Key result
Raising extracellular potassium from 5 to 10 mmol/l significantly decreased HERG block by azimilide, dofetilide, quinidine, and sotalol, while block by amiodarone remained unchanged.
Why the study?
Does high extracellular potassium affect the IKr inhibition by anti-arrhythmic agents in HERG-expressing Xenopus oocytes?
Does high extracellular potassium affect the IKr inhibition by anti-arrhythmic agents in HERG-expressing Xenopus oocytes?
High extracellular potassium diminishes the IKr blocking effects of azimilide, dofetilide, quinidine, and sotalol, but not amiodarone, which may favor re-entry arrhythmias during regional ischemia.
May attenuate IKr blockade by most agents during hyperkalemia; leaves open arrhythmia risk in ischemic tissue.
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 IC(50) was 37.0 +/- 12.5 microM for amiodarone, 5.8 +/- 0.4 microM for azimilide, 1.5 +/- 0. 2 microM for dofetilide, 9.1 +/- 1.5 microM 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 microM 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 IC(50) was increased for azimilide, dofetilide, quinidine and sotalol but not for amiodarone; the IC(50) was 24.7 +/- 7.4 microM for amiodarone, 29.3 +/- 3.9 microM for azimilide, 2.7 +/- 0.2 microM for dofetilide, 27.6 +/- 4.0 microM 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.
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Lin et al. (2006) studied this question. Increased extracellular potassium concentration vs. 5 mmol/l extracellular potassium was evaluated on IKr (HERG) current inhibition (IC50). Raising extracellular potassium from 5 to 10 mmol/l significantly decreased HERG block by azimilide, dofetilide, quinidine, and sotalol, while block by amiodarone remained unchanged.
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