Effects of <italic>N</italic>-n-butyl Haloperidol Iodide on Myocardial Ischemia/Reperfusion Injury and <italic>Egr-1</italic> Expression in Rat

Abstract

We have previously shown that N-n-butyl haloperidol iodide (F2) derived from haloperidol reduces ischemia/reperfusion-induced myocardial injury by blocking intracellular Ca2+ overload. This study tested the hypothesis that cardio-protection with F2 is associated with an attenuation in the expression of early growth response gene 1 (Egr-1). In an in vivo rat model of 60 min coronary occlusion followed by 180 min of reperfusion, treatment with F2 significantly reduced myocardial injury evidenced by the reduction in release of plasma creatine kinase, myocardial creatine kinase isoenzyme and lactate dehydrogenase. In cultured neonatal rat cardiomyocytes of hypoxia for 3 h and reoxygenation for 1 h, F2 treatment attenuated necrotic and apoptotic cell death, as demonstrated by electron microscopy. Concomitant with cardio-protection by F2, the increased expression levels of Egr-1 mRNA and protein were significantly reduced in myocardial tissue and cultured cardiomyocytes as detected by reverse transcription-polymerase chain reaction, immunohistochemistry and immunocytochemistry. In conclusion, these results suggest that the protective effect of F2 on ischemia/reperfusion- or hypoxia/reoxygenation-induced myocardial injury might be partly mediated by downregulating Egr-1 expression.

Haloperidol moderately inhibits cardiovascular L-type calcium current

“…In most experiments, including those reported here, the inhibition of calcium current was reversible upon washout (Fletcher et al 1994;Ito et al 1996;Huang et al 2003Huang et al , 2007. Recovery of calcium current amplitude upon washout was more effective in HEK 293 cells expressing recombinant Ca V 1.2 channels and in PC12 cells than in cardiomyocytes.…”

“…1 μmol/l of F 2 inhibited more than 70% of L-type calcium current amplitude in rat ventricular myocytes independent of the amplitude of depolarizing pulse (Huang et al 2003(Huang et al , 2007. This drug was moderately more effective calcium channel blocker than haloperidol.…”

“…This drug was moderately more effective calcium channel blocker than haloperidol. In contrast to lipophilic haloperidol used in our experiments, F 2 was designed to have low lipid solubility (Huang et al 2003). Therefore, its mode and/or site of action may differ and this difference could account for higher blocking efficiency of F 2 .…”

“…PC12 cells (Ito et al 1996). Huang et al (2003Huang et al ( , 2007 used rat cardiac myocytes in their experiments, nevertheless, instead of haloperidol they used its quaternary ammonium salt derivative with different chemical properties.…”

“…There are hints that such interaction may take place: i) haloperidol inhibited neuronal L-type calcium current in various preparations, e.g. in murine hippocampal neurons (Fletcher et al 1994) and in rat intracardiac and superior cervical ganglia neurons (Zhang and Cuevas 2002); ii) haloperidol quaternary ammonium salt N-n-butyl haloperidol iodide (F 2 ) reduced L-type calcium current in rat cardiomyocytes with an IC 50 of 1.19 μmol/l (Huang et al 2003(Huang et al , 2007. Interaction of F 2 with L-type calcium channels may differ from the effect of haloperidol itself because of the high polarity and the low lipid solubility of this synthesized compound.…”