Amiodarone irrecoverably impairs the function of human ether-a-go-go-related gene potassium channels
Bibliographic record
Abstract
The class III antiarrhythmic drug amiodarone (AMIO) inhibits the rapidly activating delayed rectifier K + current that is conducted by the human ether-a-go-go-related gene (hERG) encoded channel. Like other class III antiarrhythmic drugs, AMIO can cause long QT syndrome. In the present study, we investigated the effects of AMIO and its major metabolite, desethylamiodarone, on hERG channels expressed in human embryonic kidney (HEK)293 (hERG-HEK) as well as in cardiomyocyte-derived H9c2 cells. Our results show that after acute inhibition of hERG current (I hERG ) by AMIO (IC 50 of 0.2 μ M) or desethylamiodarone (IC 50 of 0.5 μ M), continuous washout of the drug for 20 to 25 minutes during whole-cell patch clamp recordings did not lead to any current recovery. Furthermore, when hERG-HEK cells were cultured with AMIO overnight, and I hERG was recorded in a drug-free bath solution, AMIO treatment resulted in a concentration-dependent inhibition of I hERG with an IC 50 of 0.3 μ M. In contrast, such overnight treatments did not affect the expression of hERG channels shown by Western blot analyses. However, the mature hERG protein of AMIO-pretreated cells cultured in a drug-free medium degraded faster than that of control cells, indicating that AMIO treatment modified the property of mature hERG channels, making them permanently nonconductive and less stable. Consistently, our results showed that following AMIO-mediated inhibition, recovery of I hERG during cell culture in drug-free conditions resulted from newly made channels, and a full recovery took up to 20 hours. Thus, AMIO-mediated hERG inhibition may persist for tens of hours after drug discontinuation, which has clinical importance. Significance Statement Amiodarone (AMIO) is a frequently used antiarrhythmic drug that blocks human ether-a-go-go-related gene (hERG) potassium channels. The present study revealed that, unlike other hERG-interacting drugs, AMIO irrecoverably inhibits hERG channel currents. Upon removal of AMIO after hERG inhibition, recovery of hERG currents relies on newly made channels in a process of up to 20 hours. Thus, lingering effects on hERG channels after AMIO discontinuation are anticipated, which have important clinical implications.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".