胍乙哌啶甲基衍生物的药理作用

小白鼠腹腔注射胍乙哌啶、BD-37、BD-38、胍乙啶和BD-31的LD_(50)分别为367,243,202,155和78 mg/kg。麻醉大白鼠和猫静脉注射胍乙啶、胍乙哌啶和BD-37出现血压短暂下降继而升压,然后再下降,而BD-38和BD-31仅有降压作用。急性降压强度BD-38和BD-31较强,BD-37和胍乙啶次之,胍乙哌啶最弱。胍乙啶、胍乙哌啶、BD-37和BD-31抑制酪胺的升压作用;对去甲肾上腺素的升压,除BD-31稍有抑制外,胍乙啶、BD-37和BD-38反有增敏作用。胍乙啶、胍乙哌啶和BD-37明显增强豚鼠心房的收缩,BD-38和BD-31则无此作用。离体豚鼠输精管和猫颈交感神经实验说明,BD-31阻断交感神经节的作用较强,对神经末梢也稍有阻断;BD-37和BD-38阻断交感神经末梢与胍乙啶的作用强度相仿;胍乙哌啶只对输精管稍有阻断作用。胍乙啶、胍乙哌啶、BD-37和BD-38可减低大鼠心脏内去甲肾上腺素的含量,BD-31未见减低。 以上结果表明:BD-38能选择地阻断交感神经末梢,而无胍乙啶的交感类似反应,并具有较强的降压效果。     

肾上腺素能神经阻滞剂二甲基哌啶乙胍的药理

麻醉猫静注二甲基哌啶乙胍(BD-38)1～5mg/kg或十二指肠内注入10mg/kg,麻醉狗静注5mg/kg,均引起血压显著下降,心电图无明显的改变。BD-38部分抑制电刺激离体豚鼠回肠壁的收缩;显著地阻断电刺激动脉周围神经引起的回肠抑制性(松弛)反应。BD-38可明显地抑制电刺激猫内脏神经离中端所引起的升压。清醒猫静脉注射胍乙啶和BD-38(5或10mg/kg)引起瞬膜松弛的作用强度相同。清醒猫灌胃给胍乙啶和BD-38(10mg/kg),胍乙啶的瞬膜松弛作用强度只有BD-38的一半,增加剂量至20mg/kg,才达到BD-38组的松弛程度,说明BD-38胃肠道吸收较胍乙啶为优。电刺激猫迷走神经外周端引起的降压和心率变慢,给BD-38后稍有阻断,1/2小时内恢复。对乙酰胆硷的作用无明显改变。BD-38也能抑制因阻断颈总动脉引起的加压反射。离体豚鼠心肺标本,血中BD-38浓度为0.25mg/ml,对心率、心输出量无改变,浓度增至2mg/ml,也不抑制心脏。BD-38不影响洋地黄毒甙的毒性。狗亚急性毒性试验,未发现对生长和肝功能的影响。BD-38具有持久的降压效果、胃肠道吸收良好、静注无急性拟交感反应、对心脏无直接抑制作用,值得临床试用。     

肾上腺素能神经阻滞剂二甲基哌啶乙胍的药理

麻醉猫静注二甲基哌啶乙胍(BD-38)1～5mg/kg或十二指肠内注入10mg/kg,麻醉狗静注5mg/kg,均引起血压显著下降,心电图无明显的改变。 BD-38部分抑制电刺激离体豚鼠回肠壁的收缩;显著地阻断电刺激动脉周围神经引起的回肠抑制性(松弛)反应。BD-38可明显地抑制电刺激猫内脏神经离中端所引起的升压。清醒猫静脉注射胍乙啶和BD-38(5或10mg/kg)引起瞬膜松弛的作用强度相同。清醒猫灌胃给胍乙啶和BD-38(10mg/kg),胍乙啶的瞬膜松弛作用强度只有BD-38的一半,增加剂量至20mg/kg,才达到BD-38组的松弛程度,说明BD-38胃肠道吸收较胍乙啶为优。 电刺激猫迷走神经外周端引起的降压和心率变慢,给BD-38后稍有阻断,1/2小时内恢复。对乙酰胆硷的作用无明显改变。BD-38也能抑制因阻断颈总动脉引起的加压反射。 离体豚鼠心肺标本,血中BD-38浓度为0.25mg/ml,对心率、心输出量无改变,浓度增至2mg/ml,也不抑制心脏。BD-38不影响洋地黄毒甙的毒性。 狗亚急性毒性试验,未发现对生长和肝功能的影响。BD-38具有持久的降压效果、胃肠道吸收良好、静注无急性拟交感反应、对心脏无直接抑制作用,值得临床试用。     

