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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
Author(s) -
So P PS,
Backx P H,
Dorian P
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.354
Subject(s) - torsades de pointes , dofetilide , repolarization , veratridine , medicine , cardiology , ventricular repolarization , qt interval , chemistry , electrophysiology , sodium channel , sodium , organic chemistry
Background and purpose: The slow delayed rectifier K + current (I Ks ) contributes to ventricular repolarization when the action potential (AP) is prolonged. I Ks 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 (MAPD 90 ) and ECG interval between the peak and the end of T wave (T peak−end ) (index of dispersion of repolarization) were measured after the administration of veratridine (125 n M , slows Na + channel inactivation), dofetilide (7.5 or 10 n M , a rapid delayed rectifier blocker) and HMR 1556 (HMR, 100 n M , an I Ks blocker), alone or in combinations ( n =6 each). Key results: HMR did not prolong MAPD 90 , whereas veratridine or 7.5 n M dofetilide prolonged MAPD 90 ( P <0.01) without inducing TdP. Veratridine+7.5 n M dofetilide additively prolonged MAPD 90 ( P <0.05), induced 4±6 TdP per heart and prolonged T peak−end by 12±10 ms. Subsequent addition of HMR did not further prolonged MAPD 90 , but increased the number of TdP to 22±18 per heart and increased T peak−end by 39±21 ms ( P <0.05). Increasing dofetilide concentration from 7.5 to 10 n M (added to veratridine) produced a longer MAPD 90 , but fewer TdP (5±5 per heart) and less T peak−end prolongation (17±8 ms) compared to the veratridine+7.5 n M dofetilide+HMR group ( P <0.05). Conclusions and implications: Adding I Ks 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