Ca^<2+>-Releasing Effect of Ceriastatin on the Sarcoplasmic Reticulum of Mouse and Rat Skeletal Muscle Fibers

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We analyzed the effect of HMG-CoA reductase inhibitors on Ca2+ release from the sarcoplasmic reticulum (SR) using chemically skinned skeletal muscle fibers from the mouse and the rat. Cerivastatin (>20 μM) released Ca2+ from the SR, while pravastatin showed only a little effect. The rates of Ca2+ release were increased by cerivastatin at all Ca2+ concentrations tested. Cerivastatin-induced Ca2+ release in the presence of Ca2+ was affected by adenosine monophosphate, Mg2+, and procaine in essentially the same way as for caffeine-induced Ca2+ release. The Ca2+-uptake capacity of the SR was reduced after co-treatment with ryanodine and cerivastatin at pCa 6.0 to a much greater extent than with ryanodine alone. Thus, cerivastatin-induced Ca2+ release in the presence of Ca2+ must be a result of the activation of the Ca2+-induced Ca2+ release (CICR) mechanism of the ryanodine receptor. However, even when CICR was maximally inhibited by Mg2+ and procaine, or in the practical absence of Ca2+ (pCa >8), cerivastatin still caused Ca2+ release. These results indicate that cerivastatin causes Ca2+ release also by activating some other mechanism(s) in addition to the activation of CICR. Either or both of these effects might be related to its adverse effect, rhabdomyolysis.
社団法人日本薬理学会の論文
2003-11-01