Additive effects of ziprasidone and D,L-sotalol on the action potential in rabbit Purkinje fibres and on the hERG potassium current.
BACKGROUND
Ziprasidone, an atypical antipsychotic has been shown to be devoid of cardiac adverse effects in spite of its propensity to prolong the QT-interval via a hERG current inhibition. However, the effects of ziprasidone on the action potential (AP) parameters have not been published yet. Moreover, very little information is available concerning pharmacodynamic interactions between ziprasidone and other hERG channel blockers. Thus, we investigated the putative interaction between ziprasidone and D,L-sotalol on the hERG channels at therapeutic concentrations and their consequences on the action potential prolongation.


METHODS
AP were recorded at 1 and 0.2 Hz. Increasing concentrations of ziprasidone (0.01-10 micromol/L) were successively superfused for 30 min alone or in D,L-sotalol 10 micromol/L pre-treated fibres. Moreover, the effects of ziprasidone, alone or in association with d,l-sotalol, were investigated on the hERG current.


RESULTS
Ziprasidone (1-10 microM) induced a concentration and reverse frequency-dependent increase in APD(90) (APD(90): +27% and +36%, respectively at 1 Hz and +50% and +70%, respectively at 0.2 Hz) due to a hERG current blockade (IC50: 0.24 micromol/L). A pre-treatment with D,L-sotalol 10 micromol/L led to an increase in APD(90) of +23% at 1 Hz, stable at 66+/-4 min. In these pre-treated fibres, ziprasidone (1 and 10 micromol/L) induced an additional AP prolongation (APD(90): +16% and +18%, respectively at 1 Hz) as compared to D,L-sotalol pre-treatment. Moreover, D,L-sotalol did not interact with the pharmacological profile of ziprasidone on the hERG channel.


CONCLUSIONS
The present study demonstrates that ziprasidone induces an AP prolongation due to its propensity to block the hERG channel. Moreover, ziprasidone and d,l-sotalol, superfused concomitantly exhibit additive effects on the AP duration since they do not interact as competitors for the hERG channel.
Ducroq
Joffrey
J
Physiostim, Z.I. de Brénas, Lautrec, 81440 Lautrec, France. joffrey.ducroq@physiostim.com
Printemps
Richard
R
Le Grand
Marie
M
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D014150:Antipsychotic Agents / Q000009:adverse effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D009924:Organ Culture Techniques; D010477:Perfusion; D010879:Piperazines / Q000009:adverse effects*; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011690:Purkinje Fibers / Q000187:drug effects / Q000503:physiopathology; D011817:Rabbits; D013015:Sotalol / Q000009:adverse effects*; D013844:Thiazoles / Q000009:adverse effects*
D000889:Anti-Arrhythmia Agents; D014150:Antipsychotic Agents; D010879:Piperazines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D013844:Thiazoles; C092292:ziprasidone; D013015:Sotalol