Effect of sigma receptor ligand haloperidol on cardiac excitability

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Authors

NOVÁKOVÁ Marie BÉBAROVÁ Markéta PÁSEK Michal MATEJOVIČ Peter TARABOVÁ Bohuslava LACINOVÁ Lubica

Year of publication 2005
Type Article in Periodical
Magazine / Source Physiological Research
MU Faculty or unit

Faculty of Medicine

Citation
Field Physiology
Keywords sigma receptor; haloperidol; cardiac excitability
Description Sigma receptor ligand haloperidol is a psychotropic drug used in the treatment of various psychiatric disorders. Severe cardiovascular side effects (mostly ventricular arrhythmias) have been reported. Thus, we have investigated the effects of haloperidol on the sodium current INa and potassium currents, the transient outward current Ito, the current at the end of 250ms-impulse IK,end (that is mainly composed of the delayed rectifier current IK) and the inward rectifier current IK1. Experiments were performed on enzymatically isolated rat ventricular cardiomyocytes by whole cell patch clamp technique at room temperature. Haloperidol inhibited reversibly and in concentration-dependent manner amplitudes of all tested ion currents with 39% inhibition of INa, 39% inhibition of Ito and 14% inhibition of IK,end in the presence of 1 ľmol/l and 95% inhibition of INa, 80% inhibition of Ito, 37% inhibition of IK,end and 29 % inhibition of IK1 in the presence of 10 ľmol/l haloperidol. Inhibition of Ito was voltage-independent, with a small (-1.4 mV; P<0.05) hyperpolarizing shift of the steady state inactivation curve. The apparent inactivation of Ito was accelerated in the presence of haloperidol (t = 27.4 ą 3.3 ms in the absence and 6.9 ą 2.3 ms in the presence of 10 ľmol/l haloperidol). Inhibition of both other tested potassium currents IK,end and IK1 did not depend on membrane voltage as well. We conclude that haloperidol causes reversible and concentration-dependent inhibition of sodium and potassium membrane currents in rat ventricular cardiomyocytes with the highest effectivity on INa and Ito. In the case of potassium currents, the inhibition was voltage-independent. The observed acceleration of apparent inactivation of Ito after aplication of haloperidol is a typical sign of interaction with Ito-channels in the open state. Simultaneously, the negligible effect of haloperidol on the steady state inactivation curve of Ito implies no interaction with the channels in the inactivated state. However, further examination with lower haloperidol concentrations is needed in order to explain frequent ventricular dysrythmias in haloperidol-treated patients.
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