著者
Kazuho Sakamoto Junko Kimura
出版者
(公社)日本薬理学会
雑誌
Journal of Pharmacological Sciences (ISSN:13478613)
巻号頁・発行日
vol.123, no.4, pp.289-294, 2013-12-20 (Released:2013-12-19)
参考文献数
30
被引用文献数
10 36

Statins, a group of drugs used for the treatment of hypercholesterolemia, have adverse effects on skeletal muscle. The symptoms of these effects range from slight myalgia to severe rhabdomyolysis. The number of patients currently taking statins is estimated to be several millions worldwide. However, the mechanism of statins’ myotoxic effects is unclear. Statins inhibit biosynthesis of mevalonate, a rate-limiting step of cholesterol synthesis, by inhibiting HMG-CoA reductase. Mevalonate is also an essential precursor for producing isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate. These isoprenoids are especially important for anchoring small GTPases to the membrane before they function; e.g., Ras GTPases modulate proliferation and apoptosis, Rho GTPases control cytoskeleton formation, and Rab GTPases are essential for intracellular vesicle trafficking. Inactivation of these small GTPases alters cellular functions. Recently, we successfully reproduced statin-induced myotoxicity in culture dishes using in vitro skeletal muscle systems (e.g., skeletal myotubes and myofibers). This review summarizes our findings that statins induce depletion of isoprenoids and inactivation of small GTPases, especially Rab, which are critical for statin-induced myotoxicity. Although further study is required, our findings may contribute to the prevention and treatment of statins’ adverse effects on skeletal muscle and development of safer anti-hypercholesterolemia drugs.
著者
HIROSHI OGATA MIDORI YATABE SHINGEN MISAKA YAYOI SHIKAMA SUGURU SATO MITSURU MUNAKATA JUNKO KIMURA
出版者
福島医学会
雑誌
FUKUSHIMA JOURNAL OF MEDICAL SCIENCE (ISSN:00162590)
巻号頁・発行日
vol.59, no.1, pp.43-48, 2013 (Released:2013-07-10)
参考文献数
25
被引用文献数
1

We previously reported a case of pulmonary hypertension, where the symptoms were improved by oral L-arginine (arginine) administration. Arginine may increase nitric oxide (NO) production in the pulmonary artery. Exhaled NO may reflect pulmonary artery NO production. It has been demonstrated that exhaled NO concentration is higher in patients with allergic diseases, but whether oral arginine administration alters exhaled NO is unknown. Therefore, in this study, we investigated whether oral arginine administration increases exhaled NO among healthy volunteers with and without a history of allergy.Eleven subjects were given a single oral dose (200 mg/kg) of arginine, and their plasma arginine concentrations and exhaled NO were measured up to 150 minutes. Baseline values of exhaled NO concentration were significantly higher in those with a history of allergy (56.4±20.3 ppb, n=5, P< 0.05) than those without (16.8±4.0 ppb, n=6). Oral arginine increased exhaled NO, which peaked at 60 minutes after the administration in those with a history of allergy (85.2±44.8 ppb, n=5). However, the increase in exhaled NO was not significant compared to the baseline values. In contrast, plasma arginine concentration was increased significantly by arginine administration (P< 0.01), regardless of an allergy history. These results suggested that the difference in exhaled NO concentration was not due to a difference in arginine absorption.Serum IgE level was significantly higher in the group with a history of allergy. Eosinophils and white blood cells were within normal range in all subjects. We conclude that oral arginine administration does not significantly increase exhaled NO, regardless of allergy history. However, as arginine administration has been reported to be effective in patients with pulmonary hypertension, it will be necessary to test exhaled NO in subjects with pulmonary hypertension in the future.