Published online before print May 2, 2005, doi: 10.1161/01.CIR.0000156448.74296.FE
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(Circulation. 2005;112:60-68.)
© 2005 American Heart Association, Inc.
Hypertension |
Elevated Blood Pressure Linked to Primary Hyperaldosteronism and Impaired Vasodilation in BK Channel–Deficient Mice
From Pharmakologie und Toxikologie, Pharmazeutisches Institut der Universität Tübingen, Tübingen, Germany (M.S., C.A., I.B., H.Z., U.S., U.A., P.K.-D., P.R.); Institut für Pharmakologie für Pharmazeuten, Universitätsklinikum Hamburg-Eppendorf, Hamburg-Eppendorf, Germany (X.Z., M.K.); Institut für Pharmakologie und Toxikologie der Technischen Universität München, München, Germany (S.F., S.K., R.F., F.H.); Helios Franz-Volhard-Klinik, Med Klinik für Nephrologie und Intensivmedizin, MDC für Molekulare Medizin, Humboldt Universität Berlin, Berlin, Germany (K.E., M.G.); Institut für Biochemische Pharmakologie, Universität Innsbruck, Innsbruck, Austria (C.A.S., H.K.); Endocrinology Unit, School of Molecular and Clinical Medicine, Molecular Medicine Centre, Western General Hospital, Edinburgh, Scotland (C.K.); Membrane Biology Group, Division of Biomedical Science, University of Edinburgh, Edinburgh, Scotland (M.J.S.); Department of Physiology and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway (J.F.S.); Anatomisches Institut, Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany (W.N.); and Institut für Physiologie der Universität Rostock, Rostock, Germany (R.S.).
Correspondence to Dr Peter Ruth, Pharmakologie und Toxikologie, Pharmazeutisches Institut der Universität Tübingen, Tübingen, Germany. E-mail peter.ruth{at}uni-tuebingen.de
Received August 4, 2004; revision received October 12, 2004; accepted October 25, 2004.
Background— Abnormally elevated blood pressure is the most prevalent risk factor for cardiovascular disease. The large-conductance, voltage- and Ca2+-dependent K+ (BK) channel has been proposed as an important effector in the control of vascular tone by linking membrane depolarization and local increases in cytosolic Ca2+ to hyperpolarizing K+ outward currents. However, the BK channel may also affect blood pressure by regulating salt and fluid homeostasis, particularly by adjusting the renin-angiotensin-aldosterone system.
Methods and Results— Here we report that deletion of the pore-forming BK channel 
subunit leads to a significant blood pressure elevation resulting from hyperaldosteronism accompanied by decreased serum K+ levels as well as increased vascular tone in small arteries. In smooth muscle from small arteries, deletion of the BK channel leads to a depolarized membrane potential, a complete lack of membrane hyperpolarizing spontaneous K+ outward currents, and an attenuated cGMP vasorelaxation associated with a reduced suppression of Ca2+ transients by cGMP. The high level of BK channel expression observed in wild-type adrenal glomerulosa cells, together with unaltered serum renin activities and corticotropin levels in mutant mice, suggests that the hyperaldosteronism results from abnormal adrenal cortical function in BK–/– mice.
Conclusions— These results identify previously unknown roles of BK channels in blood pressure regulation and raise the possibility that BK channel dysfunction may underlie specific forms of hyperaldosteronism.
Key Words: blood pressure • ion channels • vasoconstriction • vasodilation • hyperaldosteronism
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