Model-based analysis of the effects of thioridazine enantiomers on the rabbit papillary action potential
Research output: Chapter in Book/Report/Conference proceeding › Article in proceedings › Research › peer-review
Aims: We investigated mechanisms underlying the effects of the thioridazine enantiomers on the rabbit papillary action potential duration (AP, APD). Methods: An adapted computational model of the rabbit ventricular action potential was used to carry out a model-based analysis of transmembrane AP recordings from isolated right ventricular papillary muscles from 21 rabbits in four groups: control, (-)-thioridazine, (+)thioridazine, and racemate. Drug effects were determined using an inverse method and a forward method. Effects were modeled by inhibition of the IKr and ICaL currents. Results: Simultaneous inhibition of IKr and ICaL resulted in a more accurate description of the observed drug effects than could IKr inhibition alone. The following values of IKr inhibition at 10 mg L-1 were determined. Forward method: Racemate = 45%, (-)-thioridazine = 0%, and (+)-thioridazine = 85%. Inverse method: (-)thioridazine = 35%, (+)-thioridazine = 80%. Conclusion: Ikr inhibition accurately described the observed APD prolongation, and the identified levels of IKr inhibition were plausible when compared to literature. Both methods found (-)-thioridazine to cause less IKr inhibition than (+ )-thioridazine or the racemate. These results indicate that the prolonging effects observed in the experiment may be related to IKr inhibition.
Original language | English |
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Title of host publication | Computing in Cardiology Conference 2015, CinC 2015 |
Editors | Alan Murray |
Number of pages | 4 |
Publisher | IEEE Computer Society Press |
Publication date | 16 Feb 2015 |
Pages | 1089-1092 |
Article number | 7411104 |
ISBN (Electronic) | 9781509006854 |
DOIs | |
Publication status | Published - 16 Feb 2015 |
Externally published | Yes |
Event | 42nd Computing in Cardiology Conference, CinC 2015 - Nice, France Duration: 6 Sep 2015 → 9 Sep 2015 |
Conference
Conference | 42nd Computing in Cardiology Conference, CinC 2015 |
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Land | France |
By | Nice |
Periode | 06/09/2015 → 09/09/2015 |
Sponsor | CNRS Advancing the Frontiers, et al., IBM, Mortara, Physological Measurement, Universite Nice Sophia Antipolis |
Series | Computing in Cardiology |
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Volume | 42 |
ISSN | 2325-8861 |
ID: 261046493