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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.

ABSTRACT: 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.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).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).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.

SUBMITTER: So PP

PROVIDER: S-EPMC2607203 | biostudies-other | 2008 Dec

REPOSITORIES: biostudies-other

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Prevalence and Clinical Characteristics of Patients with Torsades de Pointes Complicating Acquired Atrioventricular Block.

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Project description: Not available

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Apamin induces early afterdepolarizations and torsades de pointes ventricular arrhythmia from failing rabbit ventricles exhibiting secondary rises in intracellular calcium.

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Project description: Not available

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Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current.

Project description:BackgroundNew drugs are routinely screened for IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to phosphoinositide 3-kinase inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current (INa-L) in cardiomyocytes. We tested the extent to which IKr blockers with known QT liability generate arrhythmias through this pathway.Methods and resultsAcute exposure to dofetilide, an IKr blocker without other recognized electropharmacologic actions, produced no change in ion currents or action potentials in adult mouse cardiomyocytes, which lack IKr. By contrast, 2 to 48 hours of exposure to the drug generated arrhythmogenic afterdepolarizations and ≥15-fold increases in INa-L. Including phosphatidylinositol 3,4,5-trisphosphate, a downstream effector for the phosphoinositide 3-kinase pathway, in the pipette inhibited these effects. INa-L was also increased, and inhibitable by phosphatidylinositol 3,4,5-trisphosphate, with hours of dofetilide exposure in human-induced pluripotent stem cell-derived cardiomyocytes and in Chinese hamster ovary cells transfected with SCN5A, encoding sodium current. Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased INa-L and afterdepolarizations. Other agents with variable IKr-blocking potencies and arrhythmia liability produced a range of effects on INa-L, from marked increases (E-4031, d-sotalol, thioridazine, and erythromycin) to little or no effect (haloperidol, moxifloxacin, and verapamil).ConclusionsSome but not all drugs designated as arrhythmogenic IKr blockers can generate arrhythmias by augmenting INa-L through the phosphoinositide 3-kinase pathway. These data identify a potential mechanism for individual susceptibility to proarrhythmia and highlight the need for a new paradigm to screen drugs for QT prolonging and arrhythmogenic liability.

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?-adrenergic stimulation augments transmural dispersion of repolarization via modulation of delayed rectifier currents IKs and IKr in the human ventricle.

Project description:Long QT syndrome (LQTS) is an inherited or drug induced condition associated with delayed repolarization and sudden cardiac death. The cardiac potassium channel, IKr, and the adrenergic-sensitive cardiac potassium current, IKs, are two primary contributors to cardiac repolarization. This study aimed to elucidate the role of ?-adrenergic (?-AR) stimulation in mediating the contributions of IKr and IKs to repolarizing the human left ventricle (n?=?18). Optical mapping was used to measure action potential durations (APDs) in the presence of the IKs blocker JNJ-303 and the IKr blocker E-4031. We found that JNJ-303 alone did not increase APD. However, under isoprenaline (ISO), both the application of JNJ-303 and additional E-4031 significantly increased APD. With JNJ-303, ISO decreased APD significantly more in the epicardium as compared to the endocardium, with subsequent application E-4031 increasing mid- and endocardial APD80 more significantly than in the epicardium. We found that ?-AR stimulation significantly augmented the effect of IKs blocker JNJ-303, in contrast to the reduced effect of IKr blocker E-4031. We also observed synergistic augmentation of transmural repolarization gradient by the combination of ISO and E-4031. Our results suggest ?-AR-mediated increase of transmural dispersion of repolarization, which could pose arrhythmogenic risk in LQTS patients.

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| S-EPMC5029147 | biostudies-literature

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