title: In vitro functional interactions of acetylcholine esterase inhibitors and muscarinic receptor antagonists in the urinary bladder of the rat.
abstract: Obidoxime, a weak acetylcholine-esterase (AChE) inhibitor, exerts muscarinic receptor antagonism with a significant muscarinic M2 receptor selective profile. The current examinations aimed to determine the functional significance of muscarinic M2 receptors in the state of AChE inhibition, elucidating muscarinic M2 and M3 receptor interaction. In the in vitro examinations, methacholine evoked concentration-dependent bladder contractile and atrial frequency inhibitory responses. Although atropine abolished both, methoctramine (1 μmol/L) only affected the cholinergic response in the atrial preparations. However, in the presence of methoctramine, physostigmine, an AChE inhibitor, increased the basal tension of the bladder strip preparations (+68%), as well as the contractile responses to low concentrations of methacholine (< 5 μmol/L; +90-290%). In contrast to physostigmine, obidoxime alone raised the basal tension (+58%) and the responses to low concentrations of methacholine (< 5 μmol/L; +80-450%). Physostigmine concentration-dependently increased methacholine-evoked responses, similarly to obidoxime at low concentrations. However, at large concentrations (> 5 μmol/L), obidoxime, because of its unselective muscarinic receptor antagonism, inhibited the methacholine bladder responses. In conclusion, the current results show that muscarinic M2 receptors inhibit muscarinic M3 receptor-evoked contractile responses to low concentrations of acetylcholine in the synaptic cleft. The muscarinic M2 and M3 receptor crosstalk could be a counteracting mechanism in the treatment of AChE inhibition when using reactivators, such as obidoxime.
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Kralove, Czech Republic.
authors.forename: Uday K
authors.initials: UK
authors.lastname: Killi
authors.forename: Vladimir
authors.initials: V
authors.lastname: Wsol
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.forename: Michael
authors.initials: M
authors.lastname: Winder
authors.forename: Gunnar
authors.initials: G
authors.lastname: Tobin
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003959:Diamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006325:Heart Atria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009768:Obidoxime Chloride / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D051381:Rats; D020239:Receptor Cross-Talk; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors*; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*; D001743:Urinary Bladder / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D003959:Diamines; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D016210:Methacholine Chloride; D009768:Obidoxime Chloride; D001285:Atropine; D010830:Physostigmine; C054938:methoctramine
keywords: acetylcholinesterase inhibition; heart; muscarinic M2 receptor; rat; urinary bladder