title: Non-competitive effects of disopyramide at the neuromuscular junction: evidence for endplate ion channel block.
abstract: 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.
mesh_terms: D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002645:Chickens; D004206:Disopyramide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009045:Motor Endplate / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009388:Neostigmine / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D014403:Tubocurarine / Q000494:pharmacology
chemical_list: D007473:Ion Channels; D009388:Neostigmine; D002217:Carbachol; D004206:Disopyramide; D008274:Magnesium; D014403:Tubocurarine