Use-dependent block of the delayed K+ current in rabbit ventricular myocytes

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Abstract
Summary Block of the delayed K+ current, iK, and the concomitant increase in refractoriness is considered an alternative to a decrease of conduction in the treatment of reentry arrhythmias. Ideally an agent should selectively prolong the action potential at high frequencies. A minimum requirement is use-dependent block. A number of drugs were tested for the existence of use dependence by applying a train of depolarizing clamps to single cardiac myocytes of the rabbit ventricle. Development of block during a long depolarizing clamp and recovery from block were also measured. Five of the nine drugs tested, i.e., disopyramide, encainide, quinidine, sotalol, and tedisamil, did not show use dependence. When a train of depolarizing clamps was applied, block was already present for the first depolarization and did not increase with repetition of the pulse. This result suggests block of the channel in the rested state or a very fast block of the open channel. Almokalant and amiodarone, and to a lesser extent dofetilide and E4031, showed use-dependent block, i.e., block increased during the train of depolarizing clamps. The time constant for the open channel block was 1.07 seconds for almokalant and 0.67 seconds for amiodarone. Recovery from block for almokalant and amiodarone was very slow: time constants measured at −50 mV were 13.9 and 12.7 seconds, respectively. For dofetilide it was in the order of minutes. The existence of this slow recovery explains why frequency-dependent changes in block were negligible or absent for frequencies above 0.5 Hz. Future research should be aimed to select drugs with a slower onset of active state block and faster recovery from block.

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