Studies on curare-like action of 2,2',2''-tripyridine in the mouse phrenic nerve-diaphragm

1. The curare-like action of 2,2',2''-tripyridine (a synthetic by-product of the herbicide, paraquat) was studied in mouse phrenic nerve-diaphragm preparation. The inhibition by 2,2',2''-tripyridine of nerve-evoked twitches was dependent on the concentration, ranging from 1 to 100 microM, which had no significant effect on the twitch amplitudes evoked by direct muscle stimulation. 2. The twitch inhibition by 2,2',2''-tripyridine was reversible and could be antagonized by anticholinesterase agents such as neostigmine, physostigmine as well as ecothiophate. 3. Pretreatment with either 0.7 microM (+)-tubocurarine or 2.2 microM succinylcholine shifted the concentration-inhibition curve of 2,2',2''-tripyridine to the left. 4. 2,2'2''-Tripyridine inhibited not only acetylcholine-induced contracture of the denervated mouse diaphragm but also that of the chick biventer cervicis muscle. Like (+)-tubocurarine, 2,2',2''-tripyridine protected the twitches from the inhibition by alpha-bungarotoxin and also specifically inhibited the binding of [125I]-alpha-bungarotoxin to the mouse diaphragm. All of these findings indicate that 2,2',2''-tripyridine possesses curare-like action and inhibits the muscle contractions through binding to postsynaptic acetylcholine receptors. 5. The postsynaptic inhibition exhibited by 2,2',2''-tripyridine was also implicated in the tetanic fade, a decrease in the amplitude of miniature endplate potential (m.e.p.p.) and endplate potential (e.p.p.). 6. The clinical implication of these findings is that 2,2',2''-tripyridine may be involved in the cause of respiratory failure in paraquat-intoxicated workers since 2,2',2''-tripyridine is a by-product of paraquat synthesis.