α-Conotoxin GI produces tetanic fade at the rat neuromuscular junction

Abstract

The ability of the marine snail toxin, α-conotoxin GI, to produce blockade of singly evoked twitches and to produce tetanic and train-of-four fade has been determined in the isolated rat hemidiaphragm preparation. Results were compared to those obtained with a reversible (vecuronium) and an irreversible (α-bungarotoxin) nicotinic acetylcholine antagonist and have been interpreted in terms of relative effects on post- and prejunctional nicotinic acetylcholine receptors at the neuromuscular junction. α-Conotoxin GI (0.5–2 μM) produced a concentration-dependent, readily reversible, decrease in the peak amplitude of single twitches and 50 Hz tetani, and an increase in tetanic and train-of-four fade. α-Conotoxin GI was consistently 2–3-fold more potent than vecuronium with respect to all of the measured tension parameters. Both α-conotoxin GI and vecuronium were approximately 2-fold more potent in producing tetanic fade and in blocking tetanic contractions than in blocking single twitches. In contrast to both α-conotoxin GI and vecuronium, α-bungarotoxin (0.13 μM) reduced the peak amplitude of both single twitches and 50 Hz tetani to the same extent without the appearance of a large degree of tetanic or train-of-four fade. Based on a comparison of the in vitro time course of neuromuscular block and of the relative effects of vecuronium, α-conotoxin GI and α-bungarotoxin on twitches, tetani and trains-of-four, we conclude that α-conotoxin GI has both pre- and postjunctional activity at the neuromuscular junction. In this respect, α-conotoxin GI resembles the clinically used competitive neuromuscular blocking drugs rather than the irreversible snake α-neurotoxins.