Cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel

Abstract

Lidocaine is known to inhibit the hyperpolarization-activated mixed cation current (Ih) in cardiac myocytes and neurons, as well in cells transfected with cloned Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels. However, the molecular mechanism of Ih inhibition by this drug has been limitedly explored. Here, we show that inhibition of Ih by lidocaine, recorded from Chinese hamster ovary (CHO) cells expressing the HCN1 channel, reached a steady state within one minute and was reversible. Lidocaine inhibition of Ih was greater at less negative voltages and smaller current amplitudes whereas the voltage-dependence of Ih activation was unchanged. Lidocaine inhibition of Ih measured at â '130 mV (a voltage at which Ih is fully activated) was reduced, and Ih amplitude was increased, when the concentration of extracellular potassium was raised to 60 mM from 5.4 mM. By contrast, neither Ih inhibition by the drug nor Ih amplitude at +30 mV (following a test voltage-pulse to â '130 mV) were affected by this rise in extracellular potassium. Together, these data indicate that lidocaine inhibition of Ih involves a mechanism which is antagonized by hyperpolarizing voltages and current flow.