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In the present study, the effects of 3,5-di-t-butylcatechol (DTCAT) on ryanodine receptor Ca2+ channel (RyRC) of skeletal muscle sarcoplasmic reticulum (SR) vesicles were investigated, both by monitoring extravesicular Ca2+ concentration directly with the Ca2+ indicator dye arsenazo III and by studying the high-affinity [3H]ryanodine binding. DTCAT stimulated Ca2+ release from junctional (terminal cisternae) vesicles in a concentration-dependent manner, with a threshold activating concentration of 30 μM and a pEC50 value of 3.43 ± 0.03 M. The release of Ca2+ induced by DTCAT was antagonized in a concentration-dependent manner by ruthenium red, thus indicating that RyRC is involved in the mechanism of stimulation. A structure-activity relationship analysis carried out on a limited number of compounds suggested that both hydroxy and t-butyl groups in DTCAT were important for the activation of RyRC. DTCAT inhibited [3H]ryanodine binding to SR vesicles with a Ki of 232.5 μM, thus indicating that it acted directly at the skeletal muscle ryanodine receptor binding site to stimulate Ca2+ release. In conclusion, the ability of DTCAT to release Ca2+ from TC vesicles of skeletal muscle is noteworthy in view of its possible use as an alternative compound to either caffeine or halothane for performing the “In vitro contracture test” to diagnose the susceptibility of some patients to develop malignant hyperthermia under particular pharmacological treatments.