The inhibitory efficiency of the muscle-relaxing drug dantrolene (1.5-7.5 x 10(-5) M) decreases when the stimulus frequency to the muscle increases. The mechanism of action of this effect, as well as of the inhibitory effect of the drug, has previously not been fully elucidated. The present experiments showed that a 50 Hz tetanus had to be applied to the rat diaphragm preparation to obtain a slow but complete reversal of the inhibitory effect of dantrolene. Higher frequencies (100 and 200 Hz) caused a more rapid reversal. EMG records at 20 Hz disclosed an effect which paralleled the effect on the tension records. The hypothesis that the frequency-dependent antagonistic effect might be related to the K+ efflux during tetanic activity and/or to the Ca2+ control of the responsible K+ channels was tested by varying the bath concentrations of K+ and Ca2+ and by addition of drugs known to interfere with the fluxes of K+ (tetraethylammonium and 4-aminopyridine) and Ca2+ (nifedipine). Evidence was obtained that the inhibitory effect of dantrolene, as well as its frequency-dependent antagonism, were related to the Ca2+-dependent K+ currents.
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