Extracellular acidification and hyperkalemia induce changes in HERG inhibition by ibutilide.
BACKGROUND
A high incidence of proarrhythmia has been reported with ibutilide, especially in patients with underlying heart diseases. Our previous studies have shown that extracellular acidosis and hyperkalemia attenuate the HERG-inhibitory effect of proarrhythmic drugs, e.g. quinidine, but have little impact on the less-proarrhythmic drug amiodarone. We hypothesized that ibutilide would behave like quinidine in the presence of extracellular acidosis and hyperkalemia.


RESULTS
HERG was expressed on Xenopus oocytes, and the two-electrode voltage clamp technique was employed. Our results showed that ibutilide was a potent HERG inhibitor. When extracellular solution contained 5 mM KCl and pH was 7.4, the IC(50) of ibutilide was 0.9 +/- 0.1 microM. The inhibitory effect of ibutilide was attenuated when extracellular pH decreased to 6.2. There was a significant difference in current inhibition by ibutilide at pH 7.4 versus pH 6.2 (p < 0.01). When the extracellular potassium concentration was increased from 5 to 10 mM, ibutilide produced less current inhibition, and the IC(50) was increased to 2.0 +/- 0.1 microM.


CONCLUSIONS
Extracellular acidosis and hyperkalemia attenuate the HERG-inhibitory effect of ibutilide. The differences in HERG inhibition between acidic and hyperkalemic regions compared to normal regions in the myocardium may result in heterogeneity in repolarization, which may contribute to the proarrhythmic toxicity of ibutilide.
Department of Pharmacology and Medicine, Rush University Medical Center, Chicago, IL, USA.
Congrong
C
Lin
Xiaogang
X
Ke
Vasant
V
Ranade
John
J
Somberg
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008564:Membrane Potentials; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014982:Xenopus laevis
D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D013449:Sulfonamides; C067192:ibutilide; D011188:Potassium