hERG channels mediating the rapid delayed rectifier K+ current (IKr) are important for normal ventricular repolarization (1). Various cardiac and non-cardiac drugs inhibit hERG channel function and thereby prolong the QT interval of the electrocardiogram, which carries a risk of potentially fatal torsades de pointes (TdP) arrhythmia (1, 2). Macrolide antibiotics such as erythromycin have been associated with cases of TdP, but this is usually against a background of other risk factors (3, 4). By contrast, very recent in vitro data suggest that pretreatment with low concentrations of erythromycin (that produce little pharmacological blockade of hERG) may significantly antagonise – and therefore potentially protect against – the inhibitory effects of normally potent hERG blocking drugs (5). To date the therapeutic potential and the mechanism underlying this concept have not yet been established. Here we investigated the effect of a low concentration of erythromycin on the pharmacological sensitivity of hERG current (IhERG) and native IKr to terfenadine, a potent inhibitor of the hERG channel. Whole cell patch clamp recordings were made of hERG/IKr tail currents elicited by a repolarising step to -40 mV following an activating step to +20mV either from HEK-293 stably expressing WT hERG or from rabbit ventricular myocytes isolated from the hearts of New Zealand White rabbits killed in accordance with UK Home Office legislation. Data are presented as mean ± SEM; statistical comparisons were made using an unpaired t test. IhERG and IKr tails were inhibited by 3μM of erythromycin, a concentration previously reported to cause a substantial reduction in hERG sensitivity to terfenadine (5), by 15.3 ± 6.0 % (n=5 cells) and 28.2 ± 3.8 % (n=6 cells) respectively. Terfenadine sensitivity was then assessed in the absence and presence of 3μM erythromycin. 100 nM of terfenadine, a concentration close to the half-maximal inhibitory (IC50) value for IhERG in our hands (118 ± 0.13 nM; n=4 to 6 for each of four concentrations), produced an inhibition of ventricular IKr of 33.0 ± 6.5 % (n=5 cells; vs hERG 47.8 ± 6.1 %, n=6, NS). Finally, the effect of 100 nM terfenadine was tested following a preincubation for 15 min of the cells with 3 μM erythromycin. In the maintained presence of 3 μM erythromycin, IhERG was inhibited by 49.7 ± 13.3 % (n=4) (vs 47.6 ± 6.1 % in absence of erythromycin, n=6, NS) and IKr by 14.3 ± 4.1 % (n=5) (vs 33.0 ± 6.5 %; n=5; p<0.01). These data indicate that, under the conditions of this study, exposure to a low concentration of erythromycin pretreatment resulted in reduced sensitivity of IKr but not IhERG to 100 nM terfenadine.