Removal of inactivation and blockade of cardiac Na+ channels by DPI 201-106: different voltage-dependencies of the drug actions.

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 (Vmax) of Na+-dependent action potentