Testosterone-mediated modulation of HERG blockade by proarrhythmic agents

Diverse drugs from many therapeutic classes exert cardiotoxic side effects by inducing torsades de pointes (TdP), a life threatening cardiac arrhythmi a, which often results from drug interaction with HERG (human ether-a-go-go related gene) encoded K+ channels, that generate an I-Kr component of the delayed rectifier cardiac K+ current. Men are known to be at a lower risk f or drug-induced TdP than women suggesting a role of sex steroid hormones, a ndrogens and estrogens, in modulation of drug sensitivity of cardiac K+ cha nnels, particularly those encoded by HERG. Here by using neuroleptic agents haloperidol, pimozide, and fluspirilene, all of which can induce TdP, and a steroid hormone-sensitive system Xenopus oocytes for HERG channels expres sion we show that testosterone is able to reduce HERG-blocking potency of n euroleptics. Haloperidol, pimozide, and fluspirilene inhibited HERG current with IC50 of 1.36, 1.74, and 2.34 muM, and maximal block of 73%, 76% and 6 5%, respectively. The action of these neuroleptics was voltage-dependent, m ost consistent with an open-channel blocking mechanism. Pretreatment of HER G-expressing oocytes with 1 muM testosterone increased the IC50 values to 2 .73, 2.08, and 5.04 muM, reduced the maximal block to 65%, 59%, and 64%, an d strongly diminished voltage-dependence of the blockade. Testosterone trea tment per se produced about a 35% reduction of HERG current compared with u ntreated oocytes. Our data suggest that androgens may protect against the a rrhythmogenic actions of some cardiotoxic drugs. (C) 2001 Elsevier Science Inc. All rights reserved.