title: Long-Term Haloperidol Treatment Prolongs QT Interval and Increases Expression of Sigma 1 and IP3 Receptors in Guinea Pig Hearts.
abstract: 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.
authors.affiliation: Department of Physiology, Faculty of Medicine, Masaryk University.
authors.forename: Tibor
authors.initials: T
authors.lastname: Stracina
authors.forename: Iva
authors.initials: I
authors.lastname: Slaninova
authors.forename: Hana
authors.initials: H
authors.lastname: Polanska
authors.forename: Martina
authors.initials: M
authors.lastname: Axmanova
authors.forename: Veronika
authors.initials: V
authors.lastname: Olejnickova
authors.forename: Petr
authors.initials: P
authors.lastname: Konecny
authors.forename: Michal
authors.initials: M
authors.lastname: Masarik
authors.forename: Olga
authors.initials: O
authors.lastname: Krizanova
authors.forename: Marie
authors.initials: M
authors.lastname: Novakova
mesh_terms: D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006168:Guinea Pigs; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology*; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects*; D007150:Immunohistochemistry; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D017480:Receptors, sigma / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097605:Sigma-1 Receptor
chemical_list: D018076:DNA, Complementary; D006220:Haloperidol; D053496:Inositol 1,4,5-Trisphosphate Receptors; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor