Dantrolene Sodium Can Increase or Attenuate Activity of Skeletal Muscle Ryanodine Receptor Calcium Release Channel: Clinical Implications

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BackgroundDantrolene sodium (DS) is a direct-acting skeletal muscle relaxant whose only known action is to block calcium release from intracellular storage sites. The exact site of action for DS is unknown, but its efficacy in treating and preventing anesthetic-induced malignant hyperthermia (MH) is well established.MethodsSingle ryanodine (Ry1) receptor calcium release channels were incorporated into a planar lipid bilayer for electrophysiologic recording and for subsequent analysis of the channel's gating and conductance properties. The cellular effects of low DS concentrations were investigated by isometric contracture tension responses in biopsied MH human and dog muscle fascicles and in normal, single fibers from human vastus lateralis muscle.ResultsTwo concentration-dependent DS effects on the isolated Ry sub 1 receptor were discovered, suggesting at least two different binding sites. At nanomolar concentrations, DS activated the channel by causing three- to fivefold increases in open-state probability and dwell times. At micromolar concentrations, DS first increased then reduced activity in the channels; with the dominant effect being reduced activity. A 20 nM concentration of DS produced significant contracture tension in human muscle from one MH subject and caused potentiation of twitch in muscle from another MH patient. Halothane contracture in MH dog muscle was followed by an additional increase in tension when treated with 20 nM DS. Other investigations on chemically skinned, human fibers showed that calcium loaded in the sarcoplasmic reticulum was partially released by nM DS.ConclusionsThe study results suggest that at least two binding sites for DS exist on the Ry1 receptor calcium channel. A low-affinity (micro Meter) site is associated with reduced channel gating and open-state dwell time and may relate to the established pharmacologic muscle relaxant effect of DS. The proposed high-affinity (nM) DS binding site activates the channel, producing Calcium2+ release to the myoplasm, which, under environmentally adverse conditions, could damage genetically predisposed MH muscle. Such a phenomenon, if it occurs in DS-treated MH patients, could generate a recrudescence of the syndrome.

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