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(Circulation Research. 2006;98:549.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Neurogenic Mechanisms Contribute to Hypertension in Mice With Disruption of the K-Cl Cotransporter KCC3

Marco B. Rust^*, Jörg Faulhaber^*, Mareike K. Budack, Carsten Pfeffer, Tanja Maritzen, Michael Didié, Franz-Xaver Beck, Thomas Boettger, Rudolf Schubert, Heimo Ehmke, Thomas J. Jentsch, Christian A. Hübner

From the Zentrum für Molekulare Neurobiologie Hamburg (M.B.R., C.P., T.M., T.B., T.J.J., C.A.H.), Universität Hamburg; Institut für Vegetative Physiologie und Pathophysiologie (J.F., M.K.B., H.E.), Institut für Experimentelle und Klinische Pharmakologie (M.D.), and Institut für Humangenetik (C.A.H.), Universitätsklinikum Hamburg-Eppendorf, Hamburg; Physiologisches Institut (F.-X.B.), Ludwig-Maximilians-Universität München; and Institut für Physiologie (R.S.), Universität Rostock, Germany. Present address for T.B.: Max-Planck-Institut für Herz- und Lungenforschung, Bad Nauheim, Germany.

Correspondence to Thomas J. Jentsch, ZMNH, Universität Hamburg, Falkenried 94, D-20251 Hamburg, Germany. E-mail jentsch{at}zmnh.uni-hamburg.de

The neurodegenerative disorder Andermann syndrome is caused by mutations of the K-Cl cotransporter KCC3. Mice with a targeted disruption of the corresponding gene, Slc12a6, reproduce neurodegeneration of the peripheral and central nervous system (CNS) and display arterial hypertension. Kcc3 is expressed in numerous tissues, including the CNS and vascular smooth muscle cells. As the intracellular chloride concentration may influence myogenic tone and hence blood pressure, we measured the chloride concentration in vascular smooth muscle cells. It was indeed increased in superficial brain arteries and saphenous arteries of Kcc3^–/– mice. Isolated saphenous arteries and their third-order branches, however, reacted indistinguishably to changes in intravascular pressure, stimulation of ₁-adrenoreceptors, exogenous nitric oxide, or blockade of calcium-activated chloride channels. Likewise, the responses to ₁-adrenergic stimulation or exogenous nitric oxide in vivo were identical in both genotypes. These results argue against a major vascular-intrinsic component of arterial hypertension in Kcc3^–/– mice. In contrast, either ₁-adrenergic blockade or inhibition of ganglionic transmission abolished the difference in arterial blood pressure between both genotypes. This demonstrates a neurogenic component in the maintenance of this phenotype, which is further supported by an increase of urinary norepinephrine and epinephrine excretion in Kcc3^–/– mice. Our data indicate that local control of myogenic tone does not require KCC3 and that hypertension in Kcc3^–/– mice depends on an elevated sympathetic tone.

Key Words: K-Cl cotransport • Andermann syndrome • blood pressure • vascular tone • neurogenic hypertension

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