Torsade de pointes often occurs with underlying hypokalemia and bradycardia. A common effect of many drugs producing torsade de pointes is block of the rapidly activating component of the cardiac delayed rectifier (IKr). In this study, we evaluated the effect of changing extracellular potassium ([K+]o) on IKr block by the nonspecific agent quinidine and by the specific IKr blocker dofetilide. IKr was measured in AT-1 cells, where contaminating outward currents are absent. The drug concentration producing 50% inhibition of IKr tails (IC50) was strikingly [K+]o-dependent. Elevating [K+]o from 1 to 8 mmol/L increased the IC50 for dofetilide block from 2.7 +/- 0.9 to 79 +/- 32 nmol/L and for quinidine block from 0.4 +/- 0.1 to 3.8 +/- 1.2 mumol/L. (1) The increase in drug block with low [K+]o provides a mechanism to explain the link between hypokalemia and torsade de pointes. (2) Elevations in [K+]o occur with myocardial ischemia and with rapid pacing. Possible consequences of blunted drug block with high [K+]o include loss of drug efficacy with ischemia and with rapid pacing; the latter may contribute to "reverse use-dependent" action potential prolongation. Extracellular potassium is a critical determinant of drug block of IKr, w...Continue Reading
Effects of altered extracellular potassium and pacing cycle length on the class III antiarrhythmic actions of dofetilide (UK-68,798) in guinea-pig papillary muscle
Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents
Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care
Effects of elevated extracellular potassium concentrations on the class III antiarrhythmic action of sotalol
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches
Effects of extracellular potassium accumulation and sodium pump activation on automatic canine Purkinje fibres
Comparative effects of increased extracellular potassium and pacing frequency on the class III activities of methanesulfonanilide IKr blockers dofetilide, D-sotalol, E-4031, and MK-499
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel
Inhibitory effects of AMP 579, a novel cardioprotective adenosine A1/A2A receptor agonist, on native IKr and cloned HERG current
Risperidone-induced action potential prolongation is attenuated by increased repolarization reserve due to concomitant block of I(Ca,L)
Characterization of the rapidly activating delayed rectifier potassium current, I (Kr), in HL-1 mouse atrial myocytes.
Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations
G-CSF therapy reduces myocardial repolarization reserve in the presence of increased arteriogenesis, angiogenesis and connexin 43 expression in an experimental model of pacing-induced heart failure
A quantitative analysis of the effect of cycle length on arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts
Restitution analysis of alternans and its relationship to arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts
Angiotensin II, angiotensin II antagonists and spironolactone and their modulation of cardiac repolarization
Polymorphic ventricular tachyarrhythmias in the absence of organic heart disease: classification, differential diagnosis, and implications for therapy
Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes
Ischemic, genetic and pharmacological origins of cardiac arrhythmias: the contribution of the Quebec Heart Institute.
A method for QT correction based on beat-to-beat analysis of the QT/RR interval relationship in conscious telemetred beagle dogs
Radiofrequency catheter ablation for the treatment of supraventricular tachycardias in children and adolescents
Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states
RSD1019 suppresses ischaemia-induced monophasic action potential shortening and arrhythmias in anaesthetized rabbits
Potentiation of halofantrine-induced QTc prolongation by mefloquine: correlation with blood concentrations of halofantrine
Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine
Proarrhythmia of azimilide and other class III antiarrhythmic agents in the adrenergically stimulated rabbit
QT variability during initial exposure to sotalol: experience based on a large electronic medical record
Potassium concentrations and ventricular ectopy: a prospective, observational study in post-cardiac surgery patients
Rate-independent effects of the new class III antiarrhythmic agent ambasilide on transmembrane action potentials in human ventricular endomyocardium
Frequency dependence in the action of the class III antiarrhythmic drug dofetilide is modulated by altering L-type calcium current and digitalis glucoside
Drug-related torsades de pointes in the isolated rabbit heart: comparison of clofilium, d,l-sotalol, and erythromycin
Roles of tyrosine kinase and protein kinase C in infarct size limitation by repetitive ischemic preconditioning in the rat
Effects of EGIS-7229 (S 21407), a novel class III antiarrhythmic drug, on myocardial refractoriness to electrical stimulation in vivo and in vitro
CGP 41251, a new potential anticancer drug, improves contractility of rat isolated cardiac muscle subjected to hypoxia
Desbutylhalofantrine: evaluation of QT prolongation and other cardiovascular effects after intravenous administration in vivo
Does QT widening in the Langendorff-perfused rat heart represent the effect of repolarization delay or conduction slowing?
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