Abstract
The effects of fendiline on the transient outward current (I(to)) were investigated in rat ventricular cardiomyocytes. Extracellularly applied fendiline reduced peak and steady-state current amplitude of I(to); the inactivation of I(to) was accelerated by the drug, which reflects onset of block. The described effects were concentration dependent: half-maximal effects were achieved at ~3 μM fendiline. Intracellularly applied fendiline (3 μM) did not affect I(to) within 5 min. The steady-state current amplitude of I(to) was more efficiently suppressed by the drug at 22 ± 1°C than at 36 ± 1°C. The recovery of I(to) was analyzed by the application of twin depolarizing voltage pulses, interrupted by variable pulse intervals. In the presence of fendiline, recovery of I(to) was about twofold slower than that under control conditions, independent of the drug concentration used, which reflects offset from block. Concentration-dependent onset but concentration- independent offset of block suggest that the described time constants correspond to voltage-dependent net binding and unbinding, respectively, of fendiline at its receptor sites. It is proposed that fendiline binds extracellularly at positive potentials to I(to) channels in their open state and dissociates from the channels at rest.
Original language | English |
---|---|
Pages (from-to) | 905-911 |
Number of pages | 7 |
Journal | Journal of Cardiovascular Pharmacology |
Volume | 33 |
Issue number | 6 |
DOIs | |
State | Published - Jun 1999 |
Keywords
- Binding site
- Channel state
- Fendiline
- Offset from block
- Onset of block
- Transient outward current