Key result
Physiological temperature increases erythromycin hERG channel inhibition potency ~11-fold compared to room temperature.
Why the study?
Erythromycin remarkably increases hERG inhibition from room to physiological temperature, and understanding its mechanism helps determine which compounds warrant further study.
Does erythromycin inhibit hERG channels differently at physiological temperature compared to room temperature?
Does erythromycin inhibit hERG channels differently at physiological temperature compared to room temperature?
Absolute Event Rate: 150% vs 1671%
The ~11-fold stronger hERG channel inhibition by erythromycin at physiological temperature demonstrates that preclinical proarrhythmic screening assays conducted solely at room temperature may underestimate cardiac safety risks.
Room-temperature hERG assays may underestimate erythromycin cardiotoxicity; leaves open clinical arrhythmia relevance pending human data.
Erythromycin is one of the few compounds that remarkably increase ether-a-go-go-related gene (hERG) inhibition from room temperature (RT) to physiological temperature (PT). Understanding how erythromycin inhibits the hERG could help us to decide which compounds are needed for further studies. The whole-cell patch clamp technique was used to investigate the effects of erythromycin on hERG channels at different temperatures. While erythromycin caused a concentration-dependent inhibition of cardiac hERG channels, it also shifted the steady-state activation and steady-state inactivation of the channel to the left and significantly accelerated the onset of inactivation at both temperatures, although temperature itself caused a profound change in the dynamics of hERG channels. Our data also suggest that the binding pattern to S6 of the channels changes at PT. In contrast, cisapride, a well-known hERG blocker whose inhibition is not affected by temperature, does not change its critical binding sites after the temperature is raised to PT. Our data suggest that erythromycin is unique and that the shift in hERG inhibition may not apply to other compounds.
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Cheng et al. (2023) studied hERG channel function. Erythromycin vs. Pre-drug baseline and room temperature was evaluated on IC50 for hERG channel inhibition. Erythromycin inhibited hERG channels in a temperature-dependent manner, with an IC50 of 150 μM at physiological temperature compared to 1671 μM at room temperature.
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