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

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 (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 I-Ks 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 MAPD(90), 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 MAPD(90), 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 I-Ks block markedly increases TdP incidence in hearts predisposed to TdP development by increasing the dispersion of repolarization, but without additional AP prolongation.