Elevated Blood Pressure Linked to Primary Hyperaldosteronism and Impaired Vasodilation in BK Channel–Deficient Mice

Abstract

Background-Abnormally elevated blood pressure is the most prevalent risk factor for cardiovascular disease. The large-conductance, voltage-and Ca 2ϩ -dependent K ϩ (BK) channel has been proposed as an important effector in the control of vascular tone by linking membrane depolarization and local increases in cytosolic Ca 2ϩ to hyperpolarizing K ϩ 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 ϩ 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 ϩ outward currents, and an attenuated cGMP vasorelaxation associated with a reduced suppression of Ca 2ϩ 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 Ϫ/Ϫ 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. 6,7 Recent studies raise the possibility that changes in ␤1 subunit expression contribute to the development of hypertension in rat 8 and that gain of function mutation in the same subunit decreases the prevalence of diastolic hypertension in humans. 9 However, even in the absence of functional ␤1 subunits, the ␣ subunit can still form functional channels, which might be activated at physiological potentials if their voltage and Ca 2ϩ sensitivity are increased by other factors such as endothelial factors 10,11 and/or phosphorylation. 12,13 Thus, functional BK channels may be operative in blood vessels even when the ␤1 subunit is lacking. In addition, BK channels in tissues other than vasculature, such as the adrenal gland, 14 may also influence blood pressure regulation. Therefore, we used mice lacking the BK channel ␣ subunit (BK Ϫ/Ϫ 15 to evaluate the global impact of BK channels on blood pressure regulation. MethodsDetails are given in the online-only Data Supplement. Mice BKϪ/Ϫ mice were generated as described. 15 Wild type (WT) and BK Ϫ/Ϫ mice with the hybrid SV129/C57BL6 background (always F2 generation) were used. Either litter-or age-matched animals were randomly assigned to the experimental procedures undertaken in accordance with the German legislation on protection of animals. Immunohistochemistry of Adrenal GlandFor immunofluorescence, on-slide 5-m cryostat slices from nonfixed WT and BK Ϫ/Ϫ adrenal glands were incubated with anti-BK␣ (674 -1115) . BK...

Distal Colonic K+ Secretion Occurs via BK Channels

“…An important finding of this study is that BK channels significantly contribute to the determination of the V te and therefore to the resting membrane potential. This is in agreement with findings in cerebellar Purkinje cells (13) and vascular smooth muscle cells (22), where altered membrane voltage in cells from BK Ϫ/Ϫ mice contributes to altered cellular functions. It might be speculated that BK channel-mediated colonic K ϩ loss contributes to the clinically important and life-threatening K ϩ wasting during severe diarrhea (3,21).…”

Hypertension of Kcnmb1 −/− is linked to deficient K secretion and aldosteronism

“…We found that the BK-␤1 subunit is expressed in the adrenal glands of mouse by PCR and western blot. The BK␣ subunit has been identified in the mouse adrenal cortex and the adrenal medulla with immunohistochemical staining (37), findings consistent with previous patch-clamp studies revealing the presence of BK currents in adrenal glomerulosa cells (25,26) and the chromaffin cells of the adrenal medulla (38).…”

Control of alternative pre-mRNA splicing by Ca++ signals

“…2B-D). These channels are important in neurotransmitter release [145], motor control [146], alcohol sensitivity [147][148][149], blood pressure and the fine-tuning of hearing frequencies [150,151]. The STREX-encoded peptide lies in the Ca ++ -sensitivity domain at the COOH-terminal [30,152].…”