Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with Long-QT syndrome 1 both in vitro and in vivo

Jürgen Biermann, Kezhong Wu, Katja E. Odening, Stefan Asbach, Gideon Koren, Xuwen Peng, Manfred Zehender, Christoph Bode, Michael Brunner

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Abstract

Transgenic rabbits expressing loss-of-function pore mutants of the human gene KCNQ1 (K v LQT1-Y315S) have a Long QT-Syndrome 1 (LQT1) phenotype. We evaluated for the first time the effect of nicorandil, an opener of ATP-sensitive potassium channels, and of isoproterenol on cardiac action potential duration and heart rate dependent dispersion of repolarisation in transgenic LQT1 rabbits. In vivo LQT1 and littermate control were subjected to transvenous electrophysiological studies; in vitro monophasic action potentials were recorded from explanted Langendorff-perfused hearts. In vivo ventricular effective refractory periods (VERP) at the right ventricular base were significantly prolonged in LQT1 as compared to littermate control, resulting in a more pronounced VERP dispersion in LQT1. This difference in VERP dispersion between LQT1 and littermate control disappeared after infusion of nicorandil. In vitro, mean action potential durations (APD 75 and APD 90 ) of LQT1 were significantly prolonged compared to littermate control at baseline. Nicorandil decreased APD 75 and APD 90 in LQT1 and littermate control at all stimulated heart rates. After adding nicorandil, the APD 90 at all hearts rates and the APD 75 at high heart rates were no longer different. Dispersion of repolarisation (ΔAPD 75 and ΔAPD 90 ) was heart rate dependently decreased after nicorandil at all tested stimulation cycle lengths only in LQT1. We demonstrated phenotypic differences of LQT1 and littermate control in vivo and in vitro. Nicorandil 20 μmol/l improved repolarisation abnormalities and heterogeneities in transgenic LQT1 rabbits.

Original languageEnglish (US)
Pages (from-to)309-316
Number of pages8
JournalEuropean Journal of Pharmacology
Volume650
Issue number1
DOIs
StatePublished - Jan 10 2011

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Romano-Ward Syndrome
pamidronate
Nicorandil
Rabbits
Heart Rate
Action Potentials
In Vitro Techniques
KATP Channels
Isoproterenol

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Biermann, Jürgen ; Wu, Kezhong ; Odening, Katja E. ; Asbach, Stefan ; Koren, Gideon ; Peng, Xuwen ; Zehender, Manfred ; Bode, Christoph ; Brunner, Michael. / Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with Long-QT syndrome 1 both in vitro and in vivo. In: European Journal of Pharmacology. 2011 ; Vol. 650, No. 1. pp. 309-316.
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Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with Long-QT syndrome 1 both in vitro and in vivo. / Biermann, Jürgen; Wu, Kezhong; Odening, Katja E.; Asbach, Stefan; Koren, Gideon; Peng, Xuwen; Zehender, Manfred; Bode, Christoph; Brunner, Michael.

In: European Journal of Pharmacology, Vol. 650, No. 1, 10.01.2011, p. 309-316.

Research output: Contribution to journalArticle

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AU - Biermann, Jürgen

AU - Wu, Kezhong

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AU - Asbach, Stefan

AU - Koren, Gideon

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