Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide

Abstract

The delayed K+ current (ik) and its change by dofetilide was studied in single myocytes from the guinea pig and rabbit heart using the two-electrode voltage clamp technique. In rabbit myocytes, ik consisted of only one component (Kr), which developed for moderate depolarizations and with a fast time course. In guinea pig myocytes, activation consisted of a rapid and a slow component, and the latter (Ks) only became manifest for depolarizations positive to 0 mV. Ks was resistant to block by dofetilide. Kr, however, was very sensitive: Kd 3.9 x 10(-9) M, Hill coefficient 2.0 (n = 5). The effect was voltage-dependent block increasing at depolarized levels. Block development was time dependent and occurred in two phases: a first fast and voltage-dependent phase was followed by a second much slower phase (time constant of 4.4 +/- 0.48 sec (n = 11). Recovery from block was slower as the membrane potential became more negative. This resulted in the absence of a steady-state frequency-dependent effect at negative membrane potentials. It is concluded that dofetilide is an efficient blocker of the fast component of ik. The block, as well as recovery, are voltage and time dependent. Block is greater at more depolarized levels, recovery is slower at more hyperpolarized levels.