Inhibition by fendiline of the transient outward current in rat ventricular cardiomyocytes.
The effects of fendiline on the transient outward current (Ito) were investigated in rat ventricular cardiomyocytes. Extracellularly applied fendiline reduced peak and steady-state current amplitude of Ito; the inactivation of Ito was accelerated by the drug, which reflects onset of block. The described effects were concentration dependent: half-maximal effects were achieved at approximately 3 microM fendiline. Intracellularly applied fendiline (3 microM) did not affect Ito within 5 min. The steady-state current amplitude of Ito was more efficiently suppressed by the drug at 22 +/- 1 degrees C than at 36 +/- 1 degrees C. The recovery of Ito was analyzed by the application of twin depolarizing voltage pulses, interrupted by variable pulse intervals. In the presence of fendiline, recovery of Ito 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 Ito channels in their open state and dissociates from the channels at rest.
Fassbender
V
V
Pharmakologisches Institut der Universität Mainz, Germany.
Wegener
J W
JW
Shainberg
A
A
Nawrath
H
H
D000818:Animals; D001665:Binding Sites; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D005275:Fendiline / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects*; D066298:In Vitro Techniques; D007474:Ion Exchange; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D015220:Calcium Channels; D015221:Potassium Channels; D005275:Fendiline