1. The benzophenanthrine alkaloid, sanguinarine, was studied for its effects on isolated mouse phrenic-nerve diaphragm preparations. Sanguinarine induced direct, dose-dependent effects on muscle contractility. 2. Sanguinarine-induced contracture was partially inhibited when the extracellular Ca 2+ was removed or when the diaphragm was pretreated with nifedipine. Depletion of sarcoplasmic reticulum (SR) internal calcium stores completely blocked the contracture. 3. Sanguinarine induced Ca 2+ release from the actively loaded SR vesicles was blocked by ruthenium red and dithiothreitol (DTT), consistent with the ryanodine receptor (RyR) as the site of sanguinarine action. 4. Sanguinarine altered [ 3H]-ryanodine binding to the RyR of isolated SR vesicles, potentiating [ 3H]-ryanodine binding at lower concentrations and inhibiting binding at higher concentrations. All of these effects were reversed by DTT, suggesting that sanguinarine-induced Ca 2+ release from SR occurs through oxidation of critical SH groups of the RyR SR calcium release channel.
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