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(Circulation Research. 2006;99:537.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Impaired Endothelium-Derived Hyperpolarizing Factor-Mediated Dilations and Increased Blood Pressure in Mice Deficient of the Intermediate-Conductance Ca²⁺-Activated K⁺ Channel

Han Si^*, Willm-Thomas Heyken^*, Stephanie E. Wölfle, Marcin Tysiac, Rudolf Schubert, Ivica Grgic, Larisa Vilianovich, Günter Giebing, Tanja Maier, Volkmar Gross, Michael Bader, Cor de Wit, Joachim Hoyer, Ralf Köhler

From the Department of Internal Medicine-Nephrology (H.S., W.-T.H., M.T., I.G., G.G., T.M., J.H., R.K.), Philipps-University, Marburg; Department of Physiology (S.E.W., C.d.W.), University of Lübeck; Institute of Physiology (R.S.), University of Rostock; and Max-Delbrück-Centrum for Molecular Medicine (L.V., V.G., M.B.), Berlin-Buch, Germany.

Correspondence to R. Köhler, Department of Nephrology, Philipps-University, Baldingerstrasse, 35033 Marburg, Germany. E-mail rkoehler{at}med.uni-marburg.de

The endothelium plays a key role in the control of vascular tone and alteration in endothelial cell function contributes to several cardiovascular disease states. Endothelium-dependent dilation is mediated by NO, prostacyclin, and an endothelium-derived hyperpolarizing factor (EDHF). EDHF signaling is thought to be initiated by activation of endothelial Ca²⁺-activated K⁺ channels (K_Ca), leading to hyperpolarization of the endothelium and subsequently to hyperpolarization and relaxation of vascular smooth muscle. In the present study, we tested the functional role of the endothelial intermediate-conductance K_Ca (IK_Ca/K_Ca3.1) in endothelial hyperpolarization, in EDHF-mediated dilation, and in the control of arterial pressure by targeted deletion of K_Ca3.1. K_Ca3.1-deficient mice (K_Ca3.1^–/–) were generated by conventional gene-targeting strategies. Endothelial K_Ca currents and EDHF-mediated dilations were characterized by patch-clamp analysis, myography and intravital microscopy. Disruption of the K_Ca3.1 gene abolished endothelial K_Ca3.1 currents and significantly diminished overall current through K_Ca channels. As a consequence, endothelial and smooth muscle hyperpolarization in response to acetylcholine was reduced in K_Ca3.1^–/– mice. Acetylcholine-induced dilations were impaired in the carotid artery and in resistance vessels because of a substantial reduction of EDHF-mediated dilation in K_Ca3.1^–/– mice. Moreover, the loss of K_Ca3.1 led to a significant increase in arterial blood pressure and to mild left ventricular hypertrophy. These results indicate that the endothelial K_Ca3.1 is a fundamental determinant of endothelial hyperpolarization and EDHF signaling and, thereby, a crucial determinant in the control of vascular tone and overall circulatory regulation.

Key Words: hypertension • endothelium • EDHF • intermediate-conductance Ca²⁺-activated K⁺ channel • K_Ca3.1^–/– mice

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