Pharmacological characteristics of benthiactzine's antagonism on cholinergic receptors and its antidotal effects against cholinesterase inhibitors poisoning

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,P0.05.② The 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,P0.05.The ED50±L95 value of benthiactzine antagonizing to peripheral salivation caused by pilocarpine(40 mg·kg-1,sc) in mice was(5.57±1.30) mg·kg-1,which was 11 times weaker than that of atropine(0.46±0.18 mg·kg-1,P0.01).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,P0.05).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,P0.05).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,P0.05).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.