Effects of dantrolene and its derivatives on Ca(2+) release from the sarcoplasmic reticulum of mouse skeletal muscle fibres.
1. We analysed the effect of dantrolene (Dan) and five newly synthesized derivatives (GIFs) on Ca(2+) release from the sarcoplasmic reticulum (SR) of mouse skeletal muscle. 2. 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. 3. In skinned fibres, Dan inhibited Ca(2+)-induced Ca(2+) release (CICR) under Mg(2+)-free conditions at room temperature. In contrast, GIF-0082 and GIF-0185 showed no inhibitory effect on CICR under the same conditions. 4. Dan-induced inhibition of CICR was not affected by the presence of GIF-0082, whereas it was diminished in the presence of GIF-0185. 5. GIF-0082 and GIF-0185 significantly inhibited clofibric acid (Clof)-induced Ca(2+) release, as did Dan. 6. 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 Ca(2+) release. 7. The magnitudes of inhibition of Clof-induced Ca(2+) 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-Ca(2+) release channel may be similar to that of physiological Ca(2+) release (PCR). 8. These results indicate that the difference in opening modes of the RyR-Ca(2+) release channel is recognized by certain Dan derivatives.
Ikemoto
T
T
Department of Pharmacology, Saitama Medical School, Moroyama-machi, Saitama 350-0495, Japan. tikemoto@saitama-med.ac.jp
Hosoya
T
T
Aoyama
H
H
Kihara
Y
Y
Suzuki
M
M
Endo
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002995:Clofibric Acid / Q000494:pharmacology; D003620:Dantrolene / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism
C441780:GIF 0082; C441781:GIF 0185; D009125:Muscle Relaxants, Central; D002995:Clofibric Acid; D003620:Dantrolene; D002118:Calcium