Bendroflumethiazide a potent opener of human BK channel : a new perspective for an old drug in the treatment of periodic paralysis

Abstract

Carbonic‐anhydrase inhibitors and related drugs are used in the neuromuscular diseases but their effects on human Ca2+activated‐ K+‐(BK) channels are not known. The effects of acetazolamide(ACTZ), dichlorphenamide(DCP), methazolamide(MTZ), bendroflumethiazide(BFT), ethoxzolamide(ETX) and hydrochlorthiazide(HCT) on the human BK channel alpha‐subunit(hslo) expressed in HEK293 cells were investigated using patch‐clamp technique. The data were compared with that of NS1619, quercetin(QUERC) and resveratrol(RESV). We showed that the hslo whole‐cell current was potentiated by all drugs in the range of concentration tested(10−11–10−3M) with different potency and efficacy, with the exception of HCT. The ranking of the openers at −60 mV(Vm) was BFT(EC50=1.1±3×10− 9M)>; ACTZ(EC50=1.21±2×10−7M) >;DCP(EC50=4.3±1×10−7M) ≥RESV(EC50=5.5±1×10−7M)≥ ETX(EC50=7.1±0.1×10−7M)>; NS1619(EC50=5.5±1×10−5M)>; MTZ(EC50=1.17±1×10−4M)≥ QUERC(EC50=1.5±0.1×10−4M). We found that BFT and ACTZ were the most potent drugs at −60 mV(Vm). Patch depolarization potentiated the drugs action. The observed ACTZ and DCP actions on hslo channel at −60 mV(Vm) at sub‐micromolar concentrations explain their use in hypokalemic‐PP. BFT may be used in the hyperkalemic‐PP. This work is supported by Telethon Grants.