Natural polymeric 3-alkylpyridinium salt affects vertebrate skeletal muscle contractility by preferentially blocking neuromuscular transmission

•nPoly-3-APS preferentially blocks the skeletal neuromuscular transmission.•nPoly-3-APS acts by a non-depolarizing mechanism.•In vivo toxicity of nPoly-3-APS mainly occurs through antagonist action on nAChRs.

The effects of natural polymeric alkylpyridinium salt (nPoly-3-APS), a potent acetylcholinesterase inhibitor isolated from the marine sponge Reniera sarai, were studied on isolated mouse phrenic nerve-hemidiaphragm muscle preparations using electrophysiological approaches. nPoly-3-APS inhibited nerve-evoked isometric muscle twitch and tetanic contraction in a concentration-dependent manner (IC50 = 29.4 μM and 18.5 μM, respectively) and produced a 30-44% decrease of directly muscle-elicited twitch and tetanus amplitudes at 54.4 μM. Additionally, nPoly-3-APS (9.1-27.2 μM) markedly decreased the amplitude of miniature endplate potentials, while their frequency was only affected at the highest concentration used. Endplate potentials were also inhibited by nPoly-3-APS in a concentration-dependent manner (IC50 = 20.1 μM), without significant change in the resting membrane potential of muscle fibers (up to 54.4 μM). In conclusion, our results show, for the first time, that nPoly-3-APS preferentially blocks the neuromuscular transmission, in vitro, by a non-depolarizing mechanism. This strongly suggests that the in vivo toxicity of nPoly-3-APS mainly occurs through an antagonist action of the compound on nicotinic acetylcholine receptors of skeletal muscles.