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• W2135160983 abstract "Azumolene is an analog of dantrolene, the only approved medicine for treatment of malignant hyperthermia (MH). The pharmacological mechanism of these drugs is to inhibit skeletal muscle sarcoplasmic reticulum (SR) Ca²⁺ release by modulating the activity of the SR ryanodine receptor (RyR) Ca²⁺ release channel. To investigate the effects of azumolene on SR Ca²⁺ channel gating within skeletal muscle fibers, we monitored Ca²⁺ sparks in permeabilized frog skeletal muscle fibers. Application of 0.0001 to 10 μM azumolene suppressed the frequency of spontaneous Ca²⁺ sparks in a dose-dependent manner (EC₅₀ = 0.25 μM; Hill coefficient = 1.44), but it did not cause systematic dose-dependent effects on the properties of the Ca²⁺ sparks. These results suggest that azumolene decreases the likelihood of Ca²⁺ release channel openings that initiate Ca²⁺ sparks, thereby decreasing spark frequency, but it has little effect on aggregate Ca²⁺ channel open times during a spark. To assess azumolene inhibition of RyRs activated in a manner analogous to those activated during an MH episode, we applied DP4, a synthetic peptide corresponding to a central region of RyR1 (Leu2442 to Pro2477), which mimics an MH modification. Azumolene also decreased Ca²⁺ spark frequency in a dose-dependent manner without altering spark properties in the DP4 MH model. We conclude that azumolene suppresses the opening rate but not the open time of RyR Ca²⁺ release channels within skeletal fibers." @default.
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• W2135160983 date "2005-04-14" @default.
• W2135160983 modified "2023-10-12" @default.
• W2135160983 title "Effects of Azumolene on Ca²⁺Sparks in Skeletal Muscle Fibers" @default.
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• W2135160983 doi "https://doi.org/10.1124/jpet.105.084046" @default.
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