降压药物的合成研究——Ⅲ.β-N-(带有α-取代甲基的哌啶基)乙胍和有关化合物的合成

从胍乙啶(Ⅰ)和潘必啶(Ⅱ)结构出发,作者设计了β-N-(2,2,6,6-四甲基哌啶)乙胍(Ⅲ_a,BD-31)及其β-N-(2-甲基或顺式2,6-二甲基哌啶)乙胍(Ⅲ_b,BD-37;Ⅲ_c,BD-38)类似物。它们由不同的α-甲基哌啶与氯乙腈生成相应的N-(α-甲基哌啶)乙腈(Ⅷ_(a,b,c)),经氢化锂铝还原变成β-N-(α-甲基哌啶)乙胺(Ⅶ_(a,b,c)),再用硫酸甲基异硫脲引入胍基制得。药理试验发现BD-31,32(Ⅵ),33(Ⅶ_a),38均有明显降压作用,其中以BD-31作用最强。     

降压药物的合成研究——Ⅲ.β-N-(带有α-取代甲基的哌啶基)乙胍和有关化合物的合成

从胍乙啶(Ⅰ)和潘必啶(Ⅱ)结构出发,作者设计了β-N-(2,2,6,6-四甲基哌啶)乙胍(Ⅲ_a,BD-31)及其β-N-(2-甲基或顺式2,6-二甲基哌啶)乙胍(Ⅲ_b,BD-37;Ⅲ_c,BD-38)类似物。它们由不同的α-甲基哌啶与氯乙腈生成相应的N-(α-甲基哌啶)乙腈(Ⅷ_a,b,c),经氢化锂铝还原变成β-N-(α-甲基哌啶)乙胺(Ⅶ_a,b,c),再用硫酸甲基异硫脲引入胍基制得。药理试验发现BD-31,32(Ⅵ),33(Ⅶ_a),38均有明显降压作用,其中以BD-31作用最强。     

突触前钙离子拮抗剂W-conotoxin GVI-A及其同系物

W-conotoxin GVIA及其同系物外周静脉或动脉内注射可用作抗交感神经药物,也可与EDTA钠盐或局部麻醉剂利多卡因共用。治疗范围包括交感神经阻滞反射性营养不良、原发或继发性雷诺氏综合征、原发性纤维肌痛、第3和第4期动脉堵塞以及改善四肢手术或皮肤移植后的血液循环,也能用作诊断性交感神经阻滞剂。与静注抗交感神经药胍乙啶不同;它们不引起对去甲肾上腺素的高敏反应,在极低浓度下能完全阻断大鼠尾     

可乐定中枢降压作用与中枢胆碱能神经系统的关系

从猫第四脑室给药。毒扁豆碱降压作用可被阿托品及育亨宾阻断;可乐定降压作用可被育亨宾、密胆碱及阿托品阻断,不被可卡因阻断,破坏中枢去甲肾上腺素能末梢后,阿托品的阻断作用消失;可乐定减少脑室灌流液Ach释出量。提示猫延髓胆碱能和去甲肾上腺素能神经在心血管调节功能上相互影响,它们似有可能同在一心血管神经原形成突触联系共同对血压行抑制性调节;可乐定可能通过激动通路上突触后α₂受体产生降压作用。     

