TY - JOUR
T1 - Pronounced effects of HERG-blockers E-4031 and erythromycin on APD, spatial APD dispersion and triangulation in transgenic long-QT type 1 rabbits
AU - Ziupa, David
AU - Beck, Julia
AU - Franke, Gerlind
AU - Feliz, Stefanie Perez
AU - Hartmann, Maximilian
AU - Koren, Gideon
AU - Zehender, Manfred
AU - Bode, Christoph
AU - Brunner, Michael
AU - Odening, Katja E.
N1 - Publisher Copyright: © 2014 Mineshita et al.
PY - 2014/9/22
Y1 - 2014/9/22
N2 - Background: Prolongation of action potential duration (APD), increased spatial APD dispersion, and triangulation are major factors promoting drug-induced ventricular arrhythmia. Preclinical identification of HERG/IKr-blocking drugs and their proarrhythmic potential, however, remains a challenge. We hypothesize that transgenic long-QT type 1 (LQT1) rabbits lacking repolarizing IKs current may help to sensitively detect HERG/IKr-blocking properties of drugs.Methods: Hearts of adult female transgenic LQT1 and wild type littermate control (LMC) rabbits were Langendorff-perfused with increasing concentrations of HERG/IKr-blockers E-4031 (0.001-0.1 μM, n = 9/7) or erythromycin (1-300 μM, n = 9/7) and APD, APD dispersion, and triangulation were analyzed.Results: At baseline, APD was longer in LQT1 than in LMC rabbits in LV apex and RV mid. Erythromycin and E-4031 prolonged APD in LQT1 and LMC rabbits in all positions. However, erythromycin-induced percentaged APD prolongation related to baseline (%APD) was more pronounced in LQT1 at LV base-lateral and RV mid positions (100 μM, LQT1, + 40.6±9.7% vs. LMC, +24.1±10.0%, p,0<05) and E-4031-induced %APD prolongation was more pronounced in LQT1 at LV base-lateral (0.01 μM, LQT1, +29.6±10.6% vs. LMC, +19.1±3.8%, p<0.05) and LV base-septal positions. Moreover, erythromycin significantly increased spatial APD dispersion only in LQT1 and increased triangulation only in LQT1 in LV base-septal and RV mid positions. Similarly, E-4031 increased triangulation only in LQT1 in LV apex and base-septal positions.Conclusions: E-4031 and erythromycin prolonged APD and increased triangulation more pronouncedly in LQT1 than in LMC rabbits. Moreover, erythromycin increased APD dispersion only in LQT1, indicating that transgenic LQT1 rabbits could serve as sensitive model to detect HERG/IKr-blocking properties of drugs.
AB - Background: Prolongation of action potential duration (APD), increased spatial APD dispersion, and triangulation are major factors promoting drug-induced ventricular arrhythmia. Preclinical identification of HERG/IKr-blocking drugs and their proarrhythmic potential, however, remains a challenge. We hypothesize that transgenic long-QT type 1 (LQT1) rabbits lacking repolarizing IKs current may help to sensitively detect HERG/IKr-blocking properties of drugs.Methods: Hearts of adult female transgenic LQT1 and wild type littermate control (LMC) rabbits were Langendorff-perfused with increasing concentrations of HERG/IKr-blockers E-4031 (0.001-0.1 μM, n = 9/7) or erythromycin (1-300 μM, n = 9/7) and APD, APD dispersion, and triangulation were analyzed.Results: At baseline, APD was longer in LQT1 than in LMC rabbits in LV apex and RV mid. Erythromycin and E-4031 prolonged APD in LQT1 and LMC rabbits in all positions. However, erythromycin-induced percentaged APD prolongation related to baseline (%APD) was more pronounced in LQT1 at LV base-lateral and RV mid positions (100 μM, LQT1, + 40.6±9.7% vs. LMC, +24.1±10.0%, p,0<05) and E-4031-induced %APD prolongation was more pronounced in LQT1 at LV base-lateral (0.01 μM, LQT1, +29.6±10.6% vs. LMC, +19.1±3.8%, p<0.05) and LV base-septal positions. Moreover, erythromycin significantly increased spatial APD dispersion only in LQT1 and increased triangulation only in LQT1 in LV base-septal and RV mid positions. Similarly, E-4031 increased triangulation only in LQT1 in LV apex and base-septal positions.Conclusions: E-4031 and erythromycin prolonged APD and increased triangulation more pronouncedly in LQT1 than in LMC rabbits. Moreover, erythromycin increased APD dispersion only in LQT1, indicating that transgenic LQT1 rabbits could serve as sensitive model to detect HERG/IKr-blocking properties of drugs.
UR - http://www.scopus.com/inward/record.url?scp=84907259426&partnerID=8YFLogxK
U2 - https://doi.org/10.1371/journal.pone.0107210
DO - https://doi.org/10.1371/journal.pone.0107210
M3 - مقالة
C2 - 25244401
SN - 1932-6203
VL - 9
JO - PLoS ONE
JF - PLoS ONE
IS - 9
M1 - e107210
ER -