Tohoku J. Exp. Med., 2015 July, 236(3)

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

TIBOR STRACINA,¹ IVA SLANINOVA,² HANA POLANSKA,³ MARTINA AXMANOVA,³ VERONIKA OLEJNICKOVA,¹ PETR KONECNY,⁴ MICHAL MASARIK,³ OLGA KRIZANOVA⁵ and MARIE NOVAKOVA^1,6

¹Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
²Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
³Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
⁴Department of Physiotherapy and Rehabilitation, Faculty of Medicine, Masaryk University, Brno, Czech Republic
⁵Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
⁶International Clinical Research Center, Animal Center, St. Anne's Faculty Hospital, Brno, Czech Republic

Haloperidol is a neuroleptic drug used for a medication of various psychoses and deliria. Its administration is frequently accompanied by cardiovascular side effects, expressed as QT interval prolongation and occurrence of even lethal arrhythmias. Despite these side effects, haloperidol is still prescribed in Europe in clinical practice. Haloperidol binds to sigma receptors that are coupled with inositol 1,4,5-trisphosphate (IP₃) receptors. Sigma receptors are expressed in various tissues, including heart muscle, and they modulate potassium channels. Together with IP₃ receptors, sigma receptors are also involved in calcium handling in various tissues. Therefore, the present work aimed to study the effects of long-term haloperidol administration on the cardiac function. Haloperidol (2 mg/kg once a day) or vehiculum was administered by intraperitoneal injection to guinea pigs for 21 consecutive days. We measured the responsiveness of the hearts isolated from the haloperidol-treated animals to additional application of haloperidol. Expression of the sigma 1 receptor and IP₃ receptors was studied by real time-PCR and immunohistochemical analyses. Haloperidol treatment caused the significant decrease in the relative heart rate and the prolongation of QT interval of the isolated hearts from the haloperidol-treated animals, compared to the hearts isolated from control animals. The expression of sigma 1 and IP₃ type 1 and type 2 receptors was increased in both atria of the haloperidol-treated animals but not in ventricles. The modulation of sigma 1 and IP₃ receptors may lead to altered calcium handling in cardiomyocytes and thus contribute to changed sensitivity of cardiac cells to arrhythmias.

keywords —— © 1 Tohoku University Medical Press

© 2015 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2015, 236, 199-207

Correspondence: Marie Novakova, Ph.D., Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.

e-mail: majka@med.muni.cz