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

Transgenic rabbits expressing loss-of-function pore mutants of the human gene KCHQ1 (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 litterrnate control resulting in a more pronounced VERP dispersion in LQT1 This difference in VI RP 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 APD90 it all hearts rates and the APD75 at high heart rates were no longer different Dispersion of repolarisation (AAPD(75) and Delta 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 20 mu mol/1 improved repolarisation abnormalities and heterogeneities in transgenic LQT1 rabbits (C) 2010 Elsevier B V All rights reserved