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Olanzapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current.
J Psychopharmacol. 2007 Sep; 21(7):735-41.JP

Abstract

Prolongation of the QT interval has been observed during treatment with olanzapine, a thienobenzodiazepine antipsychotic agent. Our objectives were 1) to characterize the effects of olanzapine on cardiac repolarization and 2) to evaluate effects of olanzapine on the major time-dependent outward potassium current involved in cardiac repolarization, namely I(Kr) (I(Kr): rapid component of the delayed rectifier potassium current).Isolated, buffer-perfused guinea pig hearts (n = 40) were stimulated at different pacing cycle lengths (150-250 msec) and exposed to olanzapine at concentrations ranging from 1 to 100 microM. Olanzapine increased monophasic action potential duration measured at 90% repolarization (MAPD90) in a concentration-dependent manner by 6.7 +/- 0.7 msec at 3 microM but by 26.0 +/- 4.3 msec at 100 microM (250 msec cycle length). Increase in MAPD(90) was also reverse frequency dependent; 30 microM olanzapine increased MAPD90 by 28.0 +/- 6.2 msec at a pacing cycle length of 250 msec but by only 18.9 +/- 2.2 msec at a pacing cycle length of 150 msec. Experiments in HERG-transfected (HERG: human ether-a-gogo-related gene) HEK293 cells (n = 36) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: tail current was decreased 50% at olanzapine 3.8 microM. Olanzapine possesses direct cardiac electrophysiological effects similar to those of class III anti-arrhythmic drugs. These effects were observed at concentrations that can be measured in patients under conditions of impaired drug elimination such as renal or hepatic insufficiency, during co-administration of other CYP1A2 substrates/inhibitors or after drug overdose. These results offer a new potential explanation for QT prolonging effects observed during olanzapine treatment in patients.

Authors+Show Affiliations

Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17092964

Citation

Morissette, Pierre, et al. "Olanzapine Prolongs Cardiac Repolarization By Blocking the Rapid Component of the Delayed Rectifier Potassium Current." Journal of Psychopharmacology (Oxford, England), vol. 21, no. 7, 2007, pp. 735-41.
Morissette P, Hreiche R, Mallet L, et al. Olanzapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. J Psychopharmacol (Oxford). 2007;21(7):735-41.
Morissette, P., Hreiche, R., Mallet, L., Vo, D., Knaus, E. E., & Turgeon, J. (2007). Olanzapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. Journal of Psychopharmacology (Oxford, England), 21(7), 735-41.
Morissette P, et al. Olanzapine Prolongs Cardiac Repolarization By Blocking the Rapid Component of the Delayed Rectifier Potassium Current. J Psychopharmacol (Oxford). 2007;21(7):735-41. PubMed PMID: 17092964.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Olanzapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. AU - Morissette,Pierre, AU - Hreiche,Raymond, AU - Mallet,Louise, AU - Vo,Dean, AU - Knaus,Edward E, AU - Turgeon,Jacques, Y1 - 2006/11/08/ PY - 2006/11/10/pubmed PY - 2008/2/19/medline PY - 2006/11/10/entrez SP - 735 EP - 41 JF - Journal of psychopharmacology (Oxford, England) JO - J. Psychopharmacol. (Oxford) VL - 21 IS - 7 N2 - Prolongation of the QT interval has been observed during treatment with olanzapine, a thienobenzodiazepine antipsychotic agent. Our objectives were 1) to characterize the effects of olanzapine on cardiac repolarization and 2) to evaluate effects of olanzapine on the major time-dependent outward potassium current involved in cardiac repolarization, namely I(Kr) (I(Kr): rapid component of the delayed rectifier potassium current).Isolated, buffer-perfused guinea pig hearts (n = 40) were stimulated at different pacing cycle lengths (150-250 msec) and exposed to olanzapine at concentrations ranging from 1 to 100 microM. Olanzapine increased monophasic action potential duration measured at 90% repolarization (MAPD90) in a concentration-dependent manner by 6.7 +/- 0.7 msec at 3 microM but by 26.0 +/- 4.3 msec at 100 microM (250 msec cycle length). Increase in MAPD(90) was also reverse frequency dependent; 30 microM olanzapine increased MAPD90 by 28.0 +/- 6.2 msec at a pacing cycle length of 250 msec but by only 18.9 +/- 2.2 msec at a pacing cycle length of 150 msec. Experiments in HERG-transfected (HERG: human ether-a-gogo-related gene) HEK293 cells (n = 36) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: tail current was decreased 50% at olanzapine 3.8 microM. Olanzapine possesses direct cardiac electrophysiological effects similar to those of class III anti-arrhythmic drugs. These effects were observed at concentrations that can be measured in patients under conditions of impaired drug elimination such as renal or hepatic insufficiency, during co-administration of other CYP1A2 substrates/inhibitors or after drug overdose. These results offer a new potential explanation for QT prolonging effects observed during olanzapine treatment in patients. SN - 0269-8811 UR - https://www.unboundmedicine.com/medline/citation/17092964/Olanzapine_prolongs_cardiac_repolarization_by_blocking_the_rapid_component_of_the_delayed_rectifier_potassium_current_ L2 - http://journals.sagepub.com/doi/full/10.1177/0269881106072669?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -