Electrophysiological effects of AFD-21 and AFD-19, new antiarrhythmic compounds on papillary muscles and single ventricular myocytes isolated from guinea-pig hearts.
1. The effects of AFD-21, a newly synthesized antiarrhythmic compound, and AFD-19, its active metabolite, on transmembrane action potentials were examined in right ventricular papillary muscles and single ventricular myocytes isolated from guinea-pig hearts. 2. In papillary muscles, AFD-21 10(-5) M caused a slight prolongation of action potential duration (APD), while AFD-19 above 10(-6) M shortened APD in a dose-dependent manner. 3. Both AFD-21 and AFD-19 above 10(-6) M caused a significant and dose-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential without affecting the resting membrane potential. 4. In the presence of AFD-21 or AFD-19, trains of stimuli at rates greater than or equal to 0.2 Hz led to an exponential decline in Vmax. This use-dependent block was enhanced at higher stimulation frequencies. A time constant for the recovery of Vmax from the use-dependent block was 2.9 s for AFD-21 and 3.6s for AFD-19. 5. The curves relating membrane potential and Vmax were shifted by AFD-21 (10(-5) M), or AFD-19 (10(-5) M) to the direction of more negative potentials by 5.3 mV and 5.1 mV respectively. 6. In single ventricular myocytes treated with AFD-21 (10(-5) M) or AFD-19 (10(-5) M), Vmax of test action potentials preceded by conditioning clamp pulses to 0 mV was decreased progressively as the clamp pulse duration was prolonged. 7. These findings suggest that both AFD-21 and AFD-19 have use- and voltage-dependent inhibitory action on the sodium channel by binding to the channel during its inactivated state, and that the unbinding rate is comparable to that of Class I antiarrhythmic drugs with intermediate kinetics.
Kodama
I
I
Department of Circulation and Respiration, Nagoya University, Japan.
Kamiya
K
K
Kawamura
T
T
Suzuki
R
R
Toyama
J
J
D000200:Action Potentials / Q000187:drug effects; D000605:Amino Alcohols / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D010210:Papillary Muscles / Q000187:drug effects
D000605:Amino Alcohols; D000889:Anti-Arrhythmia Agents; C060006:AFD 21; C060007:4-isobutylamino-1,1-diphenyl-1-butanol maleate