Abstract
Effects of KW-3049 on electrophysiological properties of the heart were examined using Langendorff-perfused hearts and superfused sinus nodal tissues of rabbits and superfused guinea-pig ventricular muscles. In rabbit hearts, KW-3049 at concentrations above 10-7 M caused a dose-related prolongation of atrio-His bundle conduction time (AH), whereas His bundle-ventricular conduction time (HV) was unaffected. In spontaneously firing rabbit sinus nodal tissues, KW-3049 at concentrations above 10-8 M prolonged cycle length significantly. At 10-6 M, amplitude and the maximum upstroke velocity of sinus nodal action potential were decreased as well. In normally polarized guinea-pig ventricular muscles under 4 mM [K+]0, KW-3049 at concentrations above 10-6 M shortened the action potential duration without affecting the resting membrane potential and the maximum upstroke velocity of action potential (Vmax) . The Vmax of slow action potentials induced by isoproterenol at 10-7 M was inhibited significantly by additional application of KW-3049 at concentrations above 10-9 M. At above 10-8 M, the amplitude and duration of slow action potentials were reduced significantly. The potency of this slow action potential inhibition by KW-3049 was slightly less than that of nifedipine, while it was 10 to 100 times greater than that of verapamil. Spontaneous activity of ventricular muscles induced by BaCl2 at 1 mM was abolished completely at 16 min after application of KW-3049 at 10-7 M. These results suggest that KW-3049 may have a potent and selective inhibitory action on cardiac slow calcium channels.
