Mechanism of inhibition of the Na current by tocainide in guinea-pig isolated ventricular cells

Tocainide blocked the Na current (I-Na) in ventricular myocytes in either a tonic or a phasic block manner, having a higher affinity for the inactivat ed state (Kd(i) = 18 mu M) than for the rested state (Kd(rest) = 606 mu M). The degree of phasic block was enhanced and the onset of phasic block was faster with an increase in pulse duration as well as at less-negative holdi ng potential (HP). The recovery-time constant from the phasic block of I-Na induced by tocainide was independent of either the HP or the removal of fa st inactivation. After removal of fast inactivation, tocainide showed the p ulse-duration dependency of phasic block but not the voltage dependency. Th ese results suggest that tocainide could bind to the inactivated-state rece ptor through the hydrophilic pathway and leave the receptor through the hyd rophobic pathway, producing the tonic and phasic block of I-Na. (C) 1999 El sevier Science Inc. All rights reserved.