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This Article Full Text Full Text (PDF) All Versions of this Article: 92/6/1067    most recent expphysiol.2007.038166v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hercule, H. C. Articles by Gollasch, M. Search for Related Content PubMed PubMed Citation Articles by Hercule, H. C. Articles by Gollasch, M.

¹ Nephrology/Hypertension Division, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Campus Buch, Berlin, Germany ² Medical Faculty of the Charité, Nephrology/Intensive Care Division, Campus Virchow, Berlin, Germany ³ Max Delbrück Center for Molecular Medicine, Campus Buch, Berlin, Germany ⁴ Department of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA ⁵ Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Tübingen, Tübingen, Germany

17,18-Epoxyeicosatetraenoic acid (17,18-EETeTr) stimulates vascular large-conductance K⁺ (BK) channels. BK channels are composed of the pore-forming BK and auxiliary BK β1 subunits that confer an increased sensitivity for changes in membrane potential and calcium to BK channels. Ryanodine-sensitive calcium-release channels (RyR3) in the sarcoplasmic reticulum (SR) control the process. To elucidate the mechanism of BK channel activation, we performed whole-cell and perforated-patch clamp experiments in freshly isolated cerebral and mesenteric artery vascular smooth muscle cells (VSMC) from Sprague–Dawley rats, BK β1 gene-deficient (–/–), BK (–/–), RyR3 (–/–) and wild-type mice. The 17,18-EETeTr (100 nM) increased tetraethylammonium (1 mM)-sensitive outward K⁺ currents in VSMC from wild-type rats and wild-type mice. The effects were not inhibited by the epoxyeicosatrienoic acid (EET) antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (10 µM). BK channel currents were increased 3.5-fold in VSMC from BK β1 (–/–) mice, whereas a 2.9-fold stimulation was observed in VSMC from RyR3 (–/–) mice (at membrane voltage 60 mV). The effects were similar compared with those observed in cells from wild-type mice. The BK current increase was neither influenced by strong internal calcium buffering (Ca²⁺, 100 nM), nor by external calcium influx. The 17,18-EETeTr did not induce outward currents in VSMC BK (–/–) cells. We next tested the vasodilator effects of 17,18-EETeTr on isolated arteries of BK -deficient mice. Vasodilatation was largely inhibited in cerebral and mesenteric arteries isolated from BK (–/–) mice compared with that observed in wild-type and BK β1 (–/–) arteries. We conclude that 17,18-EETeTr represents an endogenous BK channel agonist and vasodilator. Since 17,18-EETeTr is active in small arteries lacking BK β1, the data further suggest that BK represents the molecular target for the principal action of 17,18-EETeTr. Finally, the action of 17,18-EETeTr is not mediated by changes of the internal global calcium concentration or local SR calcium release events.

(Received 18 April 2007; accepted after revision 20 July 2007; first published online 3 August 2007)
Corresponding author M. Gollasch: Charité University Medicine, Nephrology and Intensive Care, Augustenburger Platz 1, 13353 Berlin, Germany. Email: maik.gollasch{at}charite.de