胍乙啶对大白鼠肾上腺皮质活动的影响

正常大白鼠腹腔注射胍乙啶每周3次,每次15—30毫克/公斤,共3周后,血压无明显变化。DOCA型高血压大白鼠给同剂量的胍乙啶组与对照组,在继续给DOCA的情况下,“浄升、降压面积百分比”分别为-1%和9%。两者相差10%,说明对DOCA型高血压大白鼠血压的继续上升,胍乙啶趋于抑制,腹腔注射20毫克/公斤的胍乙啶可使大白鼠的嗜酸性白血球和肾上腺中的抗环血酸含量在0.5—6小时内降低,但肾上腺内胆固酵含量的减低尚不明显。以上结果说明胍乙啶稍能影响腎上腺皮质的活动。     

溴苄乙铵及其有关化合物的一些药理观察

本文就国产溴苄乙铵进行了药理观察,证实了前人报告的降压作用以及对交感神经的选择作用,并发现用药后交感末梢的介质释放量显著减少;大剂量能明显改变猫、兔在位心脏的功能;在一般降压剂量时不仅增敏儿茶酚胺的升压作用,并且也能增敏其降压作用。初步试验了溴苄乙铵的异构体与类似物5个,发现间位与对位异构体同溴苄乙胺(邻位)对血压的作用相反,用药后血压略降后卽显著上升,并伴有瞬膜收缩和唾液分泌增加,阿托品能取消其降压和唾液分泌作用,而溴苄乙铵则能取消其升压作用。     

降压气雾剂

本品系含主药盐酸可乐定及环戊甲噻嗪、维生素E等的复方制剂。【作用特点】本品主要系通过减少交感神经末梢部位去甲肾上腺素的贮存而影响肾上腺素能神经的传导,因而产生降压作用。配伍维生素E,具有促进毛细血管血液循环,加强和改善人体组织中氧的供应,降低血胆固醇,防止动脉硬化等功效。     

Evidence for a competitive antagonism of guanethidine by dexamphetamine

After guanethidine had blocked the response of the cat nictitating membrane to sympathetic nerve stimulation, dexamphetamine restored the responses to all frequencies of stimulation. Dexamphetamine antagonized the sympathetic nerve block by guanethidine in the isolated sympathetically innervated rabbit ileum; the evidence suggests that the antagonism was competitive. Dexamphetamine antagonized the sympathetic nerve block by guanethidine in the isolated hypogastric nerve-vas deferens preparation of the guinea-pig. Doses of dexamphetamine, larger than those required to antagonize the blocking action of guanethidine, abolished the responses of the nictitating membrane, ileum and vas deferens to nerve stimulation. Dexamphetamine did not influence the depletion of noradrenaline by guanethidine in the heart and spleen of rabbits. The hypothesis is advanced that both dexamphetamine and guanethidine act on the store of noradrenaline at sympathetic nerve endings.     

Pre-and post-junctional receptor-mediated cholinergic interactions with adrenergic transmission in guinea-pig vas deferens

Summary Isolated, superfused, field stimulated guinea-pig vas deferens, in which the noradrenaline stores had been labelled by preincubation with tritiated (-)-noradrenaline, was used to study the interaction between exogenous and endogenous acetylcholine and adrenergic neuroeffector function. Exogenous acetylcholine was found to exert a dual muscarinic effect on the preparation, consisting of depression of the secretion of tracer noradrenaline from the sympathetic nerves, as well as enhancement of the nerve stimulation-induced contraction of the preparation. The results indicate that endogenous acetylcholine may play an analogous role, since eserine enhanced the nerve stimulation-induced contraction, without markedly affecting the secretion of labelled noradrenaline (the effect was abolished by atropine), while higher concentrations of atropine depressed the contraction and actually enhanced the secretion of labelled noradrenaline. The findings support the concept that guinea-pig vas deferens has a dual, cholinergic as well as adrenergic, innervation, and that the cholinergic nerves exert a dual modulatory effect on sympathetic neuro-effector function in this tissue: Firstly they appear to restrict the secretion of sympathetic neurotransmitter (via pre-junctional muscarinic receptors, on the adrenergic nerve terminals), and secondly they seem to enhance the excitability of the smooth muscle to sympathetic neurotransmitter (via post-junctional muscarinic receptors, on the smooth muscle cells).     

