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Published on: October 18, 2018
Slow delayed rectifier K+ current block by HMR 1556 increases dispersion of repolarization and promotes Torsades de
P P-S So1, P H Backx, P Dorian
1Keenan Research Center, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.
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 nM, slows Na(+) channel inactivation), dofetilide (7.5 or 10 nM, a rapid delayed rectifier blocker) and HMR 1556 (HMR, 100 nM, an I(Ks) blocker), alone or in combinations (n=6 each).
Key Results:
HMR did not prolong MAPD(90), whereas veratridine or 7.5 nM dofetilide prolonged MAPD(90) (P<0.01) without inducing TdP. Veratridine+7.5 nM 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 nM (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 nM 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.
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