增加。高浓度吡喹酮8×10^-4M则使mepp振幅逐渐变小和消失。吡喹酮在使神经肌肉传递阻滞不断加深的同时,尚能使终板电位的振幅变小,终致完全消失。     

Characterization of muscarinic receptors on the isolated guinea pig ileum at pharmacologically low concentrations

• 1.1. Several selective and non-selective muscarinic agonists (McN-A-343, RS-86, arecoline, oxotremorine-M, pilocarpine, cis-dioxolane, and acetylcholine) were examined for relaxant activity in the isolated guinea-pig ileum at pharmacologically low concentrations.
• 2.2. The concentrations studied include: 1 × 10⁻¹²M, 3 × 10⁻¹²M, 1 × 10⁻¹¹M, 3 × 10⁻¹¹M and 1 × 10⁻¹⁰M.
• 3.3. None of the compounds exhibited relaxant activity in both the field and non-field stimulated ileum.
• 4.4. All of the above compounds exert muscarinic agonist activity in a concentration range of 1 × 10⁻⁹M to 1 × 10⁻⁶M (Williams et al., 1992).
• 5.5. Thus, in the isolated guinea-pig ileum, muscarinic agonists do not exert relaxant activity of the gastrointestinal tract at low concentrations.

     

Spasmolytic constituents of Cedrus deodara (Roxb.) Loud: pharmacological evaluation of himachalol.

Himachalol has been identified as the major antispasmodic constituent in the wood of Cedrus deodara. The pharmacological studies of himachalol on various isolated smooth muscles (guinea pig ileum, rabbit jejunum, rat uterus, and guinea pig seminal vesicle) and against different agonists (acetylcholine, histamine, serotonin, nicotine, and barium chloride) indicated spasmolytic activity similar to that of papaverine. It was a more potent antagonist of barium chloride-induced spasm of guinea pig ileum than papaverine but less effective in reverting a similar spasm of rabbit jejunum and had no relaxing effect alone. In the conscious immobilized cat, intragastric administration of himachalol or papaverine (100 mg/kg) produced equal inhibition of carbachol-induced spasm of the intestine, lasting about 2 hr, but himachalol had a faster onset of action. Himachalol was devoid of spasmolytic effect on the bronchial musculature of guinea pig but was 3.3 times more potent than papaverine in antagonizing epinephrine-induced contraction of the guinea pig seminal vesicle. Intravenous injection of himachalol (3-10 mg/kg) in the cat produced a dose-dependent fall in blood pressure and an increased femoral blood flow.     

The Effect of Calcium,Practolol, Atropine and Phenoxybenzamine on the Rat Atrial Action Potential at Threshold and Supra-threshold Stimulation

Abstract: An increase in the concentration of calcium in the Ringer's solution increased the maximum rate of rise (dv/dt) and shortened the duration of the action potential of rat left atria in vitro. Supra-threshold stimulation increased dv/dt at low Ca⁺⁺ concentration (2.0 meq./l). This increase was completely abolished by pretreatment with an adrenergic β-receptor blocker, practolol 5 × 10^-6 M. At this concentration the drug is devoid of a quinidine-like effect. The duration of the action potential was decreased by an increase in the strength of the electrical stimulation. This decrease was completely blocked by pretreatment with atropine 1.43 × 10^-6 M and phenoxybenzamine 2.5 × 10^-6 M, an adrenergic α-receptor blocker with an atropine-like activity. At threshold stimulation neither practolol 5 × 10^-6 M nor atropine 1.43 × 10^-6 M nor phenoxybenzamine 2.5 × 10^-6 M caused any changes in the shape or the duration of the intracellularly recorded rat left atrial action potential. It is concluded that the possible liberation of autonomic mediators as well as the calcium concentration of the Ringer solution, should be taken into consideration in the interpretation of the results of experiments which involve the effects of antagonists on intracellularly recorded atrial action potentials.     

The effects of PGE1 on responses to cardiac vagus nerve stimulation and acetylcholine release

PGE₁, 2.5 × 10^?9 to 5 × 10^?9 g/ml, reduced the negative chronotropic responses to vagal stimulation and to acetylcholine in isolated guinea-pig atria. Neither ganglionic transmission nor axonal impulse conduction were depressed by the compound in anaesthetized cats. PGE₁ did not affect acetylcholine release from the parasympathetic nerve terminals of the guinea-pig ileum. These findings are in disagreement with the view that PGE₁ modulates parasympathetic transmission by reducing the release of the cholinergic transmitter. It reduces vagal bradycardia by antagonizing the effect of acetylcholine on the atrial cells. This ‘anticholinergic’ action may be related to the cyclic AMP system.     

