Vol. 290, Issue 2, 515-523, August 1999

Mechanism of Transient Outward K⁺ Channel Block by Disopyramide

Jose A. Sanchez-Chapula

Unidad de Investigacion "Carlos Mendez," Centro de Investigaciones Biomedicas de la Universidad de Colima, Colima, Mexico

The block of the transient outward K⁺ current (I_to) by disopyramide was studied in isolated rat right ventricular myocytes using whole cell patch-clamp techniques. Disopyramide at a concentration of 10 to 1000 µM reduced peak I_to and accelerated the apparent rate of current inactivation. The onset 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 conditioning 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 100 µM 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 disopyramide was trapped by the open channel. Taken together, these results suggest that disopyramide rapidly blocks channels in the open state and that unblock occurs from the inactivated state.