Elevated blood pressure linked to primary hyperaldosteronism and impaired vasodilation in BK channel-deficient mice.

TY - JOUR

T1 - Elevated blood pressure linked to primary hyperaldosteronism and impaired vasodilation in BK channel-deficient mice.

AU - Sausbier, Matthias

AU - Arntz, Claudia

AU - Bucurenciu, Iancu

AU - Zhao, Hong

AU - Zhou, Xiao-Bo

AU - Sausbier, Ulrike

AU - Feil, Susanne

AU - Kamm, Simone

AU - Essin, Kyrill

AU - Sailer, Claudia A

AU - Abdullah, Usamah

AU - Krippeit-Drews, Peter

AU - Feil, Robert

AU - Hofmann, Franz

AU - Knaus, Hans-Günther

AU - Kenyon, Chris

AU - Shipston, Michael J

AU - Storm, Johan F

AU - Neuhuber, Winfried

AU - Korth, Michael

AU - Schubert, Rudolf

AU - Gollasch, Maik

AU - Ruth, Peter

PY - 2005

Y1 - 2005

N2 - 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 alpha 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.

AB - 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 alpha 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.

M3 - SCORING: Zeitschriftenaufsatz

VL - 112

SP - 60

EP - 68

JO - CIRCULATION

JF - CIRCULATION

SN - 0009-7322

IS - 1

M1 - 1

ER -