OBJECTIVE: The aim was to compare the electrophysiological and inotropic effects of the novel class III agents H 234/09, UK-68,798, and E-4031 in vitro. METHODS: The electrophysiological effects were investigated by recording transmembrane action potentials in the isolated ventricular muscle and Purkinje fibres of the rabbit; effects on force (adjusted to the maximum isoprenaline response) and refractoriness were investigated in the isolated cat papillary muscle. RESULTS: It was shown that all the drugs induced a concentration dependent prolongation of the action potential duration, which was much more pronounced in the Purkinje fibres than in the ventricular muscle. However, when compared at concentrations giving a 15% increase of the action potential duration in ventricular muscle, H 234/09 was significantly less effective in the Purkinje fibres than the other two drugs. In the cat papillary muscle all drugs induced an increase in force development. This increase tended to parallel the increase in effective refractory period. However, at prolongations of effective refractory period of more than approximately 50% the increase in developed force levelled off. CONCLUSIONS: All the class III agents investigated showed a positive inotropic effect, which may be of advantage when compared to conventional class I antiarrhythmic agents, which have cardiodepressant actions. Compared to UK-68,798 and E-4031, H 234/09 showed a less unfavourable profile in terms of dispersion of repolarisation, which theoretically may reduce the risk of arrhythmias associated with delayed repolarisation. However, this less unfavourable profile must, like the positive inotropic effect, ultimately be investigated in clinical trials.
OBJECTIVE: The aim was to compare the electrophysiological and inotropic effects of the novel class III agents H 234/09, UK-68,798, and E-4031 in vitro. METHODS: The electrophysiological effects were investigated by recording transmembrane action potentials in the isolated ventricular muscle and Purkinje fibres of the rabbit; effects on force (adjusted to the maximum isoprenaline response) and refractoriness were investigated in the isolated cat papillary muscle. RESULTS: It was shown that all the drugs induced a concentration dependent prolongation of the action potential duration, which was much more pronounced in the Purkinje fibres than in the ventricular muscle. However, when compared at concentrations giving a 15% increase of the action potential duration in ventricular muscle, H 234/09 was significantly less effective in the Purkinje fibres than the other two drugs. In the cat papillary muscle all drugs induced an increase in force development. This increase tended to parallel the increase in effective refractory period. However, at prolongations of effective refractory period of more than approximately 50% the increase in developed force levelled off. CONCLUSIONS: All the class III agents investigated showed a positive inotropic effect, which may be of advantage when compared to conventional class I antiarrhythmic agents, which have cardiodepressant actions. Compared to UK-68,798 and E-4031, H 234/09 showed a less unfavourable profile in terms of dispersion of repolarisation, which theoretically may reduce the risk of arrhythmias associated with delayed repolarisation. However, this less unfavourable profile must, like the positive inotropic effect, ultimately be investigated in clinical trials.
Authors: Herbert M Himmel; Alexandra Bussek; Michael Hoffmann; Rolf Beckmann; Horst Lohmann; Matthias Schmidt; Erich Wettwer Journal: Br J Pharmacol Date: 2012-05 Impact factor: 8.739
Authors: Marion Aubert; Rolf Osterwalder; Björn Wagner; Isabelle Parrilla; Icilio Cavero; Lucette Doessegger; Eric A Ertel Journal: Drug Saf Date: 2006 Impact factor: 5.606
Authors: Berend J van Meer; Ana Krotenberg; Luca Sala; Richard P Davis; Thomas Eschenhagen; Chris Denning; Leon G J Tertoolen; Christine L Mummery Journal: Nat Commun Date: 2019-09-20 Impact factor: 14.919