Effect of Sigma Ligand Haloperidol on Cardiac Excitability
| Authors | |
|---|---|
| Year of publication | 2004 |
| Type | Article in Proceedings |
| Conference | New Frontiers in Basic Cardiovascular Research |
| MU Faculty or unit | |
| Citation | |
| Field | Physiology |
| Keywords | cardiac excitability; sigma receptor; haloperidol; ionic currents; inhibition |
| 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 often reported as a consequence of this treatment. Thus, we have investigated the effects of 10 ľM haloperidol on cardiac ionic currents in two models freshly isolated rat ventricular cardiomyocytes and in HEK 293 cells with transiently expressed CaV1.2 L-type calcium channel. Gene expression of sigma receptors in both models was measured by RT-PCR. Primers were designed from sequence of sigma receptors (for rat -Genbank number 38541100, for human Genbank number 22212933) and amplified 185bp fragment in the position 499 - 684 nt. The whole cell patch-clamp method has been employed to assess the effect of haloperidol on sodium, potassium and calcium currents. In rat cardiac cells, haloperidol inhibited 95% of INa activated by 40 ms voltage pulses from 75 mV to 20 mV. The inhibition of Ito and IK,end were measured by 300 ms voltage pulses from 75 mV to +40 mV. 80% inhibition of Ito and 37% inhibition of IK,end was observed. In all cases the effect was reversible. The inactivation of Ito was accelerated in the presence of haloperidol (t = 27.35 ą 3.29 ms and 6.87 ą 2,26 ms, resp.). In HEK 293 cells, haloperidol inhibited approx. 58% of ICa amplitude measured in peak of IV relation. The effect was reversible and voltagedependent. Increasing amplitude of depolarizing pulses increased strongly extent of current inhibition. The effect of 10 umol/l haloperidol on cardiac membrane is a complex one involving massive inhibition of various ionic currents. However, further examination with lower haloperidol concentrations is needed in order to explain frequent ventricular dysrythmias in haloperidol-treated patients. |
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