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（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
(C) 2006 The Medical Society of Saitama Medical School