Torsades de pointes is a polymorphic ventricular
arrhythmia resulting from congenital or
drug-induced (acquired) QT prolongation. Pharmacologic suppression of repolarizing
potassium currents is one mechanism causing the acquired long QT (LQT) syndrome. Recent studies have linked mutations in a gene encoding a
potassium channel subunit (HERG) to the LQT syndrome. Clinical experience indicates that intravenous
magnesium sulfate is effective in reversing
torsades de pointes, but the molecular basis of this effect is not understood. This study was designed to investigate the effects of extracellular
magnesium (Mg2+) on HERG
potassium currents. HERG
potassium channels were expressed in Xenopus oocytes and in a human cell line and were examined by voltage-clamp methods. Extracellular Mg2+ (0.3-10 mM) caused a concentration-dependent shift in the membrane-potential dependence of HERG channel opening, causing a reduction in K+ current. This effect was much greater than that observed in another human delayed rectifier K+ channel, hKv1.5, suggesting a specific interaction with the HERG channel.
Quinidine is an
antiarrhythmic drug that also causes
torsades de pointes under certain conditions.
Quinidine (3 microM) inhibited HERG currents expressed in oocytes by 32.1 +/- 3.2% (n = 5), whereas 1 microM
quinidine inhibited HERG currents in tsA201 cells by 75.8 +/- 2.4% (n = 12). Increasing extracellular Mg2+ did not relieve the inhibition by
quinidine, but caused additional suppression. These results indicate that extracellular Mg2+ exerts a direct action on HERG
potassium channels, resulting in suppression of outward repolarizing
potassium current. It is concluded that modulation of this important K+ current is not the mechanism by which intravenous
magnesium terminates
drug-induced LQT and
torsades de pointes. Potent suppression of HERG channel current by
quinidine, compared with that of I(Ks) and I(Na), is a likely contributor to
torsades de pointes arrhythmias.