Non-competitive effects of disopyramide at the neuromuscular junction: evidence for endplate ion channel block

The effects of disopyramide were studied at the neuromuscular junction in an attempt to elucidate the mechanism of its blocking action at this site. Disopyramide 5 X 10(-5) - 10(-3) mol litre-1 produced a concentration-dependent reduction of twitch amplitude in the indirectly stimulated chick biventer cervicis preparation, but greater concentrations were required to reduce twitches elicited directly in the presence of erabutoxin-b 1 microgram ml-1. Equieffective twitch blocking doses of either disopyramide or tubocurarine greatly reduced agonist responses to acetylcholine and carbachol, but the reduction was less for magnesium-blocked twitches. Neostigmine antagonized tubocurarine-induced, but not disopyramide-induced, blockade of twitches. Concentration-response profiles to acetylcholine and carbachol were shifted to the right in a non-parallel fashion and the maximal response was depressed by disopyramide 5 X 10(-5) - 10(-4) mol litre-1. Intracellular recording studies carried out in the cut, voltage-clamped costo-cutaneous muscle of the garter snake showed that disopyramide 5 X 10(-5) - 5 X 10(-4) mol litre-1 produced a concentration- and voltage-dependent reduction of the amplitude of neurally evoked endplate-currents (EPC) and of the time constant of decay (tau) of EPC. We conclude that disopyramide possesses a non-competitive blocking action at the neuromuscular junction, which is not reversible by anticholinesterase agents. The voltage-dependent nature of the block suggests that it is mediated via blockade of the open form of the acetylcholine-activated receptor-ion channel complex.