The effect of TYB-3823, a new antiarrhythmic drug, on sodium current in isolated cardiac cells.
1. Sodium current (INa) blockade by TYB-3823, a newly synthesized antiarrhythmic agent, was investigated in isolated single ventricular myocytes by use of the whole cell patch-clamp technique. 2. TYB-3823 blocked INa under steady-state conditions (Kd,rest = 500 microM, Kd,i = 4.9 microM), findings consistent with a shift in the steady state INa availability curve to more negative potentials. 3. TYB-3823 produced use-dependent block at 2 Hz in conjunction with increase in pulse duration (5-300 ms), that was markedly enhanced at less negative holding potentials. 4. The time course of the onset of block was accelerated and the degree of use-dependent block was decreased at more negative holding potential. The time course of the onset of block was accentuated with enhancing block at more positive holding potentials. 5. The time course of recovery from use-dependent block was accelerated at more negative holding potentials but was accentuated at more positive holding potentials. 6. These results suggest that both tonic block and use-dependent block of sodium channels in cardiac tissue might result from an interaction of TYB-3832 with sodium channels mainly in the inactivated channel states and the kinetics of the interaction between drug and receptor may be modulated by the inactivation gate.
Miyamoto
J
J
1st Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan.
Hisatome
I
I
Matsuoka
S
S
Kosaka
H
H
Kurata
Y
Y
Tanaka
Y
Y
Nawada
T
T
Kotake
H
H
Mashiba
H
H
Sato
R
R
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D015222:Sodium Channels; C059816:restacorin