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.