Electrophysiological effects of KT-362, a new antiarrhythmic agent with vasodilating action, on isolated guinea pig ventricular muscle.
The effects of KT-362, a newly synthesized vasodilating and antiarrhythmic agent, on transmembrane action potentials were examined in isolated papillary muscles of guinea pig. KT-362 (3 x 10(-6) to 3 x 10(-5) M) caused a dose-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential without affecting the resting potential. In the presence of KT-362, 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 frequency. The time constant for the recovery of Vmax from the use-dependent block was 2.8-2.9 s. The curves relating membrane potential and Vmax were shifted by KT-362 (10(-5) M) in the direction of more negative potentials (8.6 mV). In papillary muscles treated with KT-362 (10(-5) M), the Vmax of test action potential preceded by conditioning clamp pulses to 0 mV was progressively decreased with increasing number of pulses, while it was little affected by the duration of each clamp pulse within the range from 10 to 700 ms. These findings suggest that KT-362 has quinidine-like use-dependent inhibitory action on the fast sodium channel of cardiac muscles by the binding to the channel mainly during its activated state. At high concentrations (greater than or equal to 3 x 10(-5) M), KT-362 also suppressed the slow action potential in K+ depolarized papillary muscles.
Kodama
I
I
Department of Circulation and Respiration, Nagoya University, Japan.
Wakabayashi
S
S
Toyama
J
J
Shibata
S
S
Yamada
K
K
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D013841:Thiazepines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D013841:Thiazepines; D014665:Vasodilator Agents; C051271:KT 362