STATE-DEPENDENT BLOCK UNDERLIES THE TISSUE-SPECIFICITY OF LIDOCAINE ACTION ON BATRACHOTOXIN-ACTIVATED CARDIAC SODIUM-CHANNELS

We have identified two kinetically distinct modes of block, by lidocai ne, of cardiac sodium channels, activated by batrachotoxin and incorpo rated into planar lipid bilayers. Here, we analyze the slow blocking m ode which appears as a series of nonconducting events that increase in frequency and duration with increasing lidocaine concentrations. This type of block occurred rarely, if at all, for the skeletal muscle sod ium channel subtype. Kinetic analysis showed that a linear open-closed -blocked model is sufficient to account for the major features of our data. Slow block occurs from a long closed state that is a distinguish ing characteristic of cardiac channels under these conditions. Slow bl ock showed no significant voltage dependence in the range of -60 to -2 0 mV for which the detailed kinetic analysis was performed, and was no t elicited by application of the permanently charged lidocaine derivat ive QX-314. By contrast, the fast block, described in the companion pa per, results from drug binding to the open state, and is similar for c ardiac and skeletal muscle sodium channels. Application of trypsin to the cytoplasmic end of the channel eliminates both the spontaneous, lo ng, gating closures and slow block. Thus, the lidocaine-sensitive clos ed state of batrachotoxin-activated cardiac sodium channels exhibits a protease susceptibility resembling that of the inactivated state of u nmodified sodium channels. It is the slow block caused by lidocaine bi nding to this closed state that underlies the channel-subtype specific ity of lidocaine action in our experiments.