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Thesis
マウスおよびラットの骨格筋筋小胞体に対するセリバスタチンのCa²⁺放出作用

井上　亮拓
埼玉医科大学薬理学教室
（指導：丸山　敬 教授）

医学博士　乙第1022号　平成18年4月28日 （埼玉医科大学）

Ca²⁺-Releasing Effect of Cerivastatin on the Sarcoplasmic Reticulum of Mouse and Rat Skeletal Muscle Fibers
Ryotaku Inoue (Department of Pharmacology, Saitama Medical University, Moroyama, Iruma-gun, Saitama 350-0495, Japan)

　Ryanodine receptors (RyRs) play an important role as intracellular Ca²⁺-release channels in a wide variety of cells. Previously, our group reported that clofibric acid, an antihyperlipidemic agent, caused Ca²⁺ release from the sarcoplasmic reticulum (SR) in a unique mode of action on RyR-Ca²⁺ release channels in skinned skeletal muscle fibers. On the other hand, it was reported that simvastatin, a different type of antihyperlipidemic agent, increased the cytoplasmic Ca²⁺ concentration via the release of stored Ca²⁺ in L6 rat myoblasts and resulted in cell injury, although the exact mechanism is still debated. These results raise the possibility that both types of antihyperlipidemic agent may have a common ability to activate the RyR-Ca²⁺ release channel.
　In this study, the effect of cerivastatin (Cer), classified as an HMG-CoA reductase inhibitor as is simvastatin, on Ca²⁺ release from the SR was analyzed using chemically skinned skeletal muscle fibers from the mouse and the rat. The Ca²⁺ released from the SR of the skinned fibers was quantified using Fura-2, and the activity of Ca²⁺ release was expressed in terms of decay rate constants, based on the amount of Ca²⁺ remaining in the SR. Cer (>20 μM) released Ca²⁺ from the SR, while pravastatin showed only a little effect. The rates of Ca²⁺ release were increased by Cer not only at pCa 7-4.5 but also at pCa >8. Cer-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 Cer at pCa 6.0 to a much grater extent than with ryanodine alone. Thus, Cer-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 under the condition that CICR was maximally inhibited by Mg²⁺ and procaine, or in the practical absence of Ca²⁺ (pCa >8), Cer still caused Ca²⁺ release. These results indicate that Cer 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.
Keywords: Calcium release, cerivastatin, ryanodine receptor, sarcoplasmic reticulum, skeletal muscle