The Effect of High Extracellular Potassium on IKr Inhibition by Anti-Arrhythmic Agents

Abstract

Background: Hyperkalemia is a potentially life-threatening disorder frequently occurring in hospitalized patients. The ischemic myocardium releases potassium into the extracellular space which can cause regional hyperkalemia. These changes may modify the effects of anti-arrhythmic drugs acting on the rapid component of the delayed rectifier potassium current (IKr). We evaluated the influence of increased extracellular potassium concentration [K⁺]_e on IKr inhibition by amiodarone, azimilide, dofetilide, quinidine and sotalol. Methods and Results: Experiments were performed at room temperature. IKr current was studied by using HERG gene expressed in Xenopus oocytes as a model of cardiac IKr. Two-electrode voltage clamp technique was employed. The recording bath solutions contained either 5 or 10 mmol/l KCl. Amiodarone, azimilide, dofetilide, quinidine and sotalol all produced a dose-dependent inhibition of HERG current. At 5 mmol/l [K⁺]_e, the IC₅₀ was 37.0 ± 12.5 µM for amiodarone, 5.8 ± 0.4 µM for azimilide, 1.5 ± 0. 2 µM for dofetilide, 9.1 ± 1.5 µM for quinidine, and 5.1 ± 0.8 mM for sotalol. Raising the extracellular potassium to 10 mmol/l, HERG block by azimilide, dofetilide, quinidine and sotalol was significantly decreased, while the block by amiodarone was unchanged. The differences in the percentage current block produced by 3 µM drugs at 5 and 10 mmol/l [K⁺]_e were: –0.9% for amiodarone, 13.8% for quinidine, 20.5% for azimilide, and 16.2% for dofetilide. The differences in percentage block between 5 and 10 mmol/l [K⁺]_e by sotalol 10 and 30 mM were 7.1 and 5.6%. At 10 mmol/l [K⁺]_e, the IC₅₀ was increased for azimilide, dofetilide, quinidine and sotalol but not for amiodarone; the IC₅₀ was 24.7 ± 7.4 µM for amiodarone, 29.3 ± 3.9 µM for azimilide, 2.7 ± 0.2 µM for dofetilide, 27.6 ± 4.0 µM for quinidine, and 7.2 ± 1.7 mM for sotalol. Conclusion: Inhibition of IKr by azimilide, quinidine, dofetilide and sotalol was diminished by increasing [K⁺]_e, while the inhibition by amiodarone was unchanged at normal and high [K⁺]_e. The differential effects of azimilide, dofetilide, quinidine and sotalol at normal and high [K⁺]_e could be pro-arrhythmic by favoring re-entry arrhythmias. These results further support the unique electrophysiological effect of amiodarone.

Extracellular Acidification and Hyperkalemia Induce Changes in HERG Inhibition by Ibutilide

“…Our previous studies have demonstrated that for IKr-blocking antiarrhythmic drugs like azimilide, quinidine and dofetilide, their HERG-inhibitory effect decreases with extracellular acidosis and hyperkalemia [14, 15]. These antiarrhythmic drugs have been noted for their proarrhythmic toxicity.…”

“…TdP can develop in 3–4% of patients receiving dofetilide intravenously [28]. On the other hand, amiodarone exerts a similar degree of HERG inhibition despite the decreasing extracellular pH [14] or increasing extracellular potassium concentration [15]. The risk of developing TdP with amiodarone is regarded as very low compared to other antiarrhythmic drugs [29] (less than 1% [6]).…”

“…quinidine, and extracellular acidosis had little effect on the IKr-inhibitory effect of less-proarrhythmic drugs such as amiodarone [14]. In addition, increasing extracellular potassium concentration led to diminished IKr-inhibitory effect of proarrhythmic drugs like quinidine, but IKr inhibition of amiodarone was unchanged at normal and high extracellular potassium concentration [K + ] e [15]. Extracellular acidosis and hyperkalemia may provoke a proarrhythmic effect of antiarrhythmic drugs by modifying their HERG-blocking action.…”

The Additive Effects of the Active Component of Grapefruit Juice (Naringenin) and Antiarrhythmic Drugs on HERG Inhibition

“…When patients on I Kr -blocking antiarrhythmic drugs drink citrus juices, the additional I Kr inhibition by naringenin from the citrus juice may lead to excessive QT prolongation, and thus the risk of developing arrhythmias. This may be especially the case when the patient has metabolic and electrolyte disorders such as hypokalemia [16, 24], cardiac ischemia with resulting regional acidosis and hyperkalemia [25,26,27], or a congenital defect in the potassium channel [28]. …”

Ventricular Repolarization Spectra

“…In MI patients, a prolonged QT correlates with an increased risk for arrhythmias and death [4] ; increased QT variability correlates with susceptibility to reentrant ventricular tachyarrhythmias [5] , and increased T-wave alternans correlates with an increased risk of sudden death following MI [6] . Indeed, at tissue level, repolarization dispersion correlates with an increased risk of arrhythmias, and this dispersion is noted when comparing ion channel behavior between normal and ischemic conditions [7,8] .…”