TOPIC

Automated High Throughput Na+ Late Current Assay on QPatch HT Platform for CiPA28

Journal

SPS 2018

Author(s)

Muthukrishnan Renganathan, Bryan J. Koci, Andi Cook, Haiyang Wei, Diane Werth

Year

2018

In cardiac muscle, sustained inward Na+ currents, also known as late Na+ currents (INa-L), occur under physiological conditions during the cardiac Action Potential AP (AP). In addition to extending the plateau duration before AP recovery, an increased INa-L can lead to the development of various triggers and substrates (early after depolarization, EAD) for arrhythmogenesis. Inhibition of INa-L current can prevent proarrythmia by reducing or reversing EAD even in the presence of a prolonged QTc interval (e.g. Ranolazine).

Therefore, INa-L is one of the seven ion channels selected for
evaluation in the comprehensive in vitro proarrythmia assay (CiPA).

Eurofins is a contributor to the Ion-Channel Work-Group of the
FDA/HESI/CIPA initiative, supporting validation of automated high-throughput methods on the QPatch HT to support the program consortium. These methods measure 1) enhancement or 2) inhibition of INa-L current, using either step pulse or ramp pulse protocol and reference pharmacology, ATXII. Three key parameters, INa-L current, leak current, time-matched vehicle control were measured. The data generated in this study demonstrate that measuring INa-L current charge measurement is superior to measuring INa-L current amplitude for both test and ramp pulse. We investigated the effects of CiPA-28 compounds on INa-L at the EC50 of ATXII (30nM). With the un-blinding of CiPA Phase I (12) compounds, Chlorpromazine, Diltiazem, and Mexiletine were identified as hits. Our results indicate that none of the CiPA-28 compounds potentiated the INa-L current.

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