Cardiovascular adverse effects from phenothiazine drugs are common. The most serious consequences of treatment, arrhythmias and sudden death, are probably rare and most likely to be caused primarily by blockade of cardiac potassium channels such as the human ether-a-go-go-related gene (hERG) channel, which plays a central role in arrhythmogenesis. This phenomenon has been previously reported to occur with a few phenothiazine drugs. However, phenothiazine drugs are composed of pharmacologically and structurally diverse groups. The effects of many of the phenothiazine drugs on hERG channels expressed in mammalian cell lines remain unknown. Therefore, we investigated the effects of four distinct phenothiazine drugs (thioridazine, chlorpromazine, trifluoperazine, and perphenazine) on hERG channel expressed in chinese hamster ovary (CHO) cells. HERG channels were expressed in CHO cells, and ion currents were measured using the patch-clamp technique. Thioridazine, perphenazine, trifluoperazine, and chlorpromazine blocked hERG potassium channels with the following IC(50) values: IC(50) values were 224 +/- 42 nM for thioridazine, 1003 +/- 71 nM for perphenazine, 1406 +/- 124 nM for trifluoperazine, and 1561 +/- 281 nM for chloropromazine. Inhibition of hERG channels by thioridazine was characterized by significant changes in voltage dependence, the value of V(1/2), the half-maximal activation potential, and shift into negative potential, that is, the amount of block was greater at more positive potential. No significant changes were noted in other drugs.