Effect of haloperidol on transient outward potassium current in rat ventricular myocytes

Abstract

Although sigma ligand haloperidol is known to affect repolarization in heart, its effect on potassium currents in cardiomyocytes has not yet been studied. We analyzed the effect of 1 μmol/l haloperidol on transient outward K⁺ current (I_to) in enzymatically isolated rat right ventricular cardiomyocytes using the whole-cell patch-clamp technique at room temperature. Haloperidol induced a decrease of amplitude and an acceleration of apparent inactivation of I_to, both in a voltage-independent manner. The averaged inhibition of I_to, evaluated as a change of its time integral, was 23.0 ± 3.2% at stimulation frequency of 0.1 Hz. As a consequence of slow recovery of I_to from the haloperidol-induced block (time constant 1482 ±783 ms), a cumulation of the block up to about 40% appeared at 3.3 Hz. We conclude that haloperidol causes a voltage-independent block of I_to that cumulates at higher stimulation frequencies. Based on the computer reconstruction of experimental data, a block of I_to-channels in both open and open-inactivated states appears to be likely mechanism of haloperidol-induced inhibition of I_to.

Introduction

Sigma receptor binding drugs, in brief sigma ligands, have adverse effects on cardiovascular system. Sigma receptors were first reported in 1976 (Martin et al., 1976) as a mere subtype of opioid receptors in the central nervous system. However, their cloning in late nineties provided the ultimate confirmation of sigma receptors as a new, structurally and functionally autonomous class of receptors (Hanner et al., 1996). The sigma receptors were found in rather high densities in many other tissues, including heart as shown for the first time in rat myocardium (Novakova et al., 1995).

Haloperidol, an antipsychotic drug usually administered in acute and chronic psychosis, is a typical representative of sigma ligands. Except of other side effects, particularly neurological, haloperidol often induces cardiovascular adverse effects including a prolongation of QT-interval and a life-threatening polymorphic ventricular tachycardia of torsades de pointes type (Hassaballa and Balk, 2003).

In electrophysiological studies, haloperidol in clinically relevant doses has been documented to prolong both the repolarization phase and the effective refractory period in dogs (Sugiyama et al., 2001, Sugiyama, 2003, Rasty et al., 2004). The prolongation of repolarization was more expressed than the prolongation of effective refractory period. This severe proarrhytmogenic state may be manifested by early afterdepolarizations and eventually by torsades de pointes.

The effect of haloperidol in concentrations between 10^− 7 and 10^− 5 mol/l on electrophysiological properties of isolated guinea-pig papillary muscle was studied by Arlock et al. (1978). They showed that haloperidol in all applied concentrations prolonged the action potential duration measured at 100% repolarization. The action potential duration at 50% repolarization (APD₅₀) was prolonged by haloperidol in concentrations up to 10^− 6 mol/l whereas concentration 10^− 5 mol/l led to APD₅₀ shortening due to a decline of the plateau phase. This decline may be related to decreased calcium current with respect to the voltage-independent block of the L-type calcium current I_Ca–L by N-n-butyl derivative of haloperidol iodide (1 μmol/l) described by Huang et al. (2003).

The prolongation of repolarization in ventricular myocardium is very likely related to an inhibition of repolarizing potassium (K⁺) currents. Several studies demonstrated a reversible block of K⁺ currents in various neural tissues (Wilke et al., 1999, Wu et al., 2000, Akamine et al., 2002). Haloperidol was reported to block the HERG (human ether a-go-go related gene)-channels, that are responsible for the rapid component of delayed rectifier current I_Kr, expressed in HEK (human embryonic kidney) 293-cells (Martin et al., 2004, Katchman et al., 2006). The Kir6.2/SUR1 channels, expressed in HEK293-cells, and the ATP-sensitive K⁺ current I_K(ATP) in the membrane of β-cells in Langerhans islets were also reported to be sensitive to haloperidol (Yang et al., 2004). Moreover, this inhibition was mediated by Kir6.2-subunit that forms pore of cardiac K_ATP-channels as well. Unfortunately, the direct effect of haloperidol on K⁺ currents in cardiomyocytes has not been studied so far.

Considering the important role of transient outward K⁺ current (I_to) in cardiac cell repolarization, we decided to focus this study on an analysis of the effect of haloperidol on I_to in rat ventricular myocytes. Based on preliminary experiments, a concentration of 1 μmol/l was selected to be near to the reported plasma concentrations (e.g. Volavka et al., 2000, Mulder et al., 2006), however, with relevant effect on I_to.