Emesis induced by 4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343): evidence for a predominant central muscarinic M1 mediation.
The emetic action of 4-(m-chlorophenylcarbamoyloxy)-2- butynyltrimethylammonium chloride (McN-A-343) was investigated in the unanaesthetized cat, after it was injected into the cerebral ventricles, through chronically-implanted cannulae. Intracerebroventricular injection of McN-A-343 produced dose-dependent and shortlasting emesis, which was not completely abolished after ablation of the area postrema. The predominantly selective muscarinic M1 antagonist, pirenzepine as well as the mixed muscarinic M1 and M2 antagonist, atropine, injected into the cerebral ventricles, attenuated or abolished the emesis evoked by intracerebroventricular McN-A-343. Both atropine and pirenzepine produced dose-dependent inhibition of the emesis evoked by McN-A-343. However, the ID50 value for atropine was approximately five times greater than that for pirenzepine. Abolition of McN-A-343-induced emesis only occurred with the largest dose of atropine (1 mg). On the other hand, selected ganglionic blocking agents, an alpha- and beta-adrenoceptor blocking agent, a dopamine antagonist, a 5-hydroxytryptamine antagonist and an antihistamine, all injected into the cerebral ventricles, had no significant effect on emesis evoked by McN-A-343, similarly injected. The emetic response to intracerebroventricular injection of McN-A-343 was attenuated or abolished in cats pretreated with hemicholinium-3, triethylcholine, reserpine and 6-hydroxydopamine, intracerebroventricularly. On the contrary, the emetic response to intracerebroventricular injection of McN-A-343 was not altered in cats pretreated with intracerebroventricular injections of bretylium, alpha-methyl-p-tyrosine and 5,6-dihydroxytryptamine. It is postulated that the emesis produced by McN-A-343, injected into the cerebral ventricles, is mediated through muscarinic M1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Beleslin
D B
DB
Department of Pharmacology, Medical Faculty, Belgrade, Yugoslavia.
Nedelkovski
V
V
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015115:5,6-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D000865:Antazoline / Q000494:pharmacology; D001949:Bretylium Compounds / Q000494:pharmacology; D002415:Cats; D002746:Chlorpromazine / Q000494:pharmacology; D002794:Choline / Q000031:analogs & derivatives / Q000494:pharmacology; D004639:Emetics / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006426:Hemicholinium 3 / Q000494:pharmacology; D006584:Hexamethonium Compounds / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008781:Methyltyrosines / Q000494:pharmacology; D008784:Methysergide / Q000494:pharmacology; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012110:Reserpine / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology; D019805:alpha-Methyltyrosine
D001949:Bretylium Compounds; D004639:Emetics; D006584:Hexamethonium Compounds; D008781:Methyltyrosines; D009466:Neuromuscular Blocking Agents; D000644:Quaternary Ammonium Compounds; D011976:Receptors, Muscarinic; D015016:Yohimbine; D006426:Hemicholinium 3; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D019805:alpha-Methyltyrosine; D008464:Mecamylamine; D012110:Reserpine; C100239:triethylcholine; D011433:Propranolol; D000865:Antazoline; D002794:Choline; D002746:Chlorpromazine; D015115:5,6-Dihydroxytryptamine; D008784:Methysergide