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.

• MeSH
• antagonisté muskarinových receptorů farmakologie   MeSH
• atropin farmakologie   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• diaminy farmakologie   MeSH
• fysostigmin farmakologie   MeSH
• interakce mezi receptory a ligandy MeSH
• krysa rodu rattus MeSH
• methacholinchlorid farmakologie   MeSH
• močový měchýř účinky léků   enzymologie   metabolismus   MeSH
• obidoxim chlorid farmakologie   MeSH
• receptor muskarinový M2 antagonisté a inhibitory   MeSH
• receptor muskarinový M3 antagonisté a inhibitory   MeSH
• srdeční síně účinky léků   enzymologie   metabolismus   MeSH
• svalová kontrakce účinky léků   MeSH
• techniky in vitro MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The oxime reactivator K112 is a member of the new group of xylene linker-containing AChE reactivators. Its cholinergic properties could be of importance at OP poisoning and are not related to the AChE reactivation that has been studied. It has been found that, despite of reactivating potency, this compound has additional effects. These cholinergic effects include a weak inhibition of AChE (IC(50)=43.8 ± 4.88 μM), inhibition of binding to the porcine muscarinic M2 receptor (IC(50)=4.36 μM) and finally, the inhibition of HACU (68.4 ± 9.9%), a key regulatory step in the synthesis of ACh. The inhibition of the binding of (3H)-HC-3 (64.7 ± 4.7%) and the influence on the membrane fluidity have also been observed. Blocking properties of K112 on the muscarinic receptors have been revealed in the in vitro experiment (rat urinary bladder) and in the in vivo experiment (rat heart BPM) as well. All these cholinergic properties could significantly contribute to the antidotal effect of K112 at the poisoning by the organophosphates.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• fluidita membrány účinky léků   MeSH
• hipokampus účinky léků   enzymologie   MeSH
• hladké svalstvo účinky léků   enzymologie   MeSH
• krysa rodu rattus MeSH
• močový měchýř účinky léků   enzymologie   MeSH
• organofosforové sloučeniny MeSH
• otrava organofosfáty MeSH
• otrava farmakoterapie   enzymologie   MeSH
• oximy chemie   farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani Wistar MeSH
• prasata MeSH
• pyridinové sloučeniny chemie   farmakologie   MeSH
• reaktivátory cholinesterázy chemie   farmakologie   MeSH
• receptor muskarinový M2 antagonisté a inhibitory   MeSH
• rekombinantní proteiny antagonisté a inhibitory   MeSH
• srdce účinky léků   MeSH
• srdeční frekvence účinky léků   MeSH
• svalová kontrakce účinky léků   MeSH
• synaptozomy účinky léků   enzymologie   MeSH
• techniky in vitro MeSH
• vazba proteinů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH