Acute effects of sigma receptor ligand haloperidol on isolated guinea pig heart

NOGOVÁ, Kateřina and Marie NOVÁKOVÁ. Acute effects of sigma receptor ligand haloperidol on isolated guinea pig heart. 2007.

Basic information

• Original name: Acute effects of sigma receptor ligand haloperidol on isolated guinea pig heart
• Name in Czech: Akutní účinky ligandu sigma receptorů haloperidolu u izolovaného srdce morčete
• Authors: NOGOVÁ, Kateřina and Marie NOVÁKOVÁ.
• Edition: 2007.

Other information

• Original language: English
• Type of outcome: Conference abstract
• Field of Study: 30105 Physiology
• Country of publisher: Czech Republic
• Confidentiality degree: is not subject to a state or trade secret
• Organization unit: Faculty of Medicine
• Keywords in English: guinea pig;sigma receptor;haloperidol;arrhythmias
• Tags: arrhythmias, guinea pig, haloperidol, sigma receptor
• Tags: International impact

Abstract

Sigma receptor ligand haloperidol is a psychotropic drug used in treatment of various psychiatric disorders and agitation. Mechanisms of its life-threatening cardiovascular side effects (cardiac arrhythmias such as torsade de pointes, ventricular fibrillation or even cardiac arrest) are not elucidated yet. Therefore we examined the effects of haloperidol on 3-D electrogram of isolated guinea pig hearts. Six adult male guinea pigs were sacrificed under deep ether anesthesia. The hearts were perfused according to Langendorff with Krebs-Henseleit solution (K-H) at constant pressure (85mmHg) and 37C (CaCl2, 1.2 mM). The experiment consists of four 30min periods: control, 10nM haloperidol, wash-out, 10nM haloperidol. Ten successive RR intervals were averaged at the end of control (steady state heart rate). This value was used for normalization of heart rate during the rest of experiment. The incidence of arrhythmias was evaluated according to Lambeth Conventions. Normalized spontaneous heart rate showed a clear tendency to decrease during both haloperidol applications and this effect was partially reversible. In all hearts but one, typical arrhythmias were observed during both haloperidol periods (torsade de pointes, flutter and fibrillation); the hearts were mostly classified by number 4. Since nanomolar concentration is close to binding constant of sigma receptors, we can conclude that these effects are mediated by binding of the drug to cardiac sigma receptor and not by direct effect on membrane ionic channels. However, the putative downregulation of sigma receptors (known from rat heart) has not been proven because heart rate changes as well as incidence of arrhythmias were not diminished by the second haloperidol administration.

Abstract (in Czech)

Sigma receptor ligand haloperidol is a psychotropic drug used in treatment of various psychiatric disorders and agitation. Mechanisms of its life-threatening cardiovascular side effects (cardiac arrhythmias such as torsade de pointes, ventricular fibrillation or even cardiac arrest) are not elucidated yet. Therefore we examined the effects of haloperidol on 3-D electrogram of isolated guinea pig hearts. Six adult male guinea pigs were sacrificed under deep ether anesthesia. The hearts were perfused according to Langendorff with Krebs-Henseleit solution (K-H) at constant pressure (85mmHg) and 37C (CaCl2, 1.2 mM). The experiment consists of four 30min periods: control, 10nM haloperidol, wash-out, 10nM haloperidol. Ten successive RR intervals were averaged at the end of control (steady state heart rate). This value was used for normalization of heart rate during the rest of experiment. The incidence of arrhythmias was evaluated according to Lambeth Conventions. Normalized spontaneous heart rate showed a clear tendency to decrease during both haloperidol applications and this effect was partially reversible. In all hearts but one, typical arrhythmias were observed during both haloperidol periods (torsade de pointes, flutter and fibrillation); the hearts were mostly classified by number 4. Since nanomolar concentration is close to binding constant of sigma receptors, we can conclude that these effects are mediated by binding of the drug to cardiac sigma receptor and not by direct effect on membrane ionic channels. However, the putative downregulation of sigma receptors (known from rat heart) has not been proven because heart rate changes as well as incidence of arrhythmias were not diminished by the second haloperidol administration.

Links

• GA305/04/1385, research and development project: Name: Modulační úloha sigma signalizace na elektromechanické vztahy izolovaného kardiomyocytu a srdce

Investor: Czech Science Foundation, Modulatory role of sigma signalling in electromechanical coupling of isolated cardiomyocyte and heart

• MSM0021622402, plan (intention): Name: Časná diagnostika a léčba kardiovaskulárních chorob

Investor: Ministry of Education, Youth and Sports of the CR, Early diagnostics and treatment of cardiovascular diseases