Concerted suppression of I and activation of I by ivabradine, an HCN-channel inhibitor, in pituitary cells and hippocampal neurons.

Ivabradine (IVA), a heart-rate reducing agent, is recognized as an inhibitor of hyperpolarization-activated cation current (I) and also reported to ameliorate inflammatory or neuropathic pain. However, to what extent this agent can perturb another types of membrane ion currents in neurons or endocrine cells remains to be largely unknown. Therefore, the I or other types of ionic currents in pituitary tumor (GH) cells and in hippocampal mHippoE-14 neurons was studied with or without the presence of IVA or other related compounds. The IVA addition caused a time- and concentration-dependent reduction in the amplitude of I with an IC value of 0.64 μM and a K value of 0.68 μM. IVA (0.3 μM) shifted the I activation curve to a more negative potential by approximately 8 mV, despite no concomitant change in the gating charge. Additionally, IVA was found to increase M-type K current (I) together with a rightward shift in the activation curve. In cell-attached current recordings, IVA (3 μM) applied to the bath increased the open probability of M-type K channels; however, it did not modify single-channel conductance of the channel. In current-clamp voltage recordings, IVA suppressed the firing of spontaneous action potentials in GH cells; and, further addition of linopirdine attenuated its suppression of firing. In hippocampal mHippoE-14 neurons, IVA also effectively increased I amplitude. In summary, both inhibition of I and activation of I caused by IVA can synergistically combine to influence electrical behaviors in different types of electrically excitable cells occurring in vivo.