Publication details

Effect of Sigma Ligand Haloperidol on Transient Outward Potassium Current in Rat Cardiomyocytes

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Year of publication 2005
Type Article in Periodical
Magazine / Source Journal of Molecular and Cellular Cardiology
MU Faculty or unit

Faculty of Medicine

Field Physiology
Keywords transient outward current; rat cardiomyocytes; sigma receptors; haloperidol
Description Sigma receptor ligand haloperidol is a psychotropic drug with severe cardiovascular side effects, particularly ventricular arrhythmias including torsades de pointes. As was documented, haloperidol prolongs the repolarization phase of action potential and the effective refractory period. However, the effect of haloperidol on repolarizing potassium currents in cardiomyocytes has not been studied so far. Thus, we performed a preliminary analysis of the effect of haloperidol (1ľmol/l) on the transient outward potassium current Ito that plays a significant role in the initial phase of action potential repolarization. The experiments were performed on enzymatically isolated rat 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 Ito. The averaged inhibition of Ito evaluated as a change of its time integral was 31.0 ą 2.5 %. The inhibition as well as the acceleration of apparent inactivation of Ito did not depend on membrane voltage. The steady state inactivation curve was significantly shifted in the negative direction by 3.4 mV. The time course of recovery of Ito from inactivation in control conditions could be well fitted by a single exponential function with trec = 40.7 ą 3.3 ms. On the contrary, the application of haloperidol caused recovery with the fast time constant similar to that obtained control conditions and the slower one about 6 s. We conclude that 1ľmol/l haloperidol causes voltage-independent inhibition of Ito in rat ventricular myocytes. This inhibition is very likely caused by interaction of haloperidol with Ito-channels in open (the acceleration of apparent inactivation) and in inactivated state (the significant negative shift of voltage dependence of the steady state inactivation). The decelerated recovery of Ito from inactivation and block after application of haloperidol could cause a cumulation of inhibition at higher stimulation frequencies.
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