Terfenadine carboxylate, the major metabolite of terfenadine, does not block either HERG or Kv1.5, which agrees with the hypothesis that the buildup of parent terfenadine is the likely explanation for its cardiotoxicity. We propose that the blocking of HERG by terfenadine explains the acquired long QT syndrome. HERG is likely to be the primary target for the known cardiotoxic effects of other, related antihistamines.

Cisapride (Propulsid) is a gastrointestinal prokinetic agent commonly used to treat nocturnal heartburn as well as a variety of other gastrointestinal disorders. The use of cisapride has been associated with acquired long QT syndrome and ventricular arrhythmias such as torsades de pointes which produces sudden cardiac death. These cardiotoxic effects can be due to blockade of one or more types of K + channel currents in the human heart. For this reason we compared the effects of cisapride on two cloned human cardiac K + channels, Kvl.5 and the human ether-a-go-go-related gene (HERG) stably transfected into mammalian cells. Using patch clamp electrophysiology, we found that cisapride was a potent inhibitor of HERG displaying an IC50 value of 44.5 nmol/1 when tail currents at -40 mV were measured following a 2 s test depolarization to +20 mV. When HERG currents were measured at the end of prolonged (20 s) depolarizing steps to +20 mV, the apparent affinity of cisapride was increased and measured 6.70 nmol/1. The main effect of cisapride was to enhance the rate of HERG current decay thereby reducing current at the end of the voltage clamp pulse. Furthermore, the potency of cisapride for the HERG channel was similar to that observed for the class III antiarrhythmic agent dofetilide (IC50 = 15.3 nmol/1) and the nonsedating antihistamine terfenadine (IC 50 = 56.0 nmol/1). In contrast to its effects on HERG, cisapride inhibited Kvl.5 channel currents weakly displaying an IC50 value of 21.2 umol/l. It is concluded that cisapride displays specific, high affinity block of the human cardiac K + channel HERG. It is likely that this interaction underlies the proarrhythmic effects of the drug observed under certain clinical settings.

The use of nonsedating antihistamines may, on rare occasions, be associated with cardiac arrhythmias. This could be due to blockade of voltage-dependent K+ channels in the heart, leading to a prolongation in repolarization in the human myocardium. For this reason, we examined the effects of the nonsedating antihistamine loratadine on a rapidly activating delayed-rectifier K+ channel (Kv1.5) cloned from human heart and stably expressed in HEK 293 cells or mouse Ltk- cells. Using patch-clamp electrophysiology, we found that loratadine blocked Kv1.5 current measured from inside-out membrane patches at concentrations of > or = 100 nM, resulting in an IC50 value of 808 nM at +50 mV. The drug enhanced the rate of Kv1.5 current decay, and block was enhanced at membrane potentials near threshold relative to higher potentials. Loratadine did not alter the kinetics of Kv1.5 current activation or deactivation. Unitary Kv1.5 currents were recorded in cell-attached patches. At the single-channel level, the main effect of loratadine was to reduce the mean probability of opening of Kv1.5. This effect of loratadine was achieved by a reduced number of openings in bursts and burst duration. Finally, loratadine (10 microM) failed to inhibit HERG K+ channel currents expressed in Xenopus laevis oocytes. It is concluded that loratadine is an effective blocker of Kv1.5 that interacts with an activated state or states of the channel. This interaction suggests a potential for loratadine to alter cardiac excitability in vivo.