Effects of dantrolene and its derivatives on Ca2+ release from the sarcoplasmic reticulum of mouse skeletal muscle fibres

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Abstract
We analysed the effect of dantrolene (Dan) and five newly synthesized derivatives (GIFs) on Ca2+ release from the sarcoplasmic reticulum (SR) of mouse skeletal muscle. In intact muscles, GIF‐0185 reduced the size of twitch contraction induced by electrical stimulation to the same extent as Dan. GIF‐0082, an azido‐functionalized Dan derivative, also inhibited twitch contraction, although the extent of inhibition was less than that of Dan and of GIF‐0185. In skinned fibres, Dan inhibited Ca2+‐induced Ca2+ release (CICR) under Mg2+‐free conditions at room temperature. In contrast, GIF‐0082 and GIF‐0185 showed no inhibitory effect on CICR under the same conditions. Dan‐induced inhibition of CICR was not affected by the presence of GIF‐0082, whereas it was diminished in the presence of GIF‐0185. GIF‐0082 and GIF‐0185 significantly inhibited clofibric acid (Clof)‐induced Ca2+ release, as did Dan. Several Dan derivatives other than GIF‐0082 and GIF‐0185 showed an inhibitory effect on twitch tension but not on the CICR mechanism. All of these derivatives inhibited Clof‐induced Ca2+ release. The magnitudes of inhibition of Clof‐induced Ca2+ release by all Dan derivatives were well correlated with those of twitch inhibition. This supports the notion that the mode of Clof‐induced opening of the RyR‐Ca2+ release channel may be similar to that of physiological Ca2+ release (PCR). These results indicate that the difference in opening modes of the RyR‐Ca2+ release channel is recognized by certain Dan derivatives. British Journal of Pharmacology (2001) 134, 729–736; doi:10.1038/sj.bjp.0704307