Genetic Deficit of SK3 and IK1 Channels Disrupts the Endothelium-Derived Hyperpolarizing Factor Vasodilator Pathway and Causes Hypertension

• DOI: 10.1161/circulationaha.108.846634
• Publication Date: 2009-04-21T01:46:18Z
• Authors: Sebastian Brähler; Anuradha Kaistha; Volker J. Schmidt; Stephanie E. Wölfle; Christoph Busch; Brajesh P. Kaistha; Michael Kacik; Anna-Lena Hasenau; Ivica Grgic; Han Si; Chris T. Bond; John P. Adelman; Heike Wulff; Cor de Wit; Joachim Hoyer; Ralf Köhler
• Keywords: Dilator; Endothelium-derived hyperpolarizing factor; Hyperpolarization; Electrical impedance myography

It has been proposed that activation of endothelial SK3 (K(Ca)2.3) and IK1 (K(Ca)3.1) K+ channels plays a role in the arteriolar dilation attributed to an endothelium-derived hyperpolarizing factor (EDHF). However, our understanding precise function EDHF dilator response blood pressure control remains incomplete. To clarify roles their contribution vivo, we generated mice deficient for both channels.Expression IK1(-/-)/SK3(T/T) was characterized by patch-clamp, membrane potential measurements, myography, intravital microscopy. Blood measured conscious telemetry. Combined IK1/SK3 deficiency (+doxycycline) abolished K(Ca) currents impaired acetylcholine-induced smooth muscle hyperpolarization EDHF-mediated conduit arteries resistance arterioles vivo. had severe impact on vasodilation, whereas NO-mediated acetylcholine shear stress stimulation. As consequence, SK3/IK1-deficient exhibited elevated arterial pressure, which most prominent during physical activity. Overexpression partially restored EDHF- nitric oxide-mediated vasodilation lowered pressure. The IK1-opener SKA-31 enhanced SK3-deficient IK1(+/+)/SK3(T/T) normotensive levels.Our study demonstrates have distinct stimulus-dependent functions, are major players pathway, significantly contribute regulation. Endothelial may represent novel therapeutic targets treatment hypertension.