Interacting influence of diuretics and diet on BK channel-regulated K homeostasis.
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.
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States.
Donghai
D
Wen
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States.
Ryan J
RJ
Cornelius
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States. Electronic address: ssansom@unmc.edu.
Steven C
SC
Sansom
D000818:Animals; D004032:Diet; D004232:Diuretics / Q000494:pharmacology*; D018565:Food-Drug Interactions; D006706:Homeostasis / Q000187:drug effects; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011188:Potassium / Q000378:metabolism*
D004232:Diuretics; D051036:Large-Conductance Calcium-Activated Potassium Channels; D011188:Potassium