Document Detail


Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits.
MedLine Citation:
PMID:  21135701     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Bo Hjorth Bentzen; Sophia Bahrke; Kezhong Wu; Anders Peter Larsen; Katja E Odening; Gerlind Franke; Karin Storm vańs Gravesande; Jürgen Biermann; Xuwen Peng; Gideon Koren; Manfred Zehender; Christoph Bode; Morten Grunnet; Michael Brunner
Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  57     ISSN:  1533-4023     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-05-02     Completed Date:  2012-02-27     Revised Date:  2012-10-01    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  223-30     Citation Subset:  IM    
Affiliation:
Innere Medizin III, Universitätsklinik Freiburg, Freiburg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Action Potentials / drug effects,  physiology
Animals
Animals, Genetically Modified / genetics*
Cresols / pharmacology*
Cross-Over Studies
Ether-A-Go-Go Potassium Channels / agonists,  metabolism*
Female
Long QT Syndrome / genetics*,  metabolism*
Phenylurea Compounds / pharmacology*
Rabbits
Random Allocation
Chemical
Reg. No./Substance:
0/1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea; 0/Cresols; 0/ERG1 potassium channel; 0/Ether-A-Go-Go Potassium Channels; 0/Phenylurea Compounds

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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