The mode of action of tedisamil on voltage-dependent K+ channels
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The mechanism of the interaction of tedisamil with voltage-dependent K+ channels was studied using whole-cell and single-channel recordings in a variety of species and cell types. In K+ channels with rapid activation kinetics (Ito of rat ventricular myocytes; IA of mouse astroglial cells), tedisamil enhanced the kinetics of inactivation of the current without significantly suppressing the amplitude of the initial current. In K+ channels with slower activation/inactivation kinetics, tedisamil had a divergent effect. On IK of the glial cells, which have slow activation and inactivation kinetics, the kinetics of inactivation were enhanced and the initial peak current was reduced. On the other hand, in IK of guinea-pig ventricular myocytes, which have even slower activation kinetics with no inactivation, tedisamil slowed or completely suppressed the activation of the current. Finally, in K+ channels with rapid activation but slow inactivation kinetics (pedestal-type current of rat ventricular myocytes), tedisamil accelerated the inactivation without affecting the initial current. Thus, the prime determinant of the blocking mode of tedisamil appeared to be the kinetics of activation of the K+ channel; that is, the slower the kinetics of activation of the channel, the greater the initial block by the drug. Unitary Ito currents recorded in rat ventricular myocytes showed that tedisamil induced a rapid flicker block of the open channel and prolonged the time between the burst of openings without any effect on the unitary conductance. These effects were modeled by assuming that the drug bound to the open channel at a finite rate. Thus, tedisamil appears to decrease K+ currents by interacting uniformly with the open state of the channel.
Key Wordstedisamil K+ channel activation kinetics Ito IK
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