Role of BK channels in hypertension and potassium secretion

Abstract

Purpose of review To summarize recent studies of hypertension associated with a defect in renal K excretion due to genetic deletions of various components of the large, Ca-activated K channel (BK), and review new evidence and theories regarding K secretory roles of BK in intercalated cells. Recent Findings Isolated perfused tubule methods have revealed the importance of BK in flow-induced K secretion. Subsequently, mice with genetically deleted BK subunits revealed the complexities of BK-mediated K secretion. Deletion of the BKα results in extreme aldosteronism, hypertension and an absence of flow-induced K secretion. Deletion of the BKβ1 ancillary subunit results in decreased handling of a K load, increased plasma K, mild aldosteronism and hypertension that is exacerbated by a high K diet. Deletion of the BKβ4 (β4KO) leads to insufficient K handling, high plasma K, fluid retention, but with milder hypertension. Fluid retention in β4KO may be the result of insufficient flow-induced secretion of ATP, which normally inhibits epithelial Na channels (ENaC). Summary Classical physiological analysis of electrolyte handling in knock-out mice has enlightened our understanding of the mechanism of handling K loads by renal K channels. Studies have focused on the different roles of the BK-α/β1 and BK-α/β4 in the kidney. BKβ1 hypertension may be a “three-hit” hypertension, involving a K secretory defect, elevated production of aldosterone, and increased vascular tone. The disorders observed in BK knock-out mice have shed new insights on the importance of proper renal K handling for maintaining volume balance and blood pressure.

Flow-sensitive K+-coupled ATP Secretion Modulates Activity of the Epithelial Na+ Channel in the Distal Nephron

“…That blood pressure is elevated in BK-␤4 null mice is consistent with disruption of inhibitory purinergic regulation of ENaC in these animals (9,23). The current study tests these ideas.…”

“…Such inhibition is absent in BK-␤4 null mice, which lack normal BK Ca channel function in the ASDN (9,23). To exclude end-organ resistance to ATP signaling as a mechanism in these mutant mice, we tested whether ENaC in BK-␤4 null mice is responsive to exogenous ATP.…”

Cerebrovascular Dilation via Selective Targeting of the Cholane Steroid-Recognition Site in the BK Channel β1-Subunit by a Novel Nonsteroidal Agent

“…For example, KCNMB1 K/O (knockout) mice are characterized by uncoupling between vasodilating, RyR-generated Ca 21 -sparks and BK channel-generated spontaneous transient outward currents, which leads to increased myogenic tone, and systemic hypertension (Plüger et al, 2000). It should be mentioned, however, that KCNMB1 genetic ablation also results in K 1 retention and hyperaldosteronism, major contributors to the increase in blood pressure found in the KCNMB1 K/O mouse (Holtzclaw et al, 2011). Also in a mouse model, downregulation of BK b1 by NFATc3 activation contributes to systemic hypertension (Nieves-Cintrón et al, 2007).…”

Distal Convoluted Tubule

“…Both of the intracellular signals could increase the BK's open probability and thereby enhance the rate of K 1 efflux into the tubular lumen. These observations have led to an updated model for K 1 secretion in the distal nephron (Figure 8) (74,75). At baseline conditions, it has been proposed that the primary channel that mediates K 1 secretion across the DCT lumen is ROMK.…”