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Slow delayed rectifier K+ current block by HMR 1556 increases dispersion of repolarization and promotes Torsades de Pointes in rabbit ventricles.

Authors :
So, P. P.-S.
Backx, P. H.
Dorian, P.
Source :
British Journal of Pharmacology. Dec2008, Vol. 155 Issue 8, p1185-1194. 10p. 1 Chart, 6 Graphs.
Publication Year :
2008

Abstract

Background and purpose:The slow delayed rectifier K+ current (IKs) contributes to ventricular repolarization when the action potential (AP) is prolonged. IKs block during drug-induced AP prolongation may promote Torsades de Pointes (TdP), but whether this is due to additional AP prolongation is uncertain.Experimental approach:In bradycardic perfused rabbit ventricles, the incidence of spontaneous TdP, monophasic AP duration at 90% repolarization (MAPD90) and ECG interval between the peak and the end of T wave (Tpeak−end) (index of dispersion of repolarization) were measured after the administration of veratridine (125 nM, slows Na+ channel inactivation), dofetilide (7.5 or 10 nM, a rapid delayed rectifier blocker) and HMR 1556 (HMR, 100 nM, an IKs blocker), alone or in combinations (n=6 each).Key results:HMR did not prolong MAPD90, whereas veratridine or 7.5 nM dofetilide prolonged MAPD90 (P<0.01) without inducing TdP. Veratridine+7.5 nM dofetilide additively prolonged MAPD90 (P<0.05), induced 4±6 TdP per heart and prolonged Tpeak−end by 12±10 ms. Subsequent addition of HMR did not further prolonged MAPD90, but increased the number of TdP to 22±18 per heart and increased Tpeak−end by 39±21 ms (P<0.05). Increasing dofetilide concentration from 7.5 to 10 nM (added to veratridine) produced a longer MAPD90, but fewer TdP (5±5 per heart) and less Tpeak−end prolongation (17±8 ms) compared to the veratridine+7.5 nM dofetilide+HMR group (P<0.05).Conclusions and implications:Adding IKs block markedly increases TdP incidence in hearts predisposed to TdP development by increasing the dispersion of repolarization, but without additional AP prolongation.British Journal of Pharmacology (2008) 155, 1185–1194; doi:10.1038/bjp.2008.354; published online 6 October 2008 [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00071188
Volume :
155
Issue :
8
Database :
Academic Search Index
Journal :
British Journal of Pharmacology
Publication Type :
Academic Journal
Accession number :
35583632
Full Text :
https://doi.org/10.1038/bjp.2008.354