Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits
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Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits. / Bentzen, Bo Hjorth; Bahrke, Sophia; Wu, Kezhong; Larsen, Anders Peter; Odening, Katja E; Franke, Gerlind; Storm vans Gravesande, Karin; Biermann, Jürgen; Peng, Xuwen; Koren, Gideon; Zehender, Manfred; Bode, Christoph; Grunnet, Morten; Brunner, Michael.
In: Journal of Cardiovascular Pharmacology, Vol. 57, No. 2, 02.2011, p. 223-30.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits
AU - Bentzen, Bo Hjorth
AU - Bahrke, Sophia
AU - Wu, Kezhong
AU - Larsen, Anders Peter
AU - Odening, Katja E
AU - Franke, Gerlind
AU - Storm vans Gravesande, Karin
AU - Biermann, Jürgen
AU - Peng, Xuwen
AU - Koren, Gideon
AU - Zehender, Manfred
AU - Bode, Christoph
AU - Grunnet, Morten
AU - Brunner, Michael
PY - 2011/2
Y1 - 2011/2
N2 - Transgenic rabbits expressing pore mutants of K(V)7.1 display a long QT syndrome 1 (LQT1) phenotype. Recently, NS1643 has been described to increase I(Kr).We hypothesized that NS1643 would shorten the action potential duration (APD(90)) in LQT1 rabbits. Transgenic LQT1 rabbits were compared with littermate control (LMC) rabbits. In vivo electrocardiogram studies in sedated animals were performed at baseline and during 45 minutes of intravenous infusion of NS1643 or vehicle in a crossover design. Ex vivo monophasic action potentials were recorded from Langendorff-perfused hearts at baseline and during 45-minute perfusion with NS1643. Left ventricular refractory periods were assessed before and after NS1643 infusion. Genotype differences in APD accommodation were also addressed. In vivo NS1643 shortened the QTc significantly in LQT1 compared with vehicle. In Langendorff experiments, NS1643 significantly shortened the APD(90) in LQT1 and LMC [32.0 ± 4.3 milliseconds (ms); 21.0 ± 5.0 ms] and left ventricular refractory periods (23.7 ± 8.3; 22.6 ± 9.9 ms). NS1643 significantly decreased dp/dt (LQT1: 49% ± 3%; LMC: 63% ± 4%) and increased the incidence of arrhythmia. The time course of APD adaptation was impaired in LQT1 rabbits and unaffected by I(Kr) augmentation. In conclusion, K(V)11.1 channel activation shortens the cardiac APD in a rabbit model of inherited LQT1, but it comes with the risk of excessive shortening of APD.
AB - Transgenic rabbits expressing pore mutants of K(V)7.1 display a long QT syndrome 1 (LQT1) phenotype. Recently, NS1643 has been described to increase I(Kr).We hypothesized that NS1643 would shorten the action potential duration (APD(90)) in LQT1 rabbits. Transgenic LQT1 rabbits were compared with littermate control (LMC) rabbits. In vivo electrocardiogram studies in sedated animals were performed at baseline and during 45 minutes of intravenous infusion of NS1643 or vehicle in a crossover design. Ex vivo monophasic action potentials were recorded from Langendorff-perfused hearts at baseline and during 45-minute perfusion with NS1643. Left ventricular refractory periods were assessed before and after NS1643 infusion. Genotype differences in APD accommodation were also addressed. In vivo NS1643 shortened the QTc significantly in LQT1 compared with vehicle. In Langendorff experiments, NS1643 significantly shortened the APD(90) in LQT1 and LMC [32.0 ± 4.3 milliseconds (ms); 21.0 ± 5.0 ms] and left ventricular refractory periods (23.7 ± 8.3; 22.6 ± 9.9 ms). NS1643 significantly decreased dp/dt (LQT1: 49% ± 3%; LMC: 63% ± 4%) and increased the incidence of arrhythmia. The time course of APD adaptation was impaired in LQT1 rabbits and unaffected by I(Kr) augmentation. In conclusion, K(V)11.1 channel activation shortens the cardiac APD in a rabbit model of inherited LQT1, but it comes with the risk of excessive shortening of APD.
KW - Action Potentials
KW - Animals
KW - Animals, Genetically Modified
KW - Cresols
KW - Cross-Over Studies
KW - Ether-A-Go-Go Potassium Channels
KW - Female
KW - Long QT Syndrome
KW - Phenylurea Compounds
KW - Rabbits
KW - Random Allocation
U2 - 10.1097/FJC.0b013e318203a44d
DO - 10.1097/FJC.0b013e318203a44d
M3 - Journal article
C2 - 21135701
VL - 57
SP - 223
EP - 230
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
SN - 0160-2446
IS - 2
ER -
ID: 45081512