Effect of Ethanol, Haloperidol, and Lorezepam on Cardiac Conduction and Contraction

Abstract

Haloperidol and lorazepam are commonly used to sedate ethanol (E)-intoxicated patients in emergency departments. This study was conducted to explore the role of ethanol in altering the potency of haloperidol and lorazepam with respect to cardiac conduction and contraction. For mechanical studies, isolated rat hearts were studied under isovolumetric conditions by using standard Langendorff technique. Hearts were perfused with Krebs-Heinseleit-Bicarbonate buffer containing haloperidol or lorazepam in concentrations ranging from 100 to 750 ng/ml (one heart per drug concentration). For both haloperidol and lorazepam individually, significant reductions in Left ventricular-generated pressure (LVGP) were observed at a concentration of 750 ng/ml (haloperidol = 2,250 nM and lorazepam = 2,000 nM). The addition of 20 and 65 mM ethanol shifted the concentration-response effect of haloperidol such that LVGP was significantly reduced at haloperidol = 500 and 300 ng/ml, respectively (p < 0.05 vs. basal control; paired t test). Ethanol produced no observable shift on the lorazepam concentration-response for LVGP. For electrophysiologic studies, hearts were perfused with haloperidol and lorazepam (300 ng/ml) +/- 65 mM ethanol. Compared with basal control, E + H significantly decreased heart rate (-74 +/- 12 beats/min) and increased His-ventricular conduction time (+7.6 +/- 1.5 ms vs. +1.7 +/- 0.6 ms for control hearts). Both haloperidol and EH significantly increased atrioventricular (AV) effective refractory period and the atrioventricular-His (AH) conduction interval. No significant changes in any electrophysiologic parameter were observed with ethanol or lorazepam perfused individually or with the combination of ethanol and lorazepam. Ethanol potentiates haloperidol-induced electromechanical depression of isolated rat hearts. Ethanol had no such effect on lorazepam.

Apparent desensitization of the effects of sigma receptor ligand haloperidol in isolated rat and guinea pig hearts after chronic treatmentThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research.

“…Medlin et al (1996) found that haloperidol significantly reduced the left ventricular developed pressure and heart rate, and increased the atrioventricular effective refractory period, atrioventricular-His conduction time, and His-ventricular conduction time. They were the first to use haloperidol in isolated rat hearts at nanomolar concentrations.…”

Modulation of the Negative Inotropic Effect of Haloperidol by Drugs with Positive Inotropic Effects in Isolated Rabbit Heart

“…It has been reported that in the presence of ethanol, haloperidol at 100-750 ng/ml could induce significant reduction of left ventricular generated pressure and increase His ventricular conduction time and atrioventricular refractory period [26]. In this study, the effect of haloperidol was differently modified by the drugs investigated, but the interference with haloperidol was characterized by reduction of the maximum negative inotropic effect of haloperidol without any detectable shift of the curve to the right.…”

Long-Term Haloperidol Treatment Prolongs QT Interval and Increases Expression of Sigma 1 and IP₃ Receptors in Guinea Pig Hearts

“…Haloperidol causes changes in both electrical activity and mechanical performance of the heart. Decrease in heart rate, increase in atrioventricular effective refractory period, the atrioventricular conduction time, and increase in left ventricular developed pressure in isolated rat hearts were reported (Medlin et al 1996). Approving results were shown in canine models (Sugiyama et al 2001;Rasty et al 2004).…”