Model-based analysis of the effects of thioridazine enantiomers on the rabbit papillary action potential
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Model-based analysis of the effects of thioridazine enantiomers on the rabbit papillary action potential. / Jensen, Ask S.; Pennisi, Cristian P.; Sevcencu, Cristian; Christensen, Jørn B.; Kristiansen, Jette E.; Struijk, Johannes J.
Computing in Cardiology Conference 2015, CinC 2015. red. / Alan Murray. IEEE Computer Society Press, 2015. s. 1089-1092 7411104 (Computing in Cardiology, Bind 42).Publikation: Bidrag til bog/antologi/rapport › Konferencebidrag i proceedings › Forskning › fagfællebedømt
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TY - GEN
T1 - Model-based analysis of the effects of thioridazine enantiomers on the rabbit papillary action potential
AU - Jensen, Ask S.
AU - Pennisi, Cristian P.
AU - Sevcencu, Cristian
AU - Christensen, Jørn B.
AU - Kristiansen, Jette E.
AU - Struijk, Johannes J.
PY - 2015/2/16
Y1 - 2015/2/16
N2 - 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.
AB - 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.
U2 - 10.1109/CIC.2015.7411104
DO - 10.1109/CIC.2015.7411104
M3 - Article in proceedings
AN - SCOPUS:84964012150
T3 - Computing in Cardiology
SP - 1089
EP - 1092
BT - Computing in Cardiology Conference 2015, CinC 2015
A2 - Murray, Alan
PB - IEEE Computer Society Press
T2 - 42nd Computing in Cardiology Conference, CinC 2015
Y2 - 6 September 2015 through 9 September 2015
ER -
ID: 261046493