Mechanism of transient outward K+ channel block by disopyramide

The block of the transient outward K+ current (I-to) by disopyramide was st udied in isolated rat right ventricular myocytes using whole cell patch-cla mp techniques. Disopyramide at a concentration of 10 to 1000 mu M reduced p eak I-to and accelerated the apparent rate of current inactivation. The ons et of block was assessed using a double pulse protocol with steps from -70 to +50 mV. As the duration of the first (conditioning) pulse was increased from 1 to 50 ms, block was increased. Further prolongation of the condition ing pulse resulted in relief of block, which was nearly complete with a 1-s conditioning pulse. In the absence of drug, the recovery from inactivation of I-to at -70 mV was fast and best fit with a single exponential function having a time constant of 33 +/- 13 ms. In contrast, in the presence of 10 0 mu M disopyramide, recovery from apparent inactivation was biexponential with time constants of 35 +/- 13 ms and 7.16 +/- 1.5 s. The time course of the slow component was used to estimate recovery of channels from block by disopyramide. Recovery from block was voltage-dependent, suggesting that di sopyramide was trapped by the open channel. Taken together, these results s uggest that disopyramide rapidly blocks channels in the open state and that unblock occurs from the inactivated state.