目的 评价宾赛克嗪(benthiactzine)对胆碱受体功能拮抗作用及其对有机磷农药中毒的抗毒效应,并与阿托品比较.方法 ① 以烟碱诱发小鼠惊厥,离体豚鼠回肠收缩为评价中枢和外周神经元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;以槟榔碱和毛果芸香碱诱发小鼠流涎,乙酰胆碱和氧化震颤素诱发回肠收缩为评价外周M 受体功能的指标;并在烟碱和毛果芸香碱联用诱发混合性震颤模型上,研究药物的药理学特点.②在DDVP染毒小鼠模型上研究药物的抗毒效应(PR值).结果 ① 宾赛克嗪抗槟榔碱致小鼠中枢性震颤的ED50±L95为(0.31±0.06) mg·kg-1,中枢抗M作用比阿托品(1.33±0.17) mg·kg-1强3.3倍.②宾赛克嗪抗槟榔碱和毛果芸香碱诱发小鼠流涎的ED50±L95分别为(0.38±0.09) mg·kg-1和(5.57±1.30) mg·kg-1,而阿托品分别为(0.17±0.03) mg·kg-1和(0.46±0.18) mg·kg-1,宾赛克嗪的外周抗M作用弱于阿托品.③ 宾赛克嗪抗烟碱诱发惊厥的ED50±L95为(2.87±0.76) mg·kg-1,具有较强的中枢抗N作用.④ 宾赛克嗪抗烟碱诱发回肠收缩的IC50±L95为(1.1±0.18) μmol·L-1,比阿托品(13.84±1.68) μmol·L-1强约13倍,说明宾赛克嗪具有外周神经元N受体拮抗作用.⑤宾赛克嗪抗毛果芸香碱和烟碱联用诱发小鼠震颤的ED50±L95为(2.64±0.35) mg·kg-1,比阿托品(4.95±0.65) mg·kg-1强约1倍.⑥宾赛克嗪和阿托品抗DDVP致死作用的ED50±L95分别为(2.87±0.40) mg·kg-1和(6.78±3.92) mg·kg-1;宾赛克嗪10 mg·kg-1可使小鼠抗DDVP中毒的 PR值提高16.84倍,而阿托品仅能提高0.81倍.结论 宾赛克嗪中枢抗M作用强于阿托品,外周抗M作用弱于阿托品,并具有中枢和外周神经元N受体拮抗作用;宾赛克嗪对敌敌畏中毒小鼠的抗毒效应明显强于阿托品.%Aim To investigate the pharmacological characteristics of benthiactzine' s antagonism on cholinergic receptors activities and to evaluate the antidotal effects of benthiactzine against ChEI poisoning, which were compared with the effects of atropine.Methods The convulsions in mice and the construction of isolated guinea pig ileum induced by nicotine were used to assess the effects of benthiactzine on central and peripheral nicotinic receptors.The central tremor and peripheral salivation caused by arecoline, the salivation caused by pilocarpine, and the isolated guinea pig ileum construction induced by acetylcholine or oxotremorine were carried out to assess the effects of benthiactzine on central and peripheral muscarinic receptors.The mixed tremor evoked by nicotine combined with pilocarpine was also used to assess the antagonism of benthiactzine on cholinergic receptors.In addition, a poison resistance ( PR ) value was introduced to evaluate the antilethal effect of benthiactzine and atropine in organophosphorus pesticide DDVP poisoning mice.Results ① The ED50 ± L95 value of benthiactzine antagonizing to central tremor caused by arecoline ( 8 mg·kg-1, sc) in mice was (0.31 ±0.06) mg · kg-1,which was 3.3 times stronger than that of atropine (1.33±0.17)mg·kg-1, P＜0.05.②The ED50±L95 value of benthiactzine ( ip 15 min ) antagonizing to peripheral salivation caused by arecoline (8 mg·kg-1, sc) in mice was (0.38 ±0.09) mg· kg-1,which was 1.2 times weaker than that of atropine (0.17±0.03) mg· kg-1,P＜0.05.The ED50±L95 value of benthiactzine antagonizing to peripheral salivation caused by pilocarpine ( 40 mg· kg -1 , sc ) in mice was ( 5.57 ± l.30) mg· kg-1, which was 11 times weaker than that of atropine ( 0.46 ± 0.18 mg· kg-1,P ＜ 0.01 ).③ The ED50 ± L95 value of benthiactzine against convulsions induced by nicotine ( 1.0 mg·kg-1, iv ) in mice was ( 2.87 ± 0.76 ) mg · kg-1,which indicated that benthiactzine had strong antagonism on central nicotinic receptors.④ In isolated guinea pig ileum preparations, the IC50 ± L95 value of benthiactzine inhibiting the nicotine-induced contractions was ( 1.1 ± 0.18 ) μmol · L-1, which was 13 times stronger than that of atropine ( 13.84 ± 1.68 μmol · L-1, P ＜ 0.05 ).Benthiactzine was found to antagonize nicotine-induced contractions due to excitation of ganglionic nicotinic receptors.⑤ The ED50 ±L95 value of benthiactzine antagonizing to mixed tremor caused by pilocarpine ( 50 mg · kg-1 , ip ) combined with nicotine ( 2.5 mg · kg-1 , ip ) in mice was ( 2.64 ± 0.35 )mg · kg-1, which was approximately 1 times stronger than that of atropine ( 4.95 ± 0.65 mg· kg - 1,P ＜ 0.05 ).⑥ Administration of benthiactzine at a dose of 10 mg · kg-1 raised the PR value of DDVP to 17.84, whereas atropine at the same dose increased it only to 1.81, showing a weaker effect of atropine compared with benthiactzine.The ED50 ± L95 value of benthiactzine antagonizing to the lethal effect caused by DDVP(1.2 LD, sc)was(2.87±0.40) mg· kg-1,which was much lower than that of atropine ( 6.87 ±3.92 mg· kg-1, P ＜ 0.05 ).Conclusions Benthiactzine exhibits stronger central antimuscarinic effects and weaker peripheral antimuscarinic effects than atropine.Benthiactzine has definite antagonism on central and peripheral ganglionic nicotinic receptors.These features contribute to that benthiactzine possesses a more potent effect than atropine in counteracting DDVP poisoning.
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