Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 28, Pages 11800-11805Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0904635106
Keywords
adrenal medulla; BK; eplerenone; mineralcorticoid; volume expansion
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Funding
- National Institutes of Diabetes and Digestive and Kidney Diseases [RO1 DK49461, RO1 DK73070]
- American Heart Association-Heartland Affiliate Fellowship [0610059Z, DK073070-03S1]
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Mice lacking the beta 1-subunit (gene, Kcnmb1; protein, BK-beta 1) of the large Ca-activated K channel (BK) are hypertensive. This phenotype is thought to result from diminished BK currents in vascular smooth muscle where BK-beta 1 is an ancillary subunit. However, the beta 1-subunit is also expressed in the renal connecting tubule (CNT), a segment of the aldosterone-sensitive distal nephron, where it associates with BK and facilitates K secretion. Because of the correlation between certain forms of hypertension and renal defects, particularly in the distal nephron, it was determined whether the hypertension of Kcnmb1(-/-) has a renal origin. We found that Kcnmb1(-/-) are hypertensive, volume expanded, and have reduced urinary K and Na clearances. These conditions are exacerbated when the animals are fed a high K diet (5% K; HK). Supplementing HK-fed Kcnmb1(-/-) with eplerenone (mineralocorticoid receptor antagonist) corrected the fluid imbalance and more than 70% of the hypertension. Finally, plasma [aldo] was elevated in Kcnmb1(-/-) under basal conditions (control diet, 0.6% K) and increased significantly more than wild type when fed the HK diet. We conclude that the majority of the hypertension of Kcnmb1(-/-) is due to aldosteronism, resulting from renal potassium retention and hyperkalemia.
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