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 × 10−6 to 3 × 10−5M) caused a dose-dependent decrease in the maximum upstroke velocity (JOURNAL/jcph/04.02/00005344-198806000-00009/ENTITY_OV0312/v/2017-07-28T025219Z/r/image-pngmax) of the action potential without affecting the resting potential. In the presence of KT-362, trains of stimuli at rates ≥0.2 Hz led to an exponential decline in JOURNAL/jcph/04.02/00005344-198806000-00009/ENTITY_OV0312/v/2017-07-28T025219Z/r/image-pngmax. This use-dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of JOURNAL/jcph/04.02/00005344-198806000-00009/ENTITY_OV0312/v/2017-07-28T025219Z/r/image-pngmax from the use-dependent block was 2.8-2.9 s. The curves relating membrane potential and JOURNAL/jcph/04.02/00005344-198806000-00009/ENTITY_OV0312/v/2017-07-28T025219Z/r/image-pngmax were shifted by KT-362 (10−5M) in the direction of more negative potentials (8.6 mV). In papillary muscles treated with KT-362 (10−5M), the JOURNAL/jcph/04.02/00005344-198806000-00009/ENTITY_OV0312/v/2017-07-28T025219Z/r/image-pngmax 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 (≥3 × 10−5M), KT-362 also suppressed the slow action potential in K+ depolarized papillary muscles.
Received May 19, 1987; revision accepted August 25, 1987.
Address correspondence and reprint requests to Dr. I. Kodama at Department of Circulation and Respiration, The Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464, Japan.
© Lippincott-Raven Publishers.