REVERSAL OF ACTION OF AMINO-ACID ANTAGONISTS BY BARBITURATES AND OTHER HYPNOTIC DRUGS
REVERSAL OF ACTION OF AMINO-ACID ANTAGONISTS BY BARBITURATES AND OTHER HYPNOTIC DRUGS
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DOI：
10.1111/j.1476-5381.1978.tb07790.x
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发表时间：
1978-01-01
影响因子：
7.3
通讯作者：
DRAY, A
中科院分区：
文献类型：
--
作者：
BOWERY, NG;DRAY, A
1体外实验观察了戊巴比妥酮等镇静/催眠药物与氨基丁酸(γ-aminobuyric，GABA)的相互作用。2PB和其他巴比妥酸盐以剂量依赖的方式使神经节去极化(阈值浓度100-300μM，参见。GABA去极化阈值1μM)。选择性GABA拮抗剂(+)-荷包牡丹碱甲氯(Bic)可使去极化作用减弱。其他非巴比妥类镇静剂，如氯氮卓酮、阿米替林、异丙嗪，在浓度达2 mM时不会产生去极化。3浓度达80μM的PB对GABA的剂量-反应曲线有不同程度的影响。在大多数情况下，对低浓度(10μM以下)GABA的反应有轻微的增强，而对10μM以上浓度的GABA的反应有抑制作用。这种反转现象发生在PB浓度太低而不能使神经节去极化时，并且不仅依赖于PB的浓度，也依赖于Bic的浓度。5巴比妥酸盐环上C5位烷基取代基(R2)的尺寸越大，同系巴比妥酸盐的反转能力越强。当取代基含有5个碳原子(戊巴比妥酮和阿米洛比妥)时，活性最强；超过这一点，活性降低。6-PB可拮抗其他GABA拮抗剂四亚甲基二磺胺和二环磷酸异丙酯的作用，也可逆转士的宁的非选择性拮抗作用。随之而来的士的宁降低了对胆碱类似物卡巴胆碱的反应，但不被PB逆转。7非巴比妥类镇静/催眠药也能逆转Bic产生的GABA拮抗作用。苯二氮卓类药物在低于PB(氯氮卓酮的阈值浓度为0.5μM)时有效。然而，即使在远高于PB的最大有效浓度的浓度下，它们也只产生部分逆转。8从灌注液中取出后，氯氮环氧化物(和其他苯二氮卓类药物)的Bic逆转效应持续数小时。相比之下，PB在去除后仅持续15-30分钟。9氯氮卓酮(30μM)在没有Bic的情况下应用并不影响对GABA的反应，但确实减少了随后应用Bic所产生的抑制，即使氯氮卓酮已在40min前被移除。10在大鼠脑干PB内，离子导入剂量既不降低神经元自发放电频率，也不影响对GABA或甘氨酸的反应，可逆转Bic对GABA的拮抗作用(23个受试神经元)。PB还逆转了士的宁对甘氨酸的反应产生的拮抗作用，尽管这不太容易观察到(14个神经元中有5个被测试)。11离子导入应用其他巴比妥酸盐和氯氮卓酮也逆转了Bic的作用。与离体神经节一样，氯氮卓酮只有部分逆转作用，而氟西潘则不能逆转。静脉注射硫喷妥(1.3 mg/kg)、戊巴比妥钠(0.4~5.5 mg/kg)、己巴比妥钠(0.4~0.8 mg/kg)和氯硝西潘(0.1~0.2 mg/kg)也能逆转离子导入Bic的作用。氯硝西潘的逆转持续时间比巴比妥类药物长得多。13建议…的逆转
1 The effects of pentobarbitone (PB) and other sedative/hypnotic drugs have been examined in relation to γ-aminobutyric acid (GABA) in vitro on the superfused isolated superior cervical ganglion of the rat and in vivo on single units in the brain stem of the anaesthetized rat. 2 PB, and other barbiturates, depolarized the ganglion in a dose-dependent manner (threshold concentration 100-300 μM, cf. GABA depolarization threshold 1 μM). The depolarization was reduced in the presence of the selective GABA antagonist (+)-bicuculline methochloride (Bic). Other non-barbiturate sedatives e.g. chlordiazepoxide, amitriptyline, promethazine at concentrations up to 2mM produced no depolarization. 3 PB, tested at concentrations up to 80 μM, produced variable effects on the dose-response curve to GABA. On most occasions a slight potentiation occurred in responses to low concentrations of GABA (below 10 μM) coupled with a depression in the responses to concentrations of GABA greater than 10 μM. 4 Superfusion with PB in the presence of Bic reversed the depression in the response to GABA produced by Bic. This reversal phenomenon occurred at concentrations of PB too low to depolarize the ganglion and was dependent not only on the concentration of PB but also on that of Bic. 5 The reversal potency within an homologous series of barbiturates increased with the size of the alkyl substituent (R2) at C5 on the barbiturate ring. The most potent occurred when the substituent contained 5 carbon atoms (pentobarbitone and amylobarbitone); above this, activity decreased. 6 PB reversed the effects of the other GABA antagonists, tetramethylenedisulphotetramine and isopropyl bicyclophosphate and also the non-selective antagonism produced by strychnine. A concomitant reduction by strychnine of responses to the cholinomimetic, carbachol, was not reversed by PB. 7 Non-barbiturate sedative/hypnotics also reversed the GABA antagonism produced by Bic. The benzodiazepines were effective at lower concentrations than PB (chlordiazepoxide threshold concentration 0.5 μM, cf. PB 5 μM), however, they only produced a partial reversal even at concentrations much higher than the maximally effective concentration of PB. 8 The Bic reversal effect of chloridazepoxide (and other benzodiazepines) lasted many hours after removal from the superfusion solution. By contrast the effect of PB lasted only 15-30 min after its removal. 9 Chlordiazepoxide (30 μM) applied in the absence of Bic did not affect the response to GABA but did reduce the depression produced by the subsequent application of Bic even though the chlordiazepoxide had been removed 40 min earlier. 10 In the rat brain stem in vivo PB, applied iontophoretically in amounts which neither decreased the spontaneous neuronal firing rate nor affected the response to GABA or glycine, reversed the GABA antagonism induced by iontophoretic application of Bic (in all 23 neurones tested). PB also reversed the antagonism produced by strychnine of responses to glycine although this was less readily observed (5 out of 14 neurones tested). 11 Iontophoretic application of other barbiturates and chlordiazepoxide also reversed the effect of Bic. Chlordiazepoxide only produced a partial reversal, as in the isolated ganglion, and no reversal could be demonstrated with flurazepam. 12 Intravenous administration of thiopentone (1.3 mg/kg) pentobarbitone (0.4-5.5 mg/kg) hexobarbitone (0.4-0.8 mg/kg) and clonazepam (0.1-0.2 mg/kg) also reversed the effect of iontophoretically applied Bic. The reversal by clonazepam was of much longer duration than that produced by the barbiturates. 13 It is suggested that the reversal …