Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits.
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.
Innere Medizin III, Universitätsklinik Freiburg, Freiburg, Germany.
Bo Hjorth
BH
Bentzen
Sophia
S
Bahrke
Kezhong
K
Wu
Anders Peter
AP
Larsen
Katja E
KE
Odening
Gerlind
G
Franke
Karin
K
Storm vańs Gravesande
Jürgen
J
Biermann
Xuwen
X
Peng
Gideon
G
Koren
Manfred
M
Zehender
Christoph
C
Bode
Morten
M
Grunnet
Michael
M
Brunner
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics*; D003408:Cresols / Q000494:pharmacology*; D018592:Cross-Over Studies; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000819:agonists / Q000378:metabolism*; D005260:Female; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011817:Rabbits; D011897:Random Allocation
D003408:Cresols; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D010671:Phenylurea Compounds; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea