Exaggerated block of hERG (KCNH2) and prolongation of action potential duration by erythromycin at temperatures between 37°C and 42°C

Background Environmental and genetic factors interact to define susceptibility to drug-induced long QT syndrome. Although erythromycin induces long QT syndrome, substantial variability exists with regard to its incidence. Objectives Because fever frequently results in empiric antibiotic usage, we assessed whether temperatures over the range from 36° to 42°C determined responsiveness to erythromycin (100 μmol/L). Methods I hERG was recorded in mammalian cells, and action potentials were recorded in neonatal ventricular mouse myocytes. Results Erythromycin (100 μmol/L) produced no block of I hERG at 22°C but produced significant block at 37°C. Extent of block of I hERG increased linearly (r = 0.46, P hERG at 22°C, erythromycin was applied within the patch pipette. Under these conditions, erythromycin rapidly blocked I hERG even at 22°C. The F656C mutation in the distal S6 of KCNH2 completely abrogated block of I hERG measured at 37°C. Conclusion Progressively greater block of hERG and prolongation of APD by erythromycin was observed at temperatures between 36 and 42°C. Temperature-dependent block of I hERG is explained by temperature-dependent access of erythromycin to the intracellular binding site at F656.