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.

Abstract

The supposed role of cardiac sigma receptors is fine tuning of contractility. Sigma receptors affect several ionic channels and hence their signaling is reflected by the electrophysiological properties of the heart. Numerous ligands of sigma receptors are known to prolong the QT interval and therefore cause a variety of arrhythmias, including severe ones. The effects of the prototypical sigma ligand haloperidol have been studied extensively in humans as well as in various animal models, primarily after acute administration. We examined the incidence of arrhythmias, changes in heart rate, and prolongation of QT interval in isolated Langendorff-perfused rat and guinea pig hearts after they were exposed to nanomolar concentrations of haloperidol. Hearts from both untreated (acute) and pretreated (chronic) animals were investigated. While QT prolongation and arrhythmias due to haloperidol administration were observed in untreated rat and guinea pig hearts, arrhythmias were completely prevented in both species of chronically treated animals. In treated guinea pigs, the results were generally less convincing. Since the hearts were exposed to nanomolar concentration of haloperidol, we conclude that our data may be explained by desensitization of sigma receptors.

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

“…However, further washout of this bolus and another bolus did not cause any consecutive change in this parameter. This pattern resembles changes in the relative mean heart rate of isolated rat hearts of animals exposed to haloperidol for three weeks (Fialova et al 2009;Novakova et al 2010).…”

“…Guinea pig represents a suitable model for studying drug effects on electrocardiogram, since guinea pig cardiac cells exhibit specific ion channels quite comparable to those of humans (Busch et al 1994). Furthermore, outcomes of our previous studies indicate that long-term exposure to haloperidol affects electrogram parameters of isolated heart in rat and guinea pig and also expression of sigma receptors in the rat heart (Fialova et al 2009;Novakova et al 2010).…”

“…Clinical aspects of acute treatment with haloperidol and its impact on cardiovascular system, primarily QT interval prolongation and associated arrhythmias, were studied repeatedly (Metzger and Friedman 1993;Hennessy et al 2002;Beach et al 2013). Effects of the acute and/or chronic exposure to haloperidol have been also studied on various biomodels and species, including rat (Fialova et al 2009), guinea pig (Testai et al 2007;Fialova et al 2009), and rabbit (Dhein et al 2008).…”

“…Haloperidol (Sigma Aldrich, USA; 2 mg/kg once a day by intraperitoneal injection) or vehiculum (13.3 ml of 2% alcohol solution per 1 kg of actual body mass) was administered for 21 consecutive days. The dose of haloperidol was chosen according to the previous studies (Inoue et al 2000;Fialova et al 2009). The proper dose of haloperidol or vehiculum was calculated daily for each animal according to its actual body mass.…”

“…This concentration was chosen in order to approximate clinical situation; free plasma levels of haloperidol in patients are usually between 10-200 nmol/l (Flanagan 1998). Throughout the entire experiment, electrogram as three orthogonal leads was continually recorded by touch-free method (Fialova et al 2009).…”