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

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 (∆APD(75) and ∆APD(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 20μmol/l improved repolarisation abnormalities and heterogeneities in transgenic LQT1 rabbits.

• Authors: Jürgen Biermann, Kezhong Wu, Katja E Odening, Stefan Asbach, Gideon Koren, Xuwen Peng, Manfred Zehender, Christoph Bode, Michael Brunner
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 650 Issue 1 Pg. 309-16 (Jan 10 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 20959120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Nicorandil

Topics

• Action Potentials (drug effects)
• Animals
• Animals, Genetically Modified
• Disease Models, Animal
• Female
• Heart (drug effects, physiopathology)
• Humans
• In Vitro Techniques
• Male
• Nicorandil (pharmacology)
• Perfusion
• Rabbits
• Romano-Ward Syndrome (physiopathology)
• Time Factors