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

Abstract

1 We analysed the eect of dantrolene (Dan) and ®ve 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. -free conditions at room temperature. In contrast, GIF-0082 and GIF-0185 showed no inhibitory eect on CICR under the same conditions. 4 Dan-induced inhibition of CICR was not aected by the presence of GIF-0082, whereas it was diminished in the presence of GIF-0185. 5 GIF-0082 and GIF-0185 signi®cantly inhibited clo®bric acid (Clof)-induced Ca 2+ release, as did Dan. 6 Several Dan derivatives other than GIF-0082 and GIF-0185 showed an inhibitory eect 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 dierence in opening modes of the RyR-Ca 2+ release channel is recognized by certain Dan derivatives.

Ca2+-Releasing Effect of Cerivastatin on the Sarcoplasmic Reticulum of Mouse and Rat Skeletal Muscle Fibers

“…6c), which is an inhibitor of the RyR-Ca 2+ release channels of skeletal muscle not only in the mode of CICR, but also in another, physiological mode. In this respect, the effect of Cer in the absence of Ca 2+ is similar to that of Clof, which activates RyR in a mode similar to the physiological mode (3,25). However, while adenine nucleotide (AMP) showed an inhibitory effect on Clof-induced Ca 2+ release, it showed an enhancing effect on Cerinduced Ca 2+ release, even at pCa >8.…”

Dantrolene-Induced Inhibition of Skeletal L-Type Ca2+Current Requires RyR1 Expression

“…A body of evidence points to a mechanism in which Dantrolene interferes with orthograde signaling by inhibiting Ca 2+ release from the SR. This view is based largely on the observations that radiolabelled Dantrolene binds to RyR1 directly [28, 29] and inhibits RyR1-mediated Ca 2+ efflux from SR vesicles [30, 31]. However, other investigators have found little effect of Dantrolene on the single channel properties of RyR1 in reconstituted lipid bilayers [18, 25].…”

Role of Ca2+ in injury-induced changes in sodium current in rat skeletal muscle

“…4C, P Ͻ 0.01 at 20 min, n ϭ 12). This argues against ryanodine receptor-mediated release from the sarcoplasmic reticulum as the source of the increase in intracellular Ca 2ϩ (19,21,38). This suggests the intracellular Ca 2ϩ store contributing to the global increase in intracellular Ca 2ϩ following impalement-induced injury is mitochondrial Ca 2ϩ .…”