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Cerivastatin Activates Endothelial Calcium–Activated Potassium Channels and Thereby Modulates Endothelial Nitric Oxide Production and Cell Proliferation

Christoph Rüdiger Wolfram Kuhlmann^*, Christine Gast^*, Fang Li^*, Matthias Schäfer, Harald Tillmanns^*, Bernd Waldecker^* and Johannes Wiecha

*Department of Cardiology and Angiology, Justus-Liebig-University of Giessen, Giessen, Germany; Department of Physiology, Justus-Liebig-University of Giessen, Giessen, Germany; and Department of Internal Medicine, Hospital Bad Orb, Bad Orb, Germany

Corrspondence to Dr. Christoph Rüdiger Wolfram Kuhlmann, Department of Cardiology and Angiology, Justus-Liebig-University of Giessen, Klinikstrasse 36, 35 392 Giessen, Germany. Phone: 0049-641-99-47266; Fax: 0049-641-99-47219; E-mail: Chr_Kuhlmann{at}yahoo.de

ABSTRACT. Statins are known to counteract the process of arteriosclerosis by exerting direct pleiotropic effects on vascular endothelium. The aim of this study was to investigate a possible effect of cerivastatin on endothelial Ca²⁺-activated K⁺ channels (BK_Ca) and to assess their contribution to cerivastatin-mediated changes of endothelial nitric oxide (NO) production and proliferation. Membrane potential was measured using bis-1,3-dibutylbarbituric acid-trimethine oxonol–fluorescence imaging. Patch-clamp recordings of BK_Ca were performed on cultured human umbilical vein endothelial cells. NO production was measured using 4,5-diaminofluorescein–fluorescence imaging and a [³H]cGMP RIA. Proliferation was analyzed by means of cell counts and [³H]thymidine incorporation (TI). Cerivastatin (0.001 to 0.05 µmol/L) caused a significant membrane hyperpolarization (n = 30; P < 0.05). This effect was abolished using the BK_Ca inhibitor iberiotoxin (IBX; 100 nmol/L). The addition of mevalonate (500 µmol/L) blocked the BK_Ca activation induced by cerivastatin (n = 19; P < 0.05). Endothelial cGMP level was increased by acetylcholine (ACh; 1 µmol/L). The combination of ACh and cerivastatin additionally increased cGMP levels, with a maximum at 0.03 µmol/L cerivastatin (84%; n = 10, P < 0.01). ACh-induced increase of cGMP-level was significantly reduced by IBX (n = 10, P < 0.01) as it was with all combined administrations of ACh and cerivastatin. 4,5-Diaminofluorescein–fluorescence measurements revealed a significant increase of NO levels by cerivastatin, which was abolished by IBX (n = 30; P < 0.05). Cell counts and TI demonstrated significant inhibition of human umbilical vein endothelial cell proliferation with a maximum at 0.03 µmol/L (cell count, -32.2%; TI, -70%; n = 12; P < 0.01). These data show that cerivastatin activates endothelial BK_Ca, which plays an important role in the signaling of cerivastatin-mediated endothelial NO production and proliferation.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673