The repolarisation phase of cardiac action potential is characterized by sexual dimorphism suggesting the role of sex steroid hormones in the regulation of K+ channels. Here we report on the effect of testosterone on blockade of HERG-encoded K+ channels induced by neuroleptics. These compounds are used in clinics to treat psychiatric disorders, but reportedly have proarrhythmic side effects, on HERG-encoded K+ channels responsible for the rapid component of cardiac delayed rectifier K+ current, IKr. HERG was expressed in Xenopus oocytes, HERG-expressing oocytes were preincubated in 1 microM of testosterone from 3 to 8 hours before experiments. The extent of the blockade by neuroleptics in control oocytes increased with depolarization correlating with channels activation consistent with open-channel blocking mechanism. The IC50 and A (maximal block) values for the haloperidol-, pimozide- and fluspirilen-induced blockade of fully activated IKr were 1.36 microM and 73%, 1.74 microM and 76%, 2.34 microM and 65% respectively. Testosterone decreased extent of maximal block and significantly diminished block voltage-dependance of IKr inhibition, it also decreased the efficiency of block, with IC50 and A values of 2.73 microM and 65%, 2.08 microM and 59%, 5.04 microM and 64% for haloperidol, pimozide and fluspirilen respectively. Testosterone treatment increased IC50 and decreased A for all three agents. The largest decrease in A was with pimozide and the largest increase in IC50 was with fluspirilen. Our results suggest protective role of testosterone (androgens) against proarrhythmic side effects of some compounds.