The Influence of Extracellular Acidosis on the Effect of IKr Blockers

Lin, Congrong; Ke, X.; Cvetanovic, I.; Ranade, Vasant; Somberg, John C.

doi:10.1177/107424840501000108

Cited by 19 publications

(24 citation statements)

References 33 publications

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“…It is possible that the binding of extracellular protons might have attenuated the effects of nifekalant by modulating its binding property. This explanation is indirectly supported by a report that acidic conditions do not affect hERG IC 50 of amiodarone, since amiodarone is known to bind to a different site of hERG channels compared with other I Kr blockers whose IC 50 was increased under acidic conditions (11). Thus, the attenuation of pharmacological effects of nifekalant under acidic conditions as observed in this study might be due to the decrease in accessibility to I K1 channels by increased ionization of nifekalant and/or the interruption of the binding of nifekalant to I Kr channels by proton binding.…”

Section: Discussionsupporting

confidence: 63%

“…Meanwhile, with regard to the shortening of MAP duration, some studies reported that a decrease in extracellular pH shortens the action potential duration (22 -25), but the others described opposite results (26,27). It has been reported that under acidic condi- tions, H + directly binds to I Kr and I Ca channels, resulting in their current inhibitions (11,19,20,28). Inhibition of I Kr channels causes the prolongation of MAP duration, whereas inhibition of I Ca channels leads to its shortening.…”

Section: Discussionmentioning

confidence: 99%

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Effects of pH on Nifekalant-Induced Electrophysiological Change Assessed in the Langendorff Heart Model of Guinea Pigs

et al. 2014

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Abstract. Since information regarding the effects of pH on the extent of nifekalant-induced repolarization delay and torsades de pointes remains limited, we assessed it with a Langendorff heart model of guinea pigs. First, we investigated the effects of pH change from 7.4 to 6.4 on the bipolar electrogram simulating surface lead II ECG, monophasic action potential (MAP), effective refractory period (ERP), and terminal repolarization period (TRP) and found that acidic condition transiently enhanced the ventricular repolarization. Next, we investigated the effects of pH change from 6.4 to 7.4 in the presence of nifekalant (10 mM) on the ECG, MAP, ERP, TRP, and short-term variability (STV) of MAP 90 and found that the normalization of pH prolonged the MAP 90 and ERP while the TRP remained unchanged, suggesting the increase in electrical vulnerability of the ventricle. Meanwhile, the STV of MAP 90 was the largest at pH 6.4 in the presence of nifekalant, indicating the increase in temporal dispersion of repolarization, which gradually decreased with the return of pH to 7.4. Thus, a recovery period from acidosis might be more dangerous than during the acidosis, because electrical vulnerability may significantly increase for this period while temporal dispersion of repolarization remained increased.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Effects of pH on Nifekalant-Induced Electrophysiological Change Assessed in the Langendorff Heart Model of Guinea Pigs

et al. 2014

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“…However, not only extracellular potassium elevates during an ischemic episode, the extracellular acidosis also develops. In another set of experiments, we found that IKr-blocking action of sotalol was significantly decreased at acidic condition, but not that of amiodarone [29]. Our data show that the IKr inhibition and action potential-prolonging effect of amiodarone can be retained with extracellular acidosis and hyperkalemia.…”

Section: Discussionmentioning

confidence: 71%

The Effect of High Extracellular Potassium on IKr Inhibition by Anti-Arrhythmic Agents

Lin

Ke²,

Cvetanovic³

et al. 2006

Cardiology

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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. Methods and 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 IC₅₀ was 37.0 ± 12.5 µM for amiodarone, 5.8 ± 0.4 µM for azimilide, 1.5 ± 0. 2 µM for dofetilide, 9.1 ± 1.5 µM 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 µM 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 IC₅₀ was increased for azimilide, dofetilide, quinidine and sotalol but not for amiodarone; the IC₅₀ was 24.7 ± 7.4 µM for amiodarone, 29.3 ± 3.9 µM for azimilide, 2.7 ± 0.2 µM for dofetilide, 27.6 ± 4.0 µM for quinidine, and 7.2 ± 1.7 mM for sotalol. Conclusion: 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.

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“…When patients on I Kr -blocking antiarrhythmic drugs drink citrus juices, the additional I Kr inhibition by naringenin from the citrus juice may lead to excessive QT prolongation, and thus the risk of developing arrhythmias. This may be especially the case when the patient has metabolic and electrolyte disorders such as hypokalemia [16, 24], cardiac ischemia with resulting regional acidosis and hyperkalemia [25,26,27], or a congenital defect in the potassium channel [28]. …”

Section: Discussionmentioning

confidence: 99%

The Additive Effects of the Active Component of Grapefruit Juice (Naringenin) and Antiarrhythmic Drugs on HERG Inhibition

Lin

Ke²,

Ranade³

et al. 2007

Cardiology

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Background: Grapefruit juice causes significant QT prolongation in healthy volunteers and naringenin has been identified as the most potent human ether-a-go-go-related gene (HERG) channel blocker among several dietary flavonoids. The interaction between naringenin and I_Kr-blocking antiarrhythmic drugs has not been studied. We evaluated the effect of combining naringenin with I_Kr-inhibiting antiarrhythmic drugs on cardiac I_Kr. Methods and Results:I_Kr current was studied by using HERG expressed in Xenopus oocytes, and the two-electrode voltage clamp technique was employed. Antiarrhythmic drugs (azimilide, amiodarone, dofetilide and quinidine) were tested. Experiments were performed at room temperature. Naringenin blocked HERG current dose dependently with an IC₅₀ of 173.3 ± 3.1 µM. Naringenin 100 µM alone inhibited HERG current by 31 ± 6%, and this inhibitory effect was increased with coadministration of 1 or 10 µM antiarrhythmic drugs. When 100 µM naringenin was added to antiarrhythmic drugs, greater HERG inhibition was demonstrated, compared to the current inhibition caused by antiarrhythmic drugs alone. Addition of naringenin significantly increased current inhibition (p < 0.05). Conclusions: There is an additive inhibitory effect on HERG current when naringenin is combined with I_Kr-blocking antiarrhythmic drugs. This additive HERG inhibition could pose an increased risk of arrhythmias by increasing repolarization delay and possible repolarization heterogeneity.

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The Influence of Extracellular Acidosis on the Effect of IKr Blockers

Cited by 19 publications

References 33 publications

Effects of pH on Nifekalant-Induced Electrophysiological Change Assessed in the Langendorff Heart Model of Guinea Pigs

Effects of pH on Nifekalant-Induced Electrophysiological Change Assessed in the Langendorff Heart Model of Guinea Pigs

The Effect of High Extracellular Potassium on IKr Inhibition by Anti-Arrhythmic Agents

The Additive Effects of the Active Component of Grapefruit Juice (Naringenin) and Antiarrhythmic Drugs on HERG Inhibition

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