Slowly developing activation block of cardiac sodium channels by a lidocaine analog, transcainide.

The working mechanism of Na+ channel block by a lidocaine analog, transcainide, was investigated. The Na+ channel block was measured directly by recording the slowly inactivating Na+ current under voltage clamp conditions in rabbit cardiac Purkinje fibers and indirectly by using the maximal rate of depolarization as an index of Na+ current in guinea pig trabecular muscles. At a concentration of 10(-7) M, transcainide was found to bind uniquely to the activated state of the channel and not to the rested or inactivated state. The block was markedly frequency dependent. The kinetics at 37 degrees C was extremely slow with time constants for onset of block ranging between 36 min at a frequency between 0.5 s-1 and 2.2 min at a frequency of 4 s-1; time constant for recovery from block was 32 min as measured by the single stimulus method but became shorter the higher the frequency. It is concluded that transcainide is not essentially different from other antiarrhythmics of the local anesthetic type, but is characterized by very slow kinetics of binding and unbinding to the activated "open" Na+ channel.