Excitation-contraction uncoupling in the rat diaphragm by 2,3-butanedione monoxime

2,3-Butanedione monoxime (BDM), 0.5-12.5 mM, inhibited the twitches rapidly and reversibly in the rat diaphragm. A more extensive inhibition at direct than at indirect stimulation, a simultaneous effect on the electromyogram, and an attenuation of the inhibitory effect in preparations made hyperexcitable with Ca(2+)-free solution, myotonia or veratridine, indicated an interference with the gating mechanism of the sarcolemma. The excitation-contraction uncoupling with BDM was additive to the similar effect of dantrolene. A synergistic effect was not found, and neither agent alone nor both in combination caused a complete excitation-contraction uncoupling. Several differences between the effects of BDM and dantrolene were disclosed: Lowering the temperature increased and decreased the effect of BDM and dantrolene, respectively. Tetanic stimulation and high Ca2+ or high K+ antagonized the effect of dantrolene and did not affect the BDM-induced inhibition. Ca(2+)-free solution potentiated the effect of dantrolene and antagonized the effect of BDM. Caffeine and KCl contractures were inhibited by BDM, whereas the propranolol contracture due to Na,K-ATPase inhibition, which is completely inhibited by dantrolene, was unaffected by BDM.