Trazodone has been associated with prolonged QT-interval and increased risk of polymorphous ventricular tachycardias clinically and has demonstrated in vitro inhibition of hERG (human ether-á-go-go-related gene) channel current. This study attempts to put the effects of trazodone into perspective by comparing its hERG inhibition to that of three agents known to inhibit I(Kr), and comparing the effects of trazodone and cisapride on action potential duration and the QT-interval in the rabbit Langendorff heart preparation. Trazodone inhibited hERG channel current in a concentration-dependent manner with an IC50 of 0.69 microM. Like astemizole, terfenadine and cisapride, trazodone inhibits hERG channel current at clinically relevant concentrations. Like cisapride, trazodone increased both the QT-interval and APD90 in the Langendorff heart preparation in a reverse frequency-dependent manner at clinically relevant concentrations. These data strongly suggest that trazodone prolongs the QT-interval through inhibition of hERG channel current.