Interacting influence of diuretics and diet on BK channel-regulated K homeostasis

Donghai Wen, Ryan J. Cornelius, Steven C. Sansom

Research output: Contribution to journalReview article

14 Citations (Scopus)

Abstract

Large conductance, Ca-activated K channels (BK) are abundantly located in cells of vasculature, glomerulus, and distal nephron, where they are involved in maintaining blood volume, blood pressure, and K homeostasis. In mesangial cells and smooth muscle cells of vessels, the BK-α pore associates with BK-β1 subunits and regulates contraction in a Ca-mediated feedback manner. The BK-β1 also resides in connecting tubule cells of the nephron. BK-β1 knockout mice (β1KO) exhibit fluid retention, hypertension, and compromised K handling. The BK-α/β4 resides in acid/base transporting intercalated cells (IC) of the distal nephron, where they mediate K secretion in mammals on a high K, alkaline diet. BK-α expression in IC is increased by a high K diet via aldosterone. The BK-β4 subunit and alkaline urine are necessary for the luminal expression and function of BK-α in mouse IC. In distal nephron cells, membrane BK-α expression is inhibited by WNK4 in in vitro expression systems, indicating a role in the hyperkalemic phenotype in patients with familial hyperkalemic hypertension type 2 (FHHt2). β1KO and BK-β4 knockout mice (β4KO) are hypertensive because of exaggerated epithelial Na channels (ENaC) mediated Na retention in an effort to secrete K via only renal outer medullary K channels (ROMK). BK hypertension is resistant to thiazides and furosemide, and would be more amenable to ENaC and aldosterone inhibiting drugs. Activators of BK-α/β1 or BK-α/β4 might be effective blood pressure lowering agents for a subset of hypertensive patients. Inhibitors of renal BK would effectively spare K in patients with Bartter Syndrome, a renal K wasting disease.

Original languageEnglish (US)
Pages (from-to)28-32
Number of pages5
JournalCurrent Opinion in Pharmacology
Volume15
Issue number1
DOIs
StatePublished - Apr 1 2014

Fingerprint

Large-Conductance Calcium-Activated Potassium Channels
Diuretics
Nephrons
Homeostasis
Diet
Epithelial Sodium Channels
Hypertension
Aldosterone
Kidney
Knockout Mice
Bartter Syndrome
Wasting Syndrome
Blood Pressure
Thiazides
Mesangial Cells
Furosemide
Blood Volume
Smooth Muscle Myocytes
Mammals
Cell Membrane

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Interacting influence of diuretics and diet on BK channel-regulated K homeostasis. / Wen, Donghai; Cornelius, Ryan J.; Sansom, Steven C.

In: Current Opinion in Pharmacology, Vol. 15, No. 1, 01.04.2014, p. 28-32.

Research output: Contribution to journalReview article

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