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The influence of extracellular acidosis on the effect of Type III antiarrhythmic agents on the cardiac potassium channel (IKr)
Author(s) -
Somberg John C,
Lin Congrong,
Ke Xiaogang,
Ranade Vasant
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1112-a
Subject(s) - chemistry , quinidine , dofetilide , herg , acidosis , potassium , potassium channel , extracellular , pharmacology , inward rectifier potassium ion channel , medicine , biochemistry , qt interval , ion channel , receptor , organic chemistry
Ischemia may cause major changes in pH. The change in pH could influence the effect of type III agents on the rapid delayed rectifier potassium channel (IKr). We evaluated the effects of acidosis on IKr inhibition caused by amiodarone (AM), azimilide (AZ), dofetilide (D) and quinidine (Q). IKr was studied at room temperature by using HERG gene expressed in Xenopus oocytes and two electrodes voltage clamp technique was applied. The recording bath solution contained in mmol/L: 96 NaCl, 5.0 KCl, 2.0 CaCl 2 , 1.0 MgCl 2 , 5 HEPES; and pH adjusted with NaOH to 6.2 or 7.4. AZ, AM, Q at 1, 3, 10, 30, 100 μM and D at 0.03, 0.1, 0.3, 1, 3 μM caused dose dependent block in HERG current. The IC 50 was 5.8 ± 0.3 μM for AZ, 9.9 ±1.01 μM for Q and 0.5 ± 0.02 μM for D. When extracellular pH was decreased from 7.4 to 6.2, the IC 50 increased to 96 ± 11 μM for AZ, 203 ± 16 μM for Q and 13 ± 1 μM for D. The block effect was decreased 32% for AZ, 42% for D, 29% for Q when pH was decreased from 7.4 to 6.2. For AM, the IC 50 was 38 ± 9 μM at pH 7.4 and 27 ± 2 μM at and pH 6.2. There was no significant difference in the percentage of current block by AM between pH 6.2 and 7.4. Our data shows that the Ikr blocking effect of AZ, D and Q was attenuated at acidic pH while this was not the case for AM. The effect of AZ, D and Q at low pH creates heterogeneity of repolarization between ischemic and normal regions, but no change in current block would be expected with AM with regional acidosis. These observations may explain the reduced proarrhythmic effect of AM.