The influence of extracellular acidosis on the effect of IKr blockers.
BACKGROUND
Myocardial infarction causes the acidification of the cellular environment and the resultant acidosis maybe arrhythmogenic. The effect of acidosis on the action of antiarrhythmic 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 microM) 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 microM) inhibited HERG tail current by 34% +/- 3% and 1% +/- 2% at extracellular pH 7.4 and 6.2, respectively. Azimilide (10 microM) 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 microM for azimilide, 9.9 +/- 1.0 microM for quinidine, and 0.5 +/- 0.02 microM 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 microM for azimilide, 203.2 +/- 15.7 microM for quinidine, and 12.6 +/- 1.2 microM 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 microM at pH 7.4 and 27.3 +/- 1.6 microM at pH 6.2.


CONCLUSIONS
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.
Lin
Congrong
C
Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612, USA.
Ke
Xiaogang
X
Cvetanovic
Ivana
I
Ranade
Vasant
V
Somberg
John
J
D000138:Acidosis / Q000503:physiopathology*; D000200:Action Potentials / Q000187:drug effects; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006827:Hydantoins; D048289:Imidazolidines / Q000494:pharmacology; D009203:Myocardial Infarction / Q000503:physiopathology*; D009865:Oocytes; D010627:Phenethylamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects*; D011802:Quinidine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D015534:Trans-Activators; D014982:Xenopus laevis
D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D048289:Imidazolidines; D010627:Phenethylamines; D010879:Piperazines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D015534:Trans-Activators; C086123:azimilide; D011802:Quinidine; D000638:Amiodarone; C063533:dofetilide