Comparative effects of loratadine and terfenadine on cardiac K+ channels

Nonsedating H-1-receptor antagonists appear to have wide and variable effects on the QT interval, mediated through modulation of cardiac K+ channels, By using the whole-cell patch-clamp technique, we examined the effects of terfenadine, loratadine, and descarboethoxyloratadine on a large family of K+ channels in ventricular myocytes and in Xenopus oocytes expressing the HERG delayed rectifier. The channels studied included the inward rectifier (I-Kl) of rat and guinea pig, the transient outward K+ current (I-to) of rat, the maintained K+ current (I-ped) of rat, and the delayed rectifier K+ channels (I-Ks and I-Kr) of guinea pig myocytes. Loratadine and descarboethoxyloratadine, at therapeutic concentrations (30 to 100 nM), had no measurable effect on any one of the five types of K+ channels studied. At higher concentrations, 0.3 to 1.0 mu M, only terfenadine had a significant suppressive effect on I-Kl and delayed rectifier K+ channels, I-Kr and T-Ks. At higher concentrations (1 to 2.5 mu M), there were marked differences in the ability of the three drugs to suppress the five K+ channels, Generally, terfenadine was the most and loratadine, the least effective blocker of all K+ channels examined. The most susceptible K+ channels were the delayed rectifier channels (I-Ks and I-Kr) in guinea pig and and I-ped in rat myocytes. Comparative effects of loratadine and terfenadine examined on the I-Kr channel (HERG) expressed in Xenopus oocytes suggest much higher affinity of this channel to terfenadine, such that 1 mu M terfenadine completely suppressed the current, whereas loratadine had little or no effect. The preferential suppressive effect of terfenadine on the expressed HERC channel was consistent with data obtained on I-Kr in isolated guinea pig ventricular myocytes. The strong suppressive effect of terfenadine. noted particularly on the I-Kr and to a lesser extrnt on I-to, I-Kl, and I-Ks may be the cause of the reported incidence of QT prolongation and arrhythmogenesis. The absence of significant effect of loratadine and descarboethoxyloratadine, especially on I-Kr, I-to, I-ped, and I-Kl, even at 100 x highest plasma concentrations achieved, absence of significant reports of QT prolongation and arrhythmogenesis by the latter drugs.