Hormone's heart effects vary sharply by species, complicating drug safety

<p>Oestradiol (17 beta-E2) is reported to prolong the cardiac action potential duration and QT interval, in part by affecting cardiac ion channels. Previous studies found inhibiting 17 beta-E2 effects on the repolarizating cardiac KV7.1/KCNE1 channel, or its native current, in heterologous expression systems or tissue from animal species. However, there is variability in reported 17 beta-E2 effects and required concentrations. In this work, we aimed to test whether a contributing factor may be different pharmacological profiles of KV7.1/KCNE1 channels from different species. To this end, we used the two-electrode voltage clamp technique to characterize and quantitatively compare the effects of 17 beta-E2 on KV7.1/KCNE1 channels from guinea pig, zebrafish, and rabbit expressed in Xenopus oocytes. We found that KV7.1/KCNE1 of all tested species is inhibited by 17 beta-E2, although with species variability in the response. The guinea pig channel responded similar to previous reports for the human channel with a concentration-dependent reduction in the overall conductance. In contrast, the rabbit channel was sensitive to lower 17 beta-E2 concentrations, whereas the zebrafish channel responded with an additional inhibiting effect seen as a shifted voltage dependence of channel opening toward more positive voltages. By testing the 17 beta-E2 response of KV7.1 alone, and by combining KV7.1 and KCNE1 subunits from different species, we conclude that the species variability is not simply dictated by one of the subunits but rather by the KV7.1/KCNE1 complex. The species variability in the 17 beta-E2 response of KV7.1/KCNE1 could be considered when choosing appropriate animal models or interpreting findings from different experimental models.</p>