Inhibition by simvastatin, but not pravastatin, of glucose‐induced cytosolic Ca<sup>2+</sup> signalling and insulin secretion due to blockade of L‐type Ca<sup>2+</sup> channels in rat islet β‐cells
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<jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>Hypercholesterolaemia often occurs in patients with type 2 diabetes, who therefore encounter administration of HMG‐CoA reductase inhibitors. Alteration of pancreatic β‐cell function leading to an impaired insulin secretory response to glucose plays a crucial role in the pathogenesis of type 2 diabetes. Therefore, it is important to examine the effects of HMG‐CoA reductase inhibitors on β‐cell function.</jats:p></jats:list-item> <jats:list-item><jats:p>Cytosolic Ca<jats:sup>2+</jats:sup> concentration ([Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>) plays a central role in the regulation of β‐cell function. The present study examined the effects of HMG‐CoA reductase inhibitors on the glucose‐induced [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> signalling and insulin secretion in rat islet β‐cells.</jats:p></jats:list-item> <jats:list-item><jats:p>Simvastatin, a lipophilic HMG‐CoA reductase inhibitor, at 0.1–3 μg ml<jats:sup>−1</jats:sup> concentration‐dependently inhibited the first phase increase and oscillation of [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> induced by 8.3 m<jats:sc>M</jats:sc> glucose in single β‐cells. The less lipophilic inhibitor, simvastatin‐acid, inhibited the first phase [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> increase but was two orders of magnitude less potent. The hydrophilic inhibitor, pravastatin (100 μg ml<jats:sup>−1</jats:sup>), was without effect on [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>.</jats:p></jats:list-item> <jats:list-item><jats:p>Simvastatin (0.3 μg ml<jats:sup>−1</jats:sup>), more potently than simvastatin‐acid (30 μg ml<jats:sup>−1</jats:sup>), inhibited glucose‐induced insulin secretion from islets, whereas pravastatin (100 μg ml<jats:sup>−1</jats:sup>) had no effect.</jats:p></jats:list-item> <jats:list-item><jats:p>Whole‐cell patch clamp recordings demonstrated a reversible inhibition of the β‐cell L‐type Ca<jats:sup>2+</jats:sup> channels by simvastatin, but not by pravastatin. Simvastatin also inhibited the [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> increases by <jats:sc>L</jats:sc>‐arginine and KCl, agents that act <jats:italic>via</jats:italic> opening of L‐type Ca<jats:sup>2+</jats:sup> channels.</jats:p></jats:list-item> <jats:list-item><jats:p>In conclusion, lipophilic HMG‐CoA reductase inhibitors can inhibit glucose‐induced [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> signalling and insulin secretion by blocking L‐type Ca<jats:sup>2+</jats:sup> channels in β‐cells, and their inhibitory potencies parallel their lipophilicities. Precaution should be paid to these findings when HMG‐CoA reductase inhibitors are used clinically, particularly in patients with type 2 diabetes.</jats:p></jats:list-item> </jats:list> </jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (1999) <jats:bold>126</jats:bold>, 1205–1213; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0702397">10.1038/sj.bjp.0702397</jats:ext-link></jats:p>
収録刊行物
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- British Journal of Pharmacology
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British Journal of Pharmacology 126 (5), 1205-1213, 1999-03
Wiley
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詳細情報 詳細情報について
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- CRID
- 1360855569005861504
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- NII論文ID
- 80010939323
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- NII書誌ID
- AA00574810
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- ISSN
- 14765381
- 00071188
- http://id.crossref.org/issn/00071188
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