Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+channels

• Published in: Neuromuscular disorders : NMD 2006-01, Vol.16 (1), p.39-45
• Main Authors: Tricarico, Domenico, Mele, Antonietta, Conte Camerino, Diana
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - pharmacology; Animals; Ca2+-activated-K+channels; Calcium - pharmacology; Carbonic Anhydrase Inhibitors - therapeutic use; Carbonic-anhydrase inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation - methods; Hypokalaemic periodic paralysis; Hypokalemic Periodic Paralysis - drug therapy; Hypokalemic Periodic Paralysis - etiology; Hypokalemic Periodic Paralysis - metabolism; Male; Membrane Potentials - drug effects; Membrane Potentials - physiology; Membrane Potentials - radiation effects; Muscles - drug effects; Muscles - physiopathology; Patch-Clamp Techniques - methods; Potassium Channels, Calcium-Activated - drug effects; Potassium Channels, Calcium-Activated - physiology; Potassium Deficiency - complications; Rats; Rats, Wistar; Skeletal muscle; Spectrophotometry - methods
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2005.10.005

Carbonic-anhydrase inhibitors are effective in channelopathies possibly by opening the Ca2+-activated-K+channels. However, the in vivo effects of these drugs in K+-deficient rats, the animal model of familial hypokalaemic periodic paralysis(hypokalaemic-PP), are currently unknown. Measures of insulin-responses, serum electrolytes levels and patch-clamp experiments were therefore performed in K+-deficient rats treated in vivo with dichlorphenamide (DCP), ethoxzolamide (ETX), hydrochlorthiazide (HCT), methazolamide (MTZ), bendroflumethiazide (BFT) and acetazolamide (ACTZ). Ten days treatments of K+-deficient rats with DCP, BFT, ETX and ACTZ (5.6mg/kg per day) restored the serum [K+] to control values and prevented the insulin-induced paralysis. In ex vivo experiments, the carbonic-anhydrase inhibitors enhanced the activity of Ca2+-activated-K+channels with the order of efficacy: ACTZ>BFT>ETX>DCP. In contrast, HCT and MTZ failed to stimulate the Ca2+-activated-K+channels and to prevent the hypokalaemia and paralysis. At the concentration of 1mg/kg per day, all these drugs failed to ameliorate the hypokalaemic-PP symptoms. The activation of Ca2+-activated-K+channel in addition to the mild diuretic effect explained the efficacy of ACTZ and DCP in K+-deficient rats and in familial hypokalaemic-PP.