Induction of skeletal muscle contracture and calcium release from isolated sarcoplasmic reticulum vesicles by sanguinarine.
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. 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. 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. Sanguinarine altered [(3)H]-ryanodine binding to the RyR of isolated SR vesicles, potentiating [(3)H]-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.
Hu
C M
CM
Institute of Pharmaceutical Sciences, Taipei Medical College, Taipei, Taiwan, R.O.C.
Cheng
H W
HW
Cheng
Y W
YW
Kang
J J
JJ
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D053119:Benzophenanthridines; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D007546:Isoquinolines; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D012433:Ryanodine / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium
D000470:Alkaloids; D000890:Anti-Infective Agents; D053119:Benzophenanthridines; D007546:Isoquinolines; D014316:Tritium; D012433:Ryanodine; C005705:sanguinarine; D002118:Calcium