title: Cerivastatin activates endothelial calcium-activated potassium channels and thereby modulates endothelial nitric oxide production and cell proliferation.
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 Ca(2+)-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 [(3)H]cGMP RIA. Proliferation was analyzed by means of cell counts and [(3)H]thymidine incorporation (TI). Cerivastatin (0.001 to 0.05 micromol/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 micromol/L) blocked the BK(Ca) activation induced by cerivastatin (n = 19; P < 0.05). Endothelial cGMP level was increased by acetylcholine (ACh; 1 micromol/L). The combination of ACh and cerivastatin additionally increased cGMP levels, with a maximum at 0.03 micromol/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 micro mol/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.
authors.affiliation: Department of Cardiology and Angiology, Justus-Liebig-University of Giessen, Klinikstrasse 36, 35-392 Giessen, Germany. Chr_Kuhlmann@yahoo.de
authors.forename: Christoph Rüdiger Wolfram
authors.initials: CR
authors.lastname: Kuhlmann
authors.forename: Christine
authors.initials: C
authors.lastname: Gast
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Matthias
authors.initials: M
authors.lastname: Schäfer
authors.forename: Harald
authors.initials: H
authors.lastname: Tillmanns
authors.forename: Bernd
authors.initials: B
authors.lastname: Waldecker
authors.forename: Johannes
authors.initials: J
authors.lastname: Wiecha
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004727:Endothelium / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D024681:Potassium Channels, Calcium-Activated; D011725:Pyridines; D009569:Nitric Oxide; C086276:cerivastatin