A comparison of histamine effects on the sympathetic neurotransmission of testicular capsule and rat vas deferens

Histamine is an important modulatory agent of the sympathetic neurotransmission, but its exact action on the testicular capsule or rat vas deferens is not fully understood. The present study sought to further investigate the functional effects of histamine on the neuronal and exogenous noradrenaline-induced contraction of the testicular capsule and rat vas deferens as well as to evaluate the contractile properties of this drug. The testicular capsule or vas deferens from Wistar rats, 3–4 months old, weighing 300–400 g, was isolated and mounted in organ baths for functional experiments. The results indicated that the neuronally evoked contraction of the testicular capsule was affected by histamine (10^?10 to 10^?8 M) with participation of inhibitory (H₃ receptors) and excitatory (H₁ receptors) receptors. Histamine (10^?7 to 10^?4 M) modulated the field-stimulated vas deferens by excitatory (H₂ receptors) and inhibitory (H₁ receptors) receptors. Histamine was able to decrease the tonic response for noradrenaline-induced contractions with participation of H₁ receptors (testicular capsule) and H₃ receptors (vas deferens) followed by nitric oxide generation. At high concentration, histamine exerts contractile effects in both tissues. In the testicular capsule, the histamine-induced contractions were related to H₁ receptor activation followed by release of prostaglandins. In contrast, the contractile effects of histamine in the vas deferens were related to H₂ receptor activation followed by release of catecholamines from sympathetic nerve endings. Therefore, our results indicate that histamine induced several effects on the sympathetic neurotransmission of rat testicular capsule and vas deferens. These effects are dependent on the concentration used and with participation of multiple histamine receptors.     

AUTONOMIC NEUROPATHY IN THE ALLOXAN-DIABETIC RAT

• 1 This study was designed to correlate functional and ultrastructural examination of the innervation of the atria and vas deferens of rats with long-term alloxan-induced diabetes mellitus.
• 2 After 7–8 months of diabetes the responses of preparations in vitro to nerve stimulation and to exogenous autonomic transmitter were compared with those from age-matched controls.
• 3 Right atria from controls and diabetics were equally responsive to noradrenergic nerve stimulation and to exogenous noradrenaline. Left atria from diabetic rats were supersensitive to both noradrenaline and acetylcholine. The left atria gave normal inotropic responses to noradrenergic nerve stimulation but responses to cholinergic nerve stimulation were absent. The vasa deferentia from both groups gave similar responses to noradrenergic nerve stimulation and to noradrenaline.
• 4 The electron microscope revealed many abnormal, degenerate noradrenergic nerve profiles in both right atria and vas deferens. No cholinergic terminals were found in the right atria.
• 5 These findings indicate that this form of experimental diabetes causes parasympathetic denervation of the heart with some indications of degeneration of sympathetic nerves.

     

β-Endorphin. Biological activity of analogs containing dermorphin and dynorphin sequences: ileum and vas deferens assays

Biological activity of synthetic β-endorphin (β-EP) analogs containing dermorphin or dynorphin-A-(1 – 13) structure has been investigated using the guinea pig ileum and the vas deferens of the mouse, rat and rabbit. Replacement of NH₂-terminal 1–7 segment of camel β-EP [β_c-EP-(1–7)] with dermorphin caused a great increase in opiate potency of the analog. [Dermorphin (1–7)] -β_c-EP was 120 times more potent than β_c-EP in the guinea pig ileum assay, 49 times more potent in the mouse vas deferens assay; and only 4 times more potent in the rat vas deferens assay. Replacement of NH₂-terminal 1–13 segment of human β-EP [β_h-EP-(1–13)] with dynorphin-A-(1–13) caused an increase in opiate potency in both the guinea pig ileum and rabbit vas deferens assays, a complete loss of potency in the rat vas deferens assay, and no change in the mouse vas deferens assay. In comparison with dynorphin-A-(1–13), the hybrid peptide was less potent in the guinea pig ileum assay as well as in mouse and rabbit vas deferens assay. It is suggested that β_c-EP-(8–31) facilitates the dermorphin moiety to act on opiate μ and δ receptors but not on the ± receptor, while β_h-(14–31) reduces the action of dynorphin on μ, δ and k receptors.     

