Exaggerated block of hERG (KCNH2) and prolongation of action potential duration by erythromycin at temperatures between 37 degrees C and 42 degrees 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 degrees to 42 degrees C determined responsiveness to erythromycin (100 micromol/L).
METHODS: I(hERG) was recorded in mammalian cells, and action potentials were recorded in neonatal ventricular mouse myocytes.
RESULTS: Erythromycin (100 micromol/L) produced no block of I(hERG) at 22 degrees C but produced significant block at 37 degrees C. Extent of block of I(hERG) increased linearly (r = 0.46, P < .01) as temperature increased between 36 degrees C and 42 degrees C. To assess physiologic relevance, action potential duration (APD) was recorded at temperatures between 36 degrees C and 42 degrees C in neonatal ventricular myocytes. Significantly greater prolongation of APD by erythromycin was observed at 42 degrees C compared with 37 degrees C. To assess whether transmembrane diffusion of erythromycin was the rate-limiting step for block of I(hERG) at 22 degrees C, erythromycin was applied within the patch pipette. Under these conditions, erythromycin rapidly blocked I(hERG) even at 22 degrees C. The F656C mutation in the distal S6 of KCNH2 completely abrogated block of I(hERG) measured at 37 degrees C.
CONCLUSION: Progressively greater block of hERG and prolongation of APD by erythromycin was observed at temperatures between 36 and 42 degrees C. Temperature-dependent block of I(hERG) is explained by temperature-dependent access of erythromycin to the intracellular binding site at F656.