Acetazolamide opens the muscular KCa2+ channel: a novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis.
Acetazolamide is a thiazide derivative clinically used in skeletal muscle disorders related to altered K+ homeostasis such as the periodic paralyses. The mechanism of action responsible for the therapeutic effects of the drug is still unknown, however. In the present work, we investigated the mechanism of action of acetazolamide in the K-deficient diet rat, an animal model of human hypokalemic periodic paralysis (hypoPP). The in vivo administration of 2.8- and 5.6-mg/kg(-1)/day(-1) concentrations of acetazolamide to K-deficient diet rats prevented paralysis and depolarization of the fibers induced by insulin. In the acetazolamide-treated animals, intense sarcolemma Ca2+-activated K+ channel (KCa2+) activity was recorded. Acetazolamide also restored the serum K+ levels to control values. The concentrations of acetazolamide needed to enhance the KCa2+ current by 50% in vitro were 6.17 and 4.01x10(-6) M at -60 and +30 mV of membrane potentials, respectively. In normokalemic animals, the thiazide derivative enhanced the KCa2+ current with similar efficacy. Our data demonstrate that the therapeutic effects of acetazolamide in the K-deficient diet rats and possibly in human hypokalemic periodic paralysis patients can be mediated by activation of the KCa2+ channel.
Tricarico
D
D
Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, Italy.
Barbieri
M
M
Camerino
D C
DC
D000086:Acetazolamide / Q000627:therapeutic use*; D000818:Animals; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D020514:Hypokalemic Periodic Paralysis / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009132:Muscles / Q000187:drug effects* / Q000503:physiopathology; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000187:drug effects / Q000502:physiology
D015221:Potassium Channels; D000086:Acetazolamide