Effects And Mechanisms Research On Respiratory Tract And Uterus Smooth Muscle Of Penehyclidine Hydrochloride, A Selective Antagonist Of Muscarinic Receptor

Penehyclidine Hydrochlordie (PHC) is a new anticholinergic drug. It's structure is 3-(2-hydroxyl-2-cyclopentyl-2-phenyl-ethoxy)quinuclidine. PHC was used widely in the clinic as antagonist of organic phosphorus poisoning and anaesthetic premedication at present. Anticholinergic agents have many pharmacological action, so their therapeutical effects were still explored. While anticholinergic agents have important uses as bronchodilators for the treatment of obstructive airway diseases, both asthma and, more particularly, chronic obstructive pulmonary disease (COPD). But anti-asthmatic research of PHC is rare.So experiments were carried to investigate whether PHC had the effect of anti-asthmatic and selective antagonist for muscarinic receptor subtypes. In vivo the methods of the intact animal' s asthma induced by drugs in guinea-pigs and airoverflow of the lungs in rabbits have been employed to estimate the anti-asthmatic effect of PHC. In vitro the methods of isolated guinea-pig tracheas,isolated rat uterus and isolated bronchoalveoar lavage fluid were furtherly employed to estimate PHC's anti-spasm mechanisms of smooth muscle. The method of radioimmunity assay was employed to determine cAMP levels in isolated guinea-pig tracheal and lung smooth muscle for comparing with selective effect on mus(?)arinic receptor subtypes to establish foundation for the exploitation use of PHC in asthma and COPD therapy. Results:1,Anti-asthmatic effect of Penehyclidine hydrochloride aerosol (0.5 mg.ml^-1) was equivalent to that of isoprenaline (0.5 mg.ml^-1), by using the asthmatic model induced by spraying acetylcholine and histamine.2,Compared with atropine sulfate group, PA₂ values of penehyclidine hydrochloride and gallamine were larger (P＜0.001). Which indicated relaxing effect of penehyclidine hydrochloride and gallamine were obviously stronger than that of atropine sulfate in isolated guinea-pig tracheas assay of anti -bethanechoi.3,The PHC effect of decreasing bronchoalveoar lavage fluid amount was dose-dependent relationship. With increasing dose of PHC the effect of anti-contracting bronchus induced by bethanechol was augmented too, according to maximal reducing mount index, compared with both control group and atropine sulfate group, the differences were statistical significant (P＜0.001), and shortening the time of recoverying stable. The gallamine effect of anti-contracting bronchus induced by bethanechol was increasing bronchoalveoar lavage fluid amount too, and the differences were also statistical significant (P＜0.001), and shortening the time of recoverying fixing.4,At dose of 10μmol·L^-1 PHC could increase the content of cAMP in isolated guinea-pig lung smooth muscle, while decrease the content of cAMP in isolated guinea-pig tracheal smooth muscle, but the difference was no statistical significant. However, at the same dose both acetylcholine and bethanechol could decrease the content of cAMP in isolated guinea-pig tracheal and lung smooth muscle and the difference was statistical significant(P＜0.05); both atropine and gallamine could increase the content of cAMP in isolated guinea-pig tracheal and lung smooth muscle and the difference was statistical significant (P＜0.001).5,Compared with atropine sulfate group, PA₂ values of penehyclidine hydrochloride and gallamine were larger (P＜0.05). Which indicated relaxing effect of penehyclidine hydrochloride and gallamine were obviously stronger than that of atropine sulfate in isolated rat uterus assay of anti-acetylcholine. Conclusion1,Penehyclidine hydrochloride aerosol has markedly anti-asthmatic effects.2,Penehyclidinehydrochloride has strong dilating effect on the smooth muscle of respiratory tract.3,Penehyclidine hydrochloride has no or poor effect on M₂ receptor subtypes in isolated guinea-pig tracheal and lung smooth muscle.4,Penehyclidine hydrochloride has effectively relaxaion on isolated rat uterus.