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The Influence of Extracellular Acidosis on the Effect of IKr Blockers

Department of Pharmacology, Rush University Medical Center, Chicago, IL

Xiaogang Ke, MD

Department of Pharmacology, Rush University Medical Center, Chicago, IL

Ivana Cvetanovic, MD

Department of Pharmacology, Rush University Medical Center, Chicago, IL

Vasant Ranade, PhD

Department of Pharmacology, Rush University Medical Center, Chicago, IL

John Somberg, MD

Department of Pharmacology, Rush University Medical Center, Chicago, IL

Background: Myocardial infarction causes the acidification of the cellular environment and the resultant acidosis maybe arrhythmogenic. The effect of acidosis on the action of antiar-rhythmic drugs, an important issue in the antiarrhythmic drug therapy after myocardial infarction, remains to be studied.

Methods: To evaluate the effect of acidosis on rectifier potassium current (Ikr) blockers, the human ether-a-go-go-related gene (HERG), which encodes IKr, was expressed in Xenopus laevis oocytes. The two electrodes voltage clamp technique was used and the experiments were performed at room temperature.

Results: Quinidine (10 µM) inhibited HERG tail current by 37% ± 5% at pH7.4. The block decreased to 5% ± 2% with extracellular pH at 6.2. Dofetilide (0.3 µM) inhibited HERG tail current by 34% ± 3% and 1% ± 2% at extracellular pH 7.4 and 6.2, respectively. Azimilide (10 µM) inhibited HERG tail current by 59% ± 3% and 17% ± 3% at extracellular pH 7.4 and 6.2. There were significant differences in the HERG inhibition by quinidine, dofetilide, and azimilide between pH 7.4 and pH 6.2 (P < .01). The drug concentration blocking 50% of current (IC₅₀) was 5.8 ± 0.3 µM for azimilide, 9.9 ±1.0 µM for quinidine, and 0.5 ± 0.02 µM for dofetilide at pH 7.4. When extracellular pH was decreased from 7.4 to 6.2, the IC₅₀ increased to 95.5 ± 11.3 µM for azimilide, 203.2 ± 15.7 µM for quinidine, and 12.6 ± 1.2 µM for dofetilide. Unlike quinidine, dofetilide, and azimilide, there was no significant difference in the percentage of current block by amiodarone between pH 6.2 and 7.4. For amiodarone, the IC₅₀ was 38.3 ± 8.5 µM at pH 7.4 and 27.3 ± 1.6 µM at pH 6.2.

Conclusion: Our data show that the Ikr blocking effect of azimilide, dofetilide, and quinidine was attenuated at acid pH, whereas this was not the case for amiodarone. These observations may explain the efficacy of amiodarone in reducing arrhythmic death in patients after a myocardial infarction compared with other IKr blockers.

Key Words: acidosis • antiarrhythmic drugs • HERG channel

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 10, No. 1, 67-76 (2005)
DOI: 10.1177/107424840501000108


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