Twitch potentiation by organophosphate anticholinesterases in rat phrenic nerve diaphragm preparations

Abstract

1Twitch potentiation produced by anticholinesterases has been variously attributed to the prolonged postjunctional action of acetylcholine (ACh), a prejunctional action of ACh involving the initiation of antidromic firing (ADF) in the nerve or a direct action of the anticholinesterases on nerve terminals initiating ADF.2 The organophosphate anticholinesterases, paraoxon (diethyl-4-nitrophenylphosphate) and DFP (diisopropyl fluorophosphate), when applied to rat isolated diaphragm preparations for 30 min, produced twitch potentiation which subsequently declined. 3 The rates of onset and decline of twitch potentiation were directly related to the concentration of the organophosphates and the reversibility of their effects was in line with the reactivation of the phosphorylated enzymes formed by them, whether reactivation was spontaneous or induced by the oxime, N,N'-trimethylene-1, 3-bis (pyridinium-4-aldoxime). 4 Reducing the output of ACh from nerve terminals (by reducing the ratio of calcium: magnesium ions in the bathing solution) or reducing the affinity of ACh for the nicotinic cholinoceptor (using the disulphide bond reducing agent, dithiothreitol) produced the same effects as did lowering the concentration of the organophosphates. 5 It is concluded that the twitch potentiation produced by paraoxon and DFP, and its failure to be maintained when the higher concentrations of the organophosphates were used, were the direct result of the excess of ACh in the synaptic cleft, following inhibition of acetylcholinesterase.

Impaired neuromuscular function by conjoint actions of organophosphorus insecticide metabolites omethoate and cyclohexanol with implications for treatment of respiratory failure

“…Omethoate did not inhibit MMG twitch responses (Figure 2(A,B)). Rather, as reported by others in studies using isolated rodent muscle [45,46], the immediate effect was the opposite. Overall, the first (T1) twitch contraction in TOF responses increased 2.3 ± 0.2 fold (mean ± S.E.M., range, 1.1-3.6 fold; p < 0.001; paired t-test; Figure 2(C)), an increase that may have been partly due to double firing of motor axons in response to single stimuli [47,48].…”

Organoruthenium Prodrugs as a New Class of Cholinesterase and Glutathione‐S‐Transferase Inhibitors

“…The use of AChE inhibitors can have a number of unwanted (side‐)effects, which include uncontrolled muscle contraction and failure of neuromuscular transmission . Therefore, physiological evaluation was carried out for this relatively potent human AChE‐inhibitory ruthenium compound, C1 a , in terms of muscle contraction and membrane potential, using an isolated mouse hemidiaphragm preparation.…”

“…The use of AChE inhibitors can have a number of unwanted (side-)effects, which include uncontrolled muscle contraction and failure of neuromuscular transmission. [51][52][53] Therefore, physiological evaluation was carried out for this relatively potent human AChE-inhibitory ruthenium compound, C1 a, in terms of muscle contraction and membrane potential, using an isolated mouse hemidiaphragm preparation. C1 a at itsĨ C 100 (38 mm; which completely abolished hAChE activity) and at 3-and 6-fold its~IC 100 (113 and 227 mm, respectively) was tested on nerve-evoked and directly elicited single twitch and tetanic contractions in the isolated mouse hemidiaphragm preparation.…”

Discorhabdin alkaloids from Antarctic Latrunculia spp. sponges as a new class of cholinesterase inhibitors

“…The use of AChE inhibitors can produce unwanted side effects, like single twitch potentiation in muscle, and the inability of skeletal muscle to sustain tetanic contraction [32][33][34]. Therefore, additional electrophysiological investigations were carried out with one of the most active of these discorhabdins, discorhabdin G. These were designed to determine its effects on nerve-evoked and directly elicited single muscle twitches and on tetanic contractions of the isolated mouse hemidiaphragm with the corresponding nerve.…”