Publication details
Effects of sigma receptor ligands on membrane ionic currents of rat cardiomyocyte
| Authors | |
|---|---|
| Year of publication | 2005 |
| Type | Article in Periodical |
| Magazine / Source | Scripta medica |
| MU Faculty or unit | |
| Citation | |
| Field | Physiology |
| Keywords | sigma receptor, cardiomyocyte, rat, ionic currents |
| Description | Sigma receptors, first discovered in the central nervous system, have been later reported in various peripheral tissues including the heart muscle. They are involved in fine modulation of contractility. Sigma receptor ligand haloperidol is a psychotropic drug used in the treatment of various psychiatric disorders. Its severe cardiovascular side effects (mainly ventricular arrhythmias) have been repeatedly reported. The direct effect of this compound on membrane excitability has not been studied yet. Experiments were performed on enzymatically isolated rat ventricular cardiomyocytes by whole cell patch clamp technique at room temperature. The effects 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 were studied. Haloperidol inhibited reversibly and in concentration-dependent manner amplitudes of all tested ionic currents with 39% inhibition of INa, 39% inhibition of Ito and 14% inhibition of IK,end in the presence of 1 umol/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 umol/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 = 27.4ms in the absence and 6.9ms in the presence of 10 umol/l haloperidol). Inhibition of both other tested potassium currents IK,end and IK1 did not depend on membrane voltage as well. In conclusion, 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 potassium currents, the inhibition is voltage-independent. The acceleration of apparent Ito inactivation is a typical sign of interaction with Ito-channels in the open state. The negligible effect of haloperidol on the steady state inactivation curve of Ito implies no interaction with the channels in the inactivated state. More detailed study with lower haloperidol concentrations is necessary to explain frequent ventricular dysrythmias. |