Hypertension of Kcnmb1-/- is linked to deficient K secretion and aldosteronism.
Mice lacking the beta1-subunit (gene, Kcnmb1; protein, BK-beta1) 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-beta1 is an ancillary subunit. However, the beta1-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.
Grimm
P Richard
PR
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Irsik
Debra L
DL
Settles
Deann C
DC
Holtzclaw
J David
JD
Sansom
Steven C
SC
D000704:Analysis of Variance; D000818:Animals; D000077545:Eplerenone; D006929:Hyperaldosteronism / Q000150:complications* / Q000209:etiology; D006947:Hyperkalemia / Q000150:complications*; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011188:Potassium / Q000378:metabolism*; D013148:Spironolactone / Q000031:analogs & derivatives
C543091:Kcnmb1 protein, mouse; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D013148:Spironolactone; D000077545:Eplerenone; D011188:Potassium