Ask Schou Jensen

Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle

The antipsychotic drug thioridazine has potential for treatment of multidrug-resistant microbes including tuberculosis but also causes cardiotoxic QT interval prolongation. Both thioridazine enantiomers have potent antimicrobial effects, but the neuroleptic effect primarily resides with (+)-thioridazine. In this study we for the first time investigate the cardiotoxicity of the isolated thioridazine enantiomers and show their effects on ventricular repolarization. The effects of (+)-thioridazine, (-)-thioridazine, and racemate on the rabbit ventricular action potential duration (APD) were investigated in a randomized controlled blinded experiment. Action potentials were measured in papillary muscles isolated from 21 female rabbits, and the drug effect on 90% APD in comparison with control (ΔΔ-APD90) was evaluated. Increasing concentrations of (+)-thioridazine and the racemate caused significant dose-dependent ΔΔ-APD90 prolongation, while (-)-thioridazine did not. At 0.5 and 2Hz pacing, (+)-thioridazine caused 19.5% and 20.1% ΔΔ-APD90 prolongation, the racemate caused 8.0% and 12.9%, and (-)-thioridazine caused 1.5% and 1.1%. The effect of (-)-thioridazine on APD90 was significantly less than that of the other drugs at both pacing rates (P<0.01 in all cases), and there was no significant difference between (-)-thioridazine and control. The results of this study indicate that the APD prolonging effect of thioridazine is primarily due to the (+)-thioridazine enantiomer. If these results are valid in humans, (-)-thioridazine may be a safer drug for treatment of multidrug-resistant tuberculosis and other microbes.

Adaptation of rabbit ventricular cell model to reproduce action potentials in isolated papillary muscle

Aims: We sought to establish a computational model of the rabbit ventricular action potential (AP) suitable for investigation of drug effects on the AP of the isolated rabbit papillary muscle. Methods: Data consisted of transmembrane AP recordings from isolated right ventricular papillary muscles from 21 rabbits. An existing model of the rabbit ventricular AP was adapted to reproduce experimental AP amplitude and AP duration (APD90, APD60, APD30,) at multiple pacing rates by reduction of fast sodium current and overall depolarizing current. The resulting model was validated. Results: At 2.0 and 0.5 Hz pacing respectively, the experimentally recorded APD90 was 113.9±11.2 ms and 150.2±13.1 ms. The adapted model produced an APD90 of 130.5 ms and 142.5 ms. Validation of the adapted model showed that, while there was a substantial adaptation of the model APD to experimental data, model stability was maintained, and internal Ca dynamics and responses to stimuli were not substantially affected. Conclusion: A model of the rabbit ventricular AP was adapted in order to reproduce experimental AP recordings from the isolated right ventricular rabbit papillary muscle. This model is useful for analysis of drug effects on the rabbit papillary AP.

Definition of Fiducial Points in the Normal Seismocardiogram

The purpose of this work is to define fiducial points in the seismocardiogram (SCG) and to correlate them with physiological events identified in ultrasound images. For 45 healthy subjects the SCG and the electrocardiogram (ECG) were recorded simultaneously at rest. Immediately following the SCG and ECG recordings ultrasound images of the heart were also obtained at rest. For all subjects a mean SCG signal was calculated and all fiducial points (peaks and valleys) were identified and labeled in the same way across all signals. Eight physiologic events, including the valve openings and closings, were annotated from ultrasound as well and the fiducial points were correlated with those physiologic events. A total of 42 SCG signals were used in the data analysis. The smallest mean differences (±SD) between the eight events found in the ultrasound images and the fiducial points, together with their correlation coefficients (r) were: atrial systolic onset: −2 (±16) ms, r = 0.75 (p < 0.001); peak atrial inflow: 13 (±19) ms, r = 0.63 (p < 0.001); mitral valve closure: 4 (±11) ms, r = 0.71 (p < 0.01); aortic valve opening: −3 (±11) ms, r = 0.60 (p < 0.001); peak systolic inflow: 13 (±23) ms, r = 0.42 (p < 0.01); aortic valve closure: −5 (±12) ms, r = 0.94 (p < 0.001); mitral valve opening: −7 (±19) ms, r = 0.87 (p < 0.001) and peak early ventricular filling: −18 (±28 ms), r = 0.79 (p < 0.001). In conclusion eight physiologic events characterizeing the cardiac cycle, are associated with reproducible, well-defined fiducial points in the SCG.

Model-based analysis of the effects of thioridazine enantiomers on the rabbit papillary action potential

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.