Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels

Kv1.1 and Kv7.2/7.3 channels control excitability of neuronal cells. As hyperexcitability is a sign of neuropathic pain, epilepsy, and anxiety disorders, these channels may be important molecular targets of amitriptyline that cause pharmacological as well as toxicological effects by altering neuronal excitability. Since the molecular mechanisms underlying these effects of amitriptyline have not been fully elucidated, we aimed to characterize the interaction of amitriptyline with human Kv1.1 and Kv7.2/7.3 channels. We also intended to establish the interaction of amitriptyline with the Kv7.2/7.3 channel opener, retigabine.

Kv1.1 and Kv7.2/7.3 channels were expressed in human embryonic kidney cells and in Chinese hamster ovary cells. The effects of amitriptyline and retigabine were studied with the patch-clamp technique.

Amitriptyline inhibited Kv1.1 and Kv7.2/7.3 channels in a concentration-dependent and reversible manner. The IC50-value was 22 +/- 3 microM (n = 33) and 10 +/- 1 microM (n = 40), respectively. Deactivating inward currents of Kv7.2/7.3 channels were inhibited with an IC50-value of 4.2 +/- 0.6 microM (n = 32). Inhibition of Kv7.2/7.3 channels by amitriptyline reversibly depolarized the resting membrane potential. Retigabine reversed both the inhibitory action of amitriptyline on Kv7.2/7.3 channels as well as the depolarization of the membrane potential.

Since amitriptyline inhibited Kv1.1 and Kv7.2/7.3 channels only at toxicologically relevant plasma concentrations, our results suggest a role for these channels in the neuroexcitatory side effects of amitriptyline. As the inhibitory effects of amitriptyline were reversed by retigabine, a combination of amitriptyline and retigabine could be of additional benefit in the therapy of neuropathic pain.