Effect of Sigma Ligand Haloperidol on Cardiac Excitability

NOVÁKOVÁ, Marie, Markéta BÉBAROVÁ, Michal PÁSEK, Peter MATEJOVIČ, Bohuslava TARABOVÁ, Olga KRIŽANOVÁ and Lubica LACINOVÁ. Effect of Sigma Ligand Haloperidol on Cardiac Excitability. In New Frontiers in Basic Cardiovascular Research. Montpellier, Francie: INSERM, 2004, p. 33.

Basic information

• Original name: Effect of Sigma Ligand Haloperidol on Cardiac Excitability
• Name in Czech: Účinek sigma ligandu haloperidolu na srdeční excitabilitu
• Authors: NOVÁKOVÁ, Marie (203 Czech Republic, guarantor), Markéta BÉBAROVÁ (203 Czech Republic), Michal PÁSEK (203 Czech Republic), Peter MATEJOVIČ (703 Slovakia), Bohuslava TARABOVÁ (703 Slovakia), Olga KRIŽANOVÁ (703 Slovakia) and Lubica LACINOVÁ (703 Slovakia).
• Edition: Montpellier, Francie, New Frontiers in Basic Cardiovascular Research, p. 33-33, 2004.
• Publisher: INSERM

Other information

• Original language: English
• Type of outcome: Proceedings paper
• Field of Study: 30105 Physiology
• Country of publisher: France
• Confidentiality degree: is not subject to a state or trade secret
• RIV identification code: RIV/00216224:14110/04:00011578
• Organization unit: Faculty of Medicine
• Keywords in English: cardiac excitability; sigma receptor; haloperidol; ionic currents; inhibition
• Tags: cardiac excitability, haloperidol, inhibition, ionic currents, sigma receptor

Abstract

Sigma receptor ligand haloperidol is a psychotropic drug used in the treatment of various psychiatric disorders. Severe cardiovascular side effects (mostly ventricular arrhythmias) have been often reported as a consequence of this treatment. Thus, we have investigated the effects of 10 ľM haloperidol on cardiac ionic currents in two models freshly isolated rat ventricular cardiomyocytes and in HEK 293 cells with transiently expressed CaV1.2 L-type calcium channel. Gene expression of sigma receptors in both models was measured by RT-PCR. Primers were designed from sequence of sigma receptors (for rat -Genbank number 38541100, for human Genbank number 22212933) and amplified 185bp fragment in the position 499 - 684 nt. The whole cell patch-clamp method has been employed to assess the effect of haloperidol on sodium, potassium and calcium currents. In rat cardiac cells, haloperidol inhibited 95% of INa activated by 40 ms voltage pulses from 75 mV to 20 mV. The inhibition of Ito and IK,end were measured by 300 ms voltage pulses from 75 mV to +40 mV. 80% inhibition of Ito and 37% inhibition of IK,end was observed. In all cases the effect was reversible. The inactivation of Ito was accelerated in the presence of haloperidol (t = 27.35 ą 3.29 ms and 6.87 ą 2,26 ms, resp.). In HEK 293 cells, haloperidol inhibited approx. 58% of ICa amplitude measured in peak of IV relation. The effect was reversible and voltagedependent. Increasing amplitude of depolarizing pulses increased strongly extent of current inhibition. The effect of 10 umol/l haloperidol on cardiac membrane is a complex one involving massive inhibition of various ionic currents. However, further examination with lower haloperidol concentrations is needed in order to explain frequent ventricular dysrythmias in haloperidol-treated patients.

Abstract (in Czech)

Sigma receptor ligand haloperidol je psychotropní látka užívaná v léčbě různých psychiatrických onemocnění. Byly popsány těžké vedlejší účinky na kardiovaskulární systém (hlavně komorové arythmie). zkoumali jsme účinek 10 microM haloperidolu na srdeční iontové proudy u dvou modelů -izolovaných kardiomyocytů potkana a HEK293 buněk s přechodně exprimovaným CaV1.2 L-typem kalciového kanálu. Exprese sigma receptorů v obou modelech byla měřena RT-PCR. Primery were získány ze sekvence sigma receptorů (potkan-Genbank number 38541100, lidské-Genbank number 22212933) a amplifikovány 185bp fragmentem v pozici 499 - 684 nt. Metodou whole cell patch-clamp jsme zjišťovali účinek haloperidolu na sodíková, draslíkové a kalciový proudy. V kardiomyocytech potkana haloperidol inhiboval 95% INa aktivovaného 40 ms napěťovými pulzy z 75 mV do 20 mV. Inhibice Ito a IK,end byla měřena 300 ms napěťovými pulzy z 75 mV do +40 mV. Byla pozorována 80% inhibice Ito a 37% inhibice IK,end, vždy reverzibilní. Inaktivace Ito byla haloperidolem zrychlena (t = 27.35+/-3.29 ms a 6.87+/-2,26 ms). V HEK293 buňkách haloperidol inhiboval přibližně 58% amplitudy ICa měřené na vrcholu IV křivky, reverzibilně a napěťově závisle. Zvýšení amplitudy depolarizačních pulzů silně zvýšilo stupeň inhibice. Efekt 10 microM haloperidolu na srdeční membránu je komplexní a zahrnuje mohutnou inhibici různých iontových proudů. Je třeba dalšího výzkumu s nižšími koncentracemi, aby bylo možno vysvětlit častý arytmogenní efekt haloperidolu.

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