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.
While some changes in the calcium transient during simulated ischaemia are rapidly reversible with reoxygenation (in fluorocarbon), suggesting an effect of hypoxia, others are incompletely reversed or only reversed with physiological salt solution, suggesting an effect of metabolite accumulation. The pronounced dissociation between peak light and peak active tension during reoxygenation in fluorocarbon is promptly reversed by changing to physiological salt solution, suggesting that metabolite retention in the postischaemic period may contribute to depressed myocardial function after reperfusion.
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