Drug-Induced Modification of Ionic Conductance at the Neuromuscular Junction

3 In control recordings, the frequency of channel opening declined exponentially with time after formation of the gigaseal. Sarin and soman both increased the rate of this decline, indicating that they accelerated the rate of desensitization of the receptors. Eco and VX reduced the initial frequency of opening, which may have been due to enhancement of a fast phase of desensitization during gigaseal formation, or to blockade of closed channels. 4 It is concluded that the direct actions of organophosphates on nicotinic receptor ion channels are of little importance for their toxicity under normal conditions, since they occur only at much higher concentrations than those which cause inhibition of acetylcholinesterase. Such actions may become apparent, however, when therapies against the anticholinesterase effects of organophosphates increase their lethal dose sufficiently. These direct actions should also be taken into account when the effects of organophosphates on cholinergic transmission are studied.

Section: Discussionsupporting

confidence: 86%

Effects of organophosphorus anticholinesterases on nicotinic receptor ion channels at adult mouse muscle endplates

Tattersall

1990

“…Regarding the first point, it has been known for many years that the nicotinic receptor contains a number of noncompetitive inhibitor binding sites, one of high affinity in the channel pore, and several others of lower affinity located probably on the exterior of the receptor-channel complex at the protein lipid interface (Changeux et al, 1984). From the present study and others, it seems that pentobarbitone at concentrations of 10-500 gM is one of the many inhibitors known to cause channel blockade (Lambert et al, 1983), with the simplest assumption being that it sterically occludes the pore in a manner compatible with the sequential blocking model. However, even in those studies at relatively high concentrations of barbiturate where only blockade was observed, it has been generally concluded that mechanisms more complicated than steric occlusion seem to apply (Gage & McKin-)0 90>0 non, 1985;Jacobson et al, 1991;Charlesworth & Richards, 1995).…”

Section: Resultssupporting

confidence: 52%

Biphasic effect of pentobarbitone on chick myotube nicotinic receptor channel kinetics

Liu

Madsen

1996

“…In contrast, erabutoxin b does not produce rundown (Gibb & Marshall, 1984) and trimetaphan, produces rundown by a use-dependent block of the receptor activated ion channel (Gibb & Marshall, 1984). Of the drugs used in this study, tubocurarine, pancuronium and hexamethonium have all been shown to be capable ofblocking the receptor-activated ion channel at the frog neuromuscular junction, although in the cases of tubocurarine and pancuronium, only at concentrations around 10 times higher than were used in this study (Lambert et al, 1983 for review). In addition, Rang & Rylett (1984) have observed that hexamethonium blocks the acetylcholine-receptor (AChR)-activated ion channel in the rat omohyoid muscle at concentrations greater than Tubo: (n = 8) Hex: (n = 6) Atra: (n = 6) Ebtx: (n = 5) 0.4 mM.…”

Section: Discussionmentioning

confidence: 65%

Nicotinic antagonists produce differing amounts of tetanic fade in the isolated diaphragm of the rat

Gibb

Marshall

1986

1 The effects of nicotine antagonists on single twitches, trains of four twitches and tetanic contractions of the isolated diaphragm of the rat were examined. 2 Different drugs were found to produce different amounts of tetanic fade relative to depression of twitch tension. 3 The order of activity from most able, to least able to produce fade was: hexamethonium>trimeta-phan = atracurium = tubocurarine > pancuronium > erabutoxin b. 4 The effect of erabutoxin b was distinctive for its almost complete lack of tetanic fade. 5 3, 4-Diaminopyridine increased tetanic fade produced by tubocurarine, atracurium and hexamethonium, but not that produced by erabutoxin b. 6 It is concluded that nicotinic antagonists act at more than one site at the neuromuscular junction. Assuming block of the postjunctional acetylcholine receptor produces tension depression, a second or third site must be involved in producing tetanic fade. 7 The possibility that tetanic fade results from block of the ion channel associated with the postjunctional acetycholine receptor or from the block of a prejunctional nicotinic receptor is discussed.