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12.- 16.07.2021 | Physiology 2021

210613 Physiology Event

Conference Venue: Virtual Event 
Go to the Conference website here

Dr. Alison Obergrussberger (Nanion Technologies GmbH) will present the following poster:

"Reliable identification of cardiac liability in drug discovery using automated patch clamp: Considerations and best practices for high throughput recordings of NaV1.5"

When: Tuesday 13 July


For reliable identification of cardiac safety risk, compounds should be screened for effects on cardiac ion channels in addition to hERG, including NaV1.5 and CaV1.2. Automated patch clamp (APC) instruments are increasingly adopted for cardiac safety measurements but cross-site and cross-platform comparisons of IC50 values has identified the need for standardized protocols for reliable pharmacology. In this study, we identified different parameters that might affect IC50s of compounds on NaV1.5 peak and late currents recorded using APC. For example, we found that using frozen cells or running cultures did not influence IC50 values of compounds tested on NaV1.5 peak, but that voltage protocol, holding potential, temperature and incubation time could all influence IC50s. Temperature affected the Vhalf of inactivation, shifting the Vhalf of inactivation by approximately 7 mV to more negative potentials at 37°C vs room temperature, and also affected the IC50 of mexiletine which was 82.1 ± 19.4 µM (n = 14) at 37°C compared with 181.5 ± 29.0 µM (n = 10) at room temperature. The IC50s of compounds were compared on peak current elicited using different voltage protocols and using different holding potentials. For example, ranolazine and tamoxifen, two blockers known to block NaV1.5 in the open state showed more potent IC50s at a holding potential of -80 mV compared with -95 mV (ranolazine IC50 = 145.64 µM at holding potential -95 mV and 99.75 µM at holding potential -80 mV; tamoxifen IC50 = 21.43 µM at holding potential -95 mV and 2.90 µM at holding potential -80 mV). Compound incubation time also influenced IC50s and whereas compounds such as lidocaine reached steady state within 3 mins, some compounds, e.g. flecainide and bepridil required 5 mins or more to reach steady state.

We suggest outlines for best practices for recording NaV1.5 peak and late current using APC which include the use of the CiPA step-ramp protocol at physiological temperature, a minimum compound incubation time of 5 min, a replicate number of 4 and the use of positive and negative controls to ensure reliable IC50s.

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