Olanzapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current

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 mu M. Olanzapine increased monophasic action potential duration measured at 90% repolarization (MAPD(90)) in a concentration-dependent manner by 6.7 +/- 0.7 msec at 3 mu M but by 26.0 +/- 4.3 msec at 10 mu M (250 msec cycle length). Increase in MAPD(90) was also reverse frequency dependent; 30 mu M olanzapine increased MAPD(90) 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 mu M. Olanzapine possesses direct cardiac etectrophysiological 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.