Contractile and phosphatidylinositol responses of rat trachea to anti-cholinesterase drugs

Purpose: Some anticholinesterases (anti-ChE) such as neostigmine and pyrido stigmine but not edrophonium, stimulate phosphatidylinositol (PI) response. Although a direct relationship was suggested between the increase in PI re sponse and airway smooth muscle contraction, there are no data regarding th e effects of anti-ChE drugs on airway smooth muscle. Thus, we examined the contractile properties and PI responses produced by anti-ChE drugs. Methods: Contractile response. Rat tracheal ring was suspended between two stainless hooks in Krebs-Henseleit (K-H) solution, (I)Carbachol (CCh), anti -ChE drugs (neostigmine, pyridostigmine, edrophonium) or DMPP (a selective ganglionic nicotinic agonist) were added to induce active contraction. (2) The effects of 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP), an M-3 muscarinic receptor antagonist, on neostigmine- or pyridostigmine-i nduced contraction of rat tracheal ring were examined. (3) Tetrodotoxin (TT X) was tested on the anti-ChE drugs-induced responses; PI response. The tra cheal slices were incubated in K-H solution containing LiCl and (3)[H]myo-i nositol in the presence of neostigmine or pyridostigmine with or without 4- DAMP, an M-3 muscarinic receptor antagonist, (3)[H]inositol monophosphate ( IP,) formed was counted with a liquid scintillation counter Results: Carbachol (0.1 mu M), neostigmine (1 mu M), pyridostigmine (10 mu M) but not edrophonium or DMPP caused tracheal ring contraction. 4-DAMP but not tetrodotoxin, inhibited neostigmine and pyridostigmine-induced contrac tion. Neostigmine- or pyridostigmine-induced IF, accumulation was inhibited by 4-DAMP, Conclusions: The data suggest that anti-ChE drugs activate the M-3 receptor s at the tracheal effector site.