Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits

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

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)223-230
Number of pages8
JournalJournal of Cardiovascular Pharmacology
Volume57
Issue number2
DOIs
StatePublished - Feb 1 2011

Fingerprint

pamidronate
Romano-Ward Syndrome
Pharmacology
Rabbits
Action Potentials
1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea
Intravenous Infusions
Cross-Over Studies
Cardiac Arrhythmias
Electrocardiography
Perfusion
Genotype

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Bentzen, B. H., Bahrke, S., Wu, K., Larsen, A. P., Odening, K. E., Franke, G., ... Brunner, M. (2011). Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits. Journal of Cardiovascular Pharmacology, 57(2), 223-230. https://doi.org/10.1097/FJC.0b013e318203a44d
Bentzen, Bo Hjorth ; Bahrke, Sophia ; Wu, Kezhong ; Larsen, Anders Peter ; Odening, Katja E. ; Franke, Gerlind ; Vańs Gravesande, Karin Storm ; Biermann, Jürgen ; Peng, Xuwen ; Koren, Gideon ; Zehender, Manfred ; Bode, Christoph ; Grunnet, Morten ; Brunner, Michael. / Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits. In: Journal of Cardiovascular Pharmacology. 2011 ; Vol. 57, No. 2. pp. 223-230.
@article{fadb31e0f1734b91a24eb5410809ea8c,
title = "Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits",
abstract = "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.",
author = "Bentzen, {Bo Hjorth} and Sophia Bahrke and Kezhong Wu and Larsen, {Anders Peter} and Odening, {Katja E.} and Gerlind Franke and {Vańs Gravesande}, {Karin Storm} and J{\"u}rgen Biermann and Xuwen Peng and Gideon Koren and Manfred Zehender and Christoph Bode and Morten Grunnet and Michael Brunner",
year = "2011",
month = "2",
day = "1",
doi = "10.1097/FJC.0b013e318203a44d",
language = "English (US)",
volume = "57",
pages = "223--230",
journal = "Journal of Cardiovascular Pharmacology",
issn = "0160-2446",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

Bentzen, BH, Bahrke, S, Wu, K, Larsen, AP, Odening, KE, Franke, G, Vańs Gravesande, KS, Biermann, J, Peng, X, Koren, G, Zehender, M, Bode, C, Grunnet, M & Brunner, M 2011, 'Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits', Journal of Cardiovascular Pharmacology, vol. 57, no. 2, pp. 223-230. https://doi.org/10.1097/FJC.0b013e318203a44d

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; Vańs Gravesande, Karin Storm; Biermann, Jürgen; Peng, Xuwen; Koren, Gideon; Zehender, Manfred; Bode, Christoph; Grunnet, Morten; Brunner, Michael.

In: Journal of Cardiovascular Pharmacology, Vol. 57, No. 2, 01.02.2011, p. 223-230.

Research output: Contribution to journalArticle

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 - Vańs Gravesande, Karin Storm

AU - Biermann, Jürgen

AU - Peng, Xuwen

AU - Koren, Gideon

AU - Zehender, Manfred

AU - Bode, Christoph

AU - Grunnet, Morten

AU - Brunner, Michael

PY - 2011/2/1

Y1 - 2011/2/1

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.

UR - http://www.scopus.com/inward/record.url?scp=79951549769&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79951549769&partnerID=8YFLogxK

U2 - 10.1097/FJC.0b013e318203a44d

DO - 10.1097/FJC.0b013e318203a44d

M3 - Article

VL - 57

SP - 223

EP - 230

JO - Journal of Cardiovascular Pharmacology

JF - Journal of Cardiovascular Pharmacology

SN - 0160-2446

IS - 2

ER -