Cardiac Electrophysiological and Antiarrhythmic Effects of <i>N</i>-n-butyl Haloperidol Iodide

Abstract

Aims: N-n-butyl haloperidol (F₂), a novel compound of quaternary ammonium salt derivatives of haloperidol, was reported to antagonize myocardial ischemia/reperfusion injuries. The antiarrhythmic potential and electrophysiological effects of F₂ on rat cardiac tissues were investigated. Methods and Results: In Langendorff-perfused rat hearts, the ventricular arrhythmias were induced by left anterior descending coronary artery of rat heart ligated for 20 min before the release of the ligature. F₂ provided some inhibitive effects against ischemia- and reperfusion-induced ventricular arrhythmias. In His bundle electrogram and epicardial ECG recordings, the drug produced bradycardia, delayed the conduction through the atrioventricular node and prolonged the Wenckebach cycle length and atrioventricular nodal effective refractory period. In whole-cell patch-clamp study, F₂ primarily inhibited the L-type Ca²⁺ current (I_Ca,L) (IC₅₀ = 0.17 µM) with tonic blocking properties and little use-dependence. And the drug also decreased the Na⁺ current (IC₅₀ = 77.5 µM), the transient outward K⁺ current (IC₅₀ = 20.4 µM), the steady-state outward K⁺ current (IC₅₀ = 56.2 µM) and the inward rectifier K⁺ current (IC₅₀ = 127.3 µM). Conclusion: F₂ may be a promising drug for the treatment of ischemic heart disease with cardiac arrhythmia.

<i>N</i>-n-Butyl Haloperidol Iodide Preserves Cardiomyocyte Calcium Homeostasis during Hypoxia/Ischemia

“…Calcium overload and calcium transient alterations during ischemia play causal roles in the genesis of arrhythmias [31,32]. Our results indicated that F 2 could reduce the change in calcium transients caused by hypoxia, which may be related to antiarrhythmic properties in ischemia-and reperfusioninduced arrhythmias we found previously [7]. Ca 2+ transients is considered the summation of many microscopic Ca 2+ release events triggered by one or more single Ca 2+ currents [33].…”

“…Consistent with previous findings [17,26], we confirmed the series of changes occurring in calcium tran- sients during hypoxia/ischemia, which include an increase in RT25-75 and DT75-25 of Ca 2+ transients, accompanied by the amplitude reducing and increasing of basal Ca 2+ level of calcium transients during 30-min hypoxia. Previous studies showed that F 2 is an L-type calcium channel blocker that inhibited I Ca, L in rat ventricular myocytes [7,8]. In this study on the effects of F 2 on calcium transients and related factors during hypoxia/ ischemia, we found the amplitude of calcium transients reduced during 30-min hypoxia, which could be partly inhibited by F 2 .…”

“…Whole-cell patch clamp recording of the single ventricular myocytes was as described [7]. The patch-clamp amplifier was Axopatch 200B (Axon Instruments, Foster City, CA, USA).…”

“…The pipette solution contained (in mM) CsOH 120, aspartic acid 50, NaCl 20, CaCl 2 10 (free Ca Ramp pulses were given every 10 s from the holding potential of -60 mV initially depolarizing to 30 mV and then hyperpolarizing to -150 mV and depolarizing back to -60 mV with a constant speed of 0.72 Vs -1 . The descending limb of the pulse was used to obtain the data [7,22]. First the descending limbs (from +30 to -150mV) which plotted as the I-V relationship without capacitance compensation were obtained before hypoxia; Hypoxia condition was made by perfusing the cell with 10-min hypoxia solution and the current-voltage (I-V) recorded.…”

“…F 2 played a protective role in rat heart ischemia-reperfusion injury in a dosedependent manner, which reduced the release of creatine kinase (CK), creatine kinase isoenzyme MB, lactate dehydrogenase, -hydroxybutyrate dehydrogenase and glutamic oxalic transaminase, preserved the activity of superoxide dismutase and dose-dependently decreased the malondialdehyde content [6]. F 2 also exerted antiarrhythmic properties in ischemia-and reperfusioninduced arrhythmias [7]. Its cardioprotective mechanisms might be associated with the inhibition of Ca 2+ overload by blocking the L-type calcium channels of ventricular myocytes [6,8] and suppressing the expression of early growth response 1 [9,10].…”