MECHANISM OF ACTION OF DANTROLENE SODIUM

Abstract

Dantrolene sodium is thought to affect some step in the excitation-contraction coupling process. Using a point voltage clamp to determine mechanical thresholds of individual fibers of frog, rat and goat skeletal muscle preparations, dantrolene was found to raise (moves to more positive potentials) the rheobasic potential and increase the steepness of the strength-duration curve for mechanical threshold. The effect of raising the rheobase reaches a maximum at 1.2 .times. 10-5 M dantrolene whereas the steepness effect occurs only at a saturating concentration (3.8 .times. 10-5 M), indicating that dantrolene has 2 sites of action. The rheobase effect was absent below 18.degree. C (suggesting a phase transition) and it was competitively antagonized by the Ca ionophore A23187 [2-[(3.beta.,9.alpha.,11.beta.-trimethyl)-8-(2-pyrrole carboxymethyl)-1,7-dioxaspiro[6.6]undecyl-2.beta.-methyl]5-methyl-aminobenzoxazole-4-carboxylic acid] which can release Ca from the sarcoplasmic reticulum. Dantrolene appears to raise the rheobase by directly decreasing the release of Ca from the sarcoplasmic reticulum. Dantrolene inhibits the movement of a natural Ca ionophore. Measurements of the voltage-dependent charge movement associated with excitation-contraction coupling showed that dantrolene did not significantly change the amount of charge moved. The time to peak of the on current was not significantly changed, but that of the off current was significantly shortened. This action of dantrolene on the kinetics of the off current may account for its effect on the steepness of the strength-duration curve.