Prejunctional inhibitory alpha-adrenoceptors and dopaminoceptors of the rat vas deferens and the guinea-pig ileum in vitro.

The effects of α-adrenoceptor and dopaminoceptor agonists and antagonists were investigated on prejunctional receptors of the rat vas deferens and the guinea-pig ileum. The order of potency of the agonists for twitch inhibition of the rat vas deferens was clonidine > oxymetazoline > dopamine > apomorphine > noradrenaline whilst the order of potency for inhibiting the stimulated guinea-pig ileum was clonidine > oxymetazoline > noradrenaline > dopamine > apomorphine. Yohimbine readily blocked the inhibitory effects of clonidine, oxymetazoline and noradrenaline in both tissues but was less effective against dopamine and apomorphine. Pimozide selectively blocked the effects of dopamine and apomorphine on the rat vas deferens and was almost completely ineffective against clonidine, oxymetazoline and noradrenaline. However, pimozide significantly antagonized the noradrenaline-induced twitch inhibition of the stimulated guinea-pig ileum in addition to antagonising dopamine and apomorphine action. The pA₂ values for pimozide against dopamine, apomorphine and noradrenaline in both tissues were significantly different. It is concluded that the prejunctional α-adrenoceptors of the rat vas deferens are the same as those located on the terminal cholinergic neurones of the guinea-pig ileum whilst the prejunctional dopaminoceptors in these tissues appear to differ from one another.     

The effects of calcium on adrenergic neuron blockade

The effects of increasing extracellular calcium were investigated on the responses to sympathetic nerve stimulation of three isolated organs; rabbit ileum, guinea-pig vas deferens and rabbit ear artery. A rise in the calcium concentration increased the responses of the ileum to low frequency stimulation, the maximum increase being obtained at 8.8 mM calcium. After partial blockade by guanethidine of the responses of the ileum to high frequency stimulation, raised calcium concentrations again increased the responses. The increase was similar in guanethidine-treated and untreated preparations and the maximum increase in both was obtained using 8.8 mM calcium. In the vas deferens and rabbit ear artery preparations an increase in extracellular calcium did not antagonize the blocking action of guanethidine. These experiments do not therefore support the theory that guanethidine acts by preventing the entry of calcium into the sympathetic nerve endings.     

The presynaptic activity of huwentoxin-I, a neurotoxin from the venom of the chinese bird spider Selenocosmia huwena.

Three different types of isolated nerve-synapse preparations, guinea pig ileum, rat vas deferens and toad heart, were used to investigate the physiological activity of Huwentoxin-I, a neurotoxin from the venom of the spider Selenocosmia huwena. The twitch response of isolated guinea pig ileum induced by electrical stimulus can be inhibited by HWTX-I. After blockage, contraction of the ileum can be induced by exogenously applied acetylcholine. HWTX-I caused the inhibition of the twitch response to electrical nerve stimulation in the rat vas deferens. After the twitch was completely inhibited, noradrenaline triggered rhythmic contraction of the vas deferens. The inhibitory effect on heart of toad induced by stimulating sympathetic-vagus nerve can be reversed by HWTX-I, although exogenously applied acetylcholine still acts as an effective inhibitor. All of these results support the conclusion that HWTX-I has the presynaptic activity that effects the release of neurotransmitter from the nerve endings of both the cholinergic synapse and the adrenergic synapse.