Effects of oblongine chloride,an alkaloid from Leontice leontopetalum on guinea-pig isolated smooth muscle and heart

1. The effects of (−)oblongine chloride, a quaternary alkaloid from Leontice leontopetalum, on guinea-pig isolated ileal longitudinal segments, main pulmonary artery rings, spontaneously-beating atrium and isolated perfused heart were studied.2. Oblongine chloride (3 × 10⁻⁵−10⁻³ M) caused concentration-dependent relaxation of ileum, an effect which was not blocked by propranolol (10⁻⁶ M) alone or in combination with prazosin (3 × 10⁻⁸ M), or by indomethacin (10⁻⁶ M), but was reduced by desensitization of the preparation by prior exposure to 3 × 10⁻⁵ M ATP and, at high concentrations of oblongine, by a combination of propranolol and yohimbine (3 × 10⁻⁶ M).3. Oblongine chloride (10⁻⁵−3 × 10⁻³ M) caused concentration-dependent relaxation of epinephrine-precontracted pulmonary artery. This effect was not affected by propranolol or by indomethacin but was significantly attenuated by pretreatment with 3 × 10⁻⁵ M ATP and potentiated by pretreatment with quinacrine (10⁻⁵ M).4. Oblongine chloride (10⁻⁵M−3 × 10⁻³ M) caused concentration-dependent increase in the contractility but did not affect the rate of the atrium. Similar effects were obtained with isolated perfused heart except that large concentrations of oblongine (10⁻³, 3 × 10⁻³ M) inhibited both contractility and rate of the heart. The inotropic effects of oblongine on the atrium were not blocked by propranolol or indomethacin but were significantly blocked by quinacrine.5. These observations suggest that the effects of oblongine chloride are not mediated by the stimulation of adrenergic receptors on these preparations but are mediated by purinergic receptors and by an interference with the arachidonic acid metabolism but not along the cyclooxygenase pathway.     

Pharmacological evaluation of a new Ca2+ antagonist, 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8): studies in smooth muscles

The pharmacology of 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) has been studied using guinea pig ileum and vas deferens preparations. TMB-8 inhibited responses to drugs that excite specific receptors (acetylcholine and norepinephrine) as well as to agents whose actions are not mediated via specific receptors (KCl and BaCl₂) with ID₅₀'s of 3.8 × 10^?6 to 1 × 10^?4 M. TMB-8 inhibited responses to acetylcholine, norepinephrine, nicotine, dimethylphenylpiperazinium and KCl in an insurmountable manner in the guinea pig ileum, while responses to BaCl₂ were inhibited in a competitive manner. Increasing Ca²⁺ concentrations of the bathing medium from 1.35 to 5.40 mM effectively antagonized the TMB-8 inhibition of responses to KCl in the guinea pig ileum and vas deferens preparations. These results indicate that TMB-8 may produce its inhibitory effects in smooth muscle by interfering with the availability of Ca²⁺ for muscle contraction by blocking the Ca²⁺ release from intracellular bound stores.     

CONTRACTURES PRODUCED BY CARBAMATE ANTICHOLINESTERASES IN BOVINE TRACHEAL SMOOTH MUSCLE

1. In isolated strips of bovine tracheal muscle the carbamate anticholinesterases, neostigmine and eserine caused similar, slowly-developing, sustained spasms which were concentration-related in the range 10^?7-10^?4 mol/l; these spasms could be abolished either by withdrawing the anticholinesterase or by addition of atropine (5 × 10^?7 mol/l). 2. Depletion of tissue stores of acetylcholine using hemicholinium-3 with or without electrical stimulation rendered the muscle unresponsive to neostigmine (10^?6 mol/l). Responses to acetylcholine itself were not impaired. 3. A low concentration of neostigmine (10^?8 mol/l) did not cause spasm but enhanced the contractile response of bovine trachealis to acetylcholine, carbachol and histamine. This concentration of neostigmine also increased the muscle's contraction upon exposure to a high-potassium solution, even in the presence of atropine (5 × 10^?7 mol/l). 4. It is concluded that neostigmine and eserine cause spasm not only by preventing breakdown of endogenously released acetylcholine but also by stimulating release of acetylcholine from nerve terminals and by a non-specific enhancement of muscle contraction.