Use-dependent block of sodium current by ethmozin in voltage-clamped internally perfused canine cardiac purkinje cells

Block of sodium current ( I Na) by ethmozin (moricizine), an antiarrhythmic drug, was investigated in isolated, voltage-clamped, canine cardiac Purkinje cells. Initial block of I Na by ethmozin (2μ m) in non-inactivated cells (held at −150 mV) was 9.3±1.2% ( s.d.). Additional “use-dependent” block developed in response to repetitive depolarizations. This block was both frequency-dependent and dose-dependent with the fall in peak I Na greater at increasing depolarization frequencies (0.625 to 4 Hz) and with increasing dose (2 μ m to 20 μ m). Use-dependent block was modeled according to the guarded receptor hypothesis assuming ingress to the channel binding site during the open state of the channel, and egress from the channel independent of the kinetic state of the channel. The rate constants (on-rate=2100±100 ( s.d.)/ m/ms and off-rate=1.7±0.3 ( s.d.) 10 −5/ms) were used to predict the time course of I Na block in response to repeated depolarizations and the dose-response relationship of steady-state used-dependent block measured in independent experiments. We conclude that ethmozin blocks I Na in Purkinje cells in both a non-use-dependent and a use-dependent manner and that the guarded receptor model is useful in describing the use-dependent block.