State dependence of ethacizin and ethmozin block of sodium current in voltage clamped and internally perfused cardiac Purkinje cells.

Ethacizin, a positively charged analog of ethmozin, reduces the cardiac action potential upstroke and blocks peak sodium current (INa). We investigated ethacizin block of INa in 11 cells and ethmozin block in 4 cells at 20 degrees C. Rest block measured as the relative INa decrease for the first pulse in drug after 3 to 6 min at the holding potential was negligible for ethacizin but substantial (16% at 5 microM) for ethmozin. Use-dependent block developed exponentially; the time course of block and relative INa remaining were concentration-dependent. Frequency dependence of block between 0.5 and 4 cps was weak for ethacizin. Varying the depolarization duration from 5 to 100 msec, while keeping the recovery interval constant, did not alter the block by ethacizin. In contrast, prolonging the clamp step in ethmozin from 5 to 100 msec increased the rate and depth of block. Apparent binding rates for each drug were calculated using the assumptions of the guarded receptor model. We conclude that ethacizin blocks INa in a use-dependent manner by binding to a transiently available state such as the open state. In contrast, ethmozin block of INa exhibits both rest block and use-dependent block. Use-dependent block can be attributed to binding to a state (or states) maintained during depolarization such as the inactivated state. With these similar drugs, charge appears to be an important determinant of state-dependent binding.