Influence of electrolyte imbalance, acidosis and temperature on
block of hERG.
For each drug, we measured how the potency of hERG block was modified by
i) kalaemic variation (3/5/7 mM K+ representing hypo-,
normo-, and hyper-kalaemia, respectively); ii) variation in
extracellular magnesium (0.5/1/2 mM Mg2+ representing
hypo-, normo-, and hyper-magnesemia, respectively); iii) pH (pH 7.4, 7
and 6.5 representing normal, acidosis and severe acidosis,
respectively); and iv) temperature (37 °C and 42 °C representing
physiological and febrile temperature). Hypokalaemia significantly
increased potency of hERG block for both chloroquine and
hydroxychloroquine (1.4- and 2.0-fold increase, respectively) while
hyperkalaemia significantly decreased potency of chloroquine (2.1-fold
decrease). Azithromycin was insensitive to kalaemic variation (Figure 2,
Table 1). Hypomagnesemia had no significant effect on potency of any of
the drugs. However, hypermagnesemia significantly increased potency of
hERG block for both chloroquine and hydroxychloroquine (2.8-fold and
1.3-fold respectively (Figure 2, Table 1)). Reduction in pH from 7.4 to
7 significantly decreased potency of all drugs (3.4-, 5.0- and 2.2-fold
for chloroquine, hydroxychloroquine, and azithromycin respectively) and
this trend continued with further reductions in potency observed at pH
6.5 (Figure 2, Table 1). Finally, increased temperature (42 °C)
significantly decreased potency of chloroquine and hydroxychloroquine by
1.9- and 1.6-fold respectively, but increased potency of azithromycin by
3.9-fold (Figure 2, Table 1).