Selective inhibition of Kir currents by antihistamines

In the present study, the effects of antihistamines on inwardly rectifying potassium (Kir) channels expressed in Xenopus oocyte were investigated using two-electrode voltage clamp technique. Firstly, effects of antihistamines on two members of Kir2.0 sub-family, Kir2.1 and Kir2.3 were compared. For antihistamines that selectively block histamine H1 receptor, the first-generation antihistamines mepyramine and diphenhydramine inhibited Kir2.3 current by 25.0 ± 2.9% and 17.3 ± 0.7% at concentrations of 100 μM, respectively. In contrast, the second- and third-generation antihistamines astemizole and desloratadine were completely devoid of any inhibitory effect on Kir2.3 current. Histamine H2 receptor antagonist cimetidine, at 100 μM, failed to inhibit Kir2.3 current. On the other hand, Kir2.1 current was not sensitive to any of these drugs. The mepyramine-induced inhibition of Kir2.3 current was significantly reduced by a single point mutation in Kir2.3 (Kir2.3(I213L)), which enhances Kir2.3-PIP2 interaction. Secondly, the effect of mepyramine was also tested on Kir3.4⁎, another member of Kir family. 100 μM mepyramine produced a 30.3 ± 4.6% inhibition on Kir3.4⁎ current. These results suggest that the first-generation histamine H1 receptor antagonists selectively inhibit Kir currents. The inhibitory effect of antihistamines on Kir currents may be involved in their neuronal and cardiac toxic effects caused by drug overdosing.