Prejunctional action of neostigmine on mouse neuromuscular preparations.
We have studied the effects of neostigmine on the mouse diaphragm and triangularis sterni isolated nerve-muscle preparations. Mechanical responses of the muscle, end-plate potentials and miniature end-plate potentials, and extracellularly recorded nerve ending currents were recorded. In the mouse diaphragm nerve-muscle preparations, neostigmine 1 mumol litre-1 continued to produce some antagonism of tubocurarine-induced block after cholinesterase had been inactivated completely by diisopropyl fluorophosphate 22 mumol litre-1. In the mouse triangularis sterni preparation, neostigmine 0.1-1 mumol litre-1 increased the quantal content of the end-plate potential in a concentration-dependent manner. This effect appeared to be sufficient to account for the cholinesterase-independent antagonistic action to tubocurarine under the conditions of the experiments. Neostigmine 1-100 mumol litre-1 depressed the amplitude of the K+ currents of the perineural waveforms in a concentration-dependent manner, and this may account for its ability to increase the quantal content of the end-plate potential. Although inhibition of acetyl-cholinesterase is the main mechanism of action of neostigmine, the drug also exerts an additional direct action on motor nerve endings to block the delayed rectifier K+ channels and enhance transmitter release. This effect occurred at clinically relevant concentrations of neostigmine. Physostigmine and pyridostigmine did not possess this additional action.
Braga
M F
MF
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow.
Rowan
E G
EG
Harvey
A L
AL
Bowman
W C
WC
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003964:Diaphragm / Q000294:innervation; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009388:Neostigmine / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects*; D010791:Phrenic Nerve; D015221:Potassium Channels / Q000187:drug effects; D014403:Tubocurarine / Q000037:antagonists & inhibitors
D002800:Cholinesterase Inhibitors; D015221:Potassium Channels; D009388:Neostigmine; D014403:Tubocurarine