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Vol. 288, Issue 3, 1261-1268, March 1999
Quebec Heart Institute, Laval Hospital and Faculties of Pharmacy
and Medicine, Laval University, Sainte-Foy, Quebec, Canada
Proarrhythmia has been observed with the antipsychotic agent
thioridazine (THIO). The mechanisms underlying these effects are
unknown. The objectives of this study were 1) to characterize the
effects of THIO on cardiac repolarization and 2) to determine whether
lengthening of the Q-T interval could be explained by blocking major
K+-repolarizing currents. Isolated, buffer-perfused guinea
pig hearts (n = 32) were stimulated at various
pacing cycle lengths (150-250 ms) and exposed to THIO at
concentrations ranging from 300 nM to 3 µM. THIO increased monophasic
action potential duration at 90% repolarization (MAPD90)
in a concentration-dependent manner from 14.9 ± 1.8 at 300 nM to
37.1 ± 3.2 ms at 3 µM. Increase in MAPD90 was also
reverse frequency-dependent; THIO (300 nM) increased MAPD90
by 14.9 ± 1.8 ms at a pacing cycle length of 250 ms, but by only
7.7 ± 1.2 ms at a pacing cycle length of 150 ms. Patch-clamp experiments demonstrated that THIO decreases the time-dependent outward
K+ current elicited by short depolarizations (250 ms;
IK250) in a concentration-dependent manner. Estimated
IC50 for IK250, which mostly underlies
IKr, was 1.25 µM. Time-dependent outward K+
current elicited in tsA201 cells expressing high levels of HERG protein
was also decreased approximately 50% by 1.25 µM THIO. On the other
hand, THIO was less potent (IC50 of 14 µM) to decrease time-dependent K+ current elicited by long pulses (5000 ms;
IK5000). Under the latter conditions, IK5000
corresponds mainly to IKs. Thus, these results demonstrate
block of K+ currents and lengthening of cardiac
repolarization by THIO in a concentration-dependent manner. This may
provide an explanation of Q-T prolongation observed in some patients
treated with THIO.
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