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

Abstract

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.

Fig. 1.

Bar plots illustrating the effects of a high K diet (HK) and HK with eplerenone (HK+E) or vehicle (HK+V) on plasma K concentration (A) and K clearance (B) of WT and Kcnmb1^−/−. Values are means ± SEM. *, P < 0.05 vs. WT using unpaired t test. ‡, P < 0.05 vs. control using ANOVA plus SNK test. ¶, P < 0.05 vs., HK using ANOVA plus SNK test. Control group was fed regular mouse chow. § = *, ‡, and ¶.

Fig. 2.

Bar plots illustrating the effects of HK and HK+ E or HK+V on mean plasma Na concentration (A), and Na clearance (B) of WT and Kcnmb1^−/−. All symbols are the same as in Fig. 1.

Fig. 3.

Bar plots illustrating the effects of HK and HK+ E or HK+V on mean hematocrit (Hct.) of WT and Kcnmb1^−/−. All symbols are the same as in Fig. 1.

Fig. 4.

Mean arterial blood pressure. (A) Bar plots illustrating the effects of eplerenone (E) or vehicle (V) on mean arterial blood pressure (MAP) of WT and Kcnmb1^−/−. (B) Bar plots showing the effects of a low K diet (LK), HK and HK+ E or HK+V on MAP in WT and Kcnmb1^−/−. All symbols are the same as in Fig. 1.

Fig. 5.

Bar plots illustrating the effects of HK and HK+ E or HK+V on plasma [aldo] of WT and Kcnmb1^−/−. All symbols are the same as in Fig. 1.

Fig. 6.

RT-PCR (A) and western blot (B) determination of BK-β1 expression in mouse adrenal glands. (A) BK-β1 mRNA is expressed at the correct size (561 bp) in WT but not in Kcnmb1^−/− negative control. (B) BK-β1 protein (28 kDa) was expressed in adrenals of WT but not in Kcnmb1^−/− negative control.

Fig. 7.

Plots of the plasma [K] vs. plasma [aldo] for WT (closed circles) and Kcnmb1^−/− (open circles). The r values (correlation coefficients) were highly significant for WT (P < 0.05) and Kcnmb1^−/− (P < 0.05). The slopes of the relations for plasma K vs. aldo concentrations are 74 and 127 for WT and Kcnmb1^−/−, respectively.