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

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