Cardiac safety testing is a pivotal aspect of drug development, ensuring that new therapeutics don’t inadvertently harm the heart. A key player in this arena is the rapid delayed rectifier potassium current (I_Kr), mediated by the hERG channel, crucial for cardiac repolarization. Testing drug interference with hERG function is an integral part of the comprehensive in vitro proarrhythmia assay (CiPA) used to assess preclinical proarrhythmic liabilities of new drugs using human-based model systems (such as human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)).

However, measuring I_Kr in hiPSC-CMs is quite challenging (particularly when using high-throughput automated patch-clamp platforms) due to its low current density. A recent study has offered a possible solution to this issue.

Generally, the hERG current is recorded in patch clamp experiments using potassium as the charge carrier. However, unlike many other potassium channels, under certain conditions, the hERG channel is also permeable to cesium (equimolar internal and external cesium). Previous manual patch clamp studies indicated that cesium-based hERG currents can be about five- to ten-fold larger than those based on potassium, suggesting that in certain cases, cesium solutions might be more suitable for measuring drug effects on hERG channel function.

In a recent study, researchers compared the use of traditional potassium ions to equimolar cesium as charge carriers in automated patch-clamp experiments (using Nanion Patchliner and SyncroPatch 384 platforms). They further explored the effects of various (pre)clinical drugs on hERG currents in both CHO-hERG cells and hiPSC-CMs in K⁺ and Cs⁺ solutions.

The use of equimolar Cs⁺ solutions resulted in a ten-fold larger hERG conductance compared to K⁺. This increase in conductance offered a clearer window into the impact of drugs on the hERG channel, particularly important in hiPSC-CMs, where I_Kr currents are typically small. The Cs⁺ currents observed were very similar qualitatively and quantitatively to those recorded earlier in manual patch clamp experiments. Also, testing drug effects on hERG current yielded similar results in K⁺ and Cs⁺ solutions, although the relative amount of inhibition by desipramine, dofetilide, or moxifloxacin was somewhat smaller for the Cs⁺ despite the larger current magnitudes. Importantly, when drugs impact channel inactivation kinetics, cesium should be used with caution.

Overall, the larger conductance observed with cesium could potentially offer a more robust and reliable method for evaluating the effects of certain drugs on the hERG channel, especially in cells with small I_Kr currents, such as hiPSC-CMs or native cardiac cells.

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Find the original article here: Recording ten-fold larger I_Kr conductances with automated patch clamping using equimolar Cs⁺ solutions

Learn more about the automated patch clamp.