Summary
The influence of the novel cardiotonic diphenylpiperazinylindole derivative. the racemic DPI 201-106. on cardiac Na+ channels was studied in conventional microelectrode experiments on papillary muscles of guinea pigs and in patch clamp experiments using inside-out patches excised from cultured neonatal rat cardiocytes. The maximal rate of rise (V max) of Na+-dependent action potentials was taken as an estimate for INa. Racemic DPI (3 × 10−6 mol/1) exerts a dual effect as it removes channel inactivation and may also block cardiac Na+ channels. Both drug actions proved highly voltage-dependent but a given change in membrane potential had a strictly different modulating influence on the two effects. The \0V max depression induced by racemic DPI became attenuated due to hyperpolarization and finally tended to disappear at about -90 mV. while at the same time I Na modification became increasingly accentuated. An increase in holding potential caused the non-decaying portion of the macroscopic I Na to increase significantly. Resting inactivation remained operative in non-inactivating cardiac Na+ channels and showed a similar voltage-dependence as in normal Na+ channels. The differential voltage-dependencies of both DPI effects strongly suggest the existence of two binding sites for DPI.
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This work was supported by a grant of the Deutsche Forschungsgemeinschaft (Ko 778/2-1). Bonn, Federal Republic of Germany
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Kohlhardt, M., Fröbe, U. & Herzig, J.W. Removal of inactivation and blockade of cardiac Na+ channels by DPI 201-106 different voltage-dependencies of the drug actions. Naunyn-Schmiedeberg's Arch Pharmacol 335, 183–188 (1987). https://doi.org/10.1007/BF00177721
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DOI: https://doi.org/10.1007/BF00177721