title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Congrong
authors.initials: C
authors.lastname: Lin
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Ke
authors.forename: Ivana
authors.initials: I
authors.lastname: Cvetanovic
authors.forename: Vasant
authors.initials: V
authors.lastname: Ranade
authors.forename: John
authors.initials: J
authors.lastname: Somberg
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004594:Electrophysiology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006827:Hydantoins; D006947:Hyperkalemia / Q000188:drug therapy / Q000503:physiopathology; D048289:Imidazolidines / Q000494:pharmacology; D009865:Oocytes / Q000166:cytology / Q000187:drug effects*; D010627:Phenethylamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects*; D011336:Probability; D012680:Sensitivity and Specificity; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D048289:Imidazolidines; D010627:Phenethylamines; D010879:Piperazines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C086123:azimilide; D013015:Sotalol; C063533:dofetilide