Induction of skeletal muscle contracture and calcium release from isolatedsarcoplasmic reticulum vesicles by sanguinarine

1 The benzophenanthrine alkaloid, sanguinarine, was studied for its effects on isolated mouse phrenic-nerve diaphragm preparations. Sanguinarine induc ed direct, dose-dependent effects on muscle contractility. 2 Sanguinarine-induced contracture was partially inhibited when the extrace llular Ca2+ was removed or when the diaphragm was pretreated with nifedipin e. Depletion of sarcoplasmic reticulum (SR) internal calcium stores complet ely blocked the contracture. 3 Sanguinarine induced Ca2+ release from the actively loaded SR vesicles wa s blocked by ruthenium red and dithiothreitol (DTT), consistent with the ry anodine receptor (RyR) as the site of sanguinarine action. 4 Sanguinarine altered [H-3]-ryanodine binding to the RyR of isolated SR ve sicles, potentiating [H-3]-ryanodine binding at lower concentrations and in hibiting binding at higher concentrations. All of these effects were revers ed by DTT, suggesting that sanguinarine-induced Ca2+ release from SR occurs through oxidation of critical SH groups of the RyR SR calcium release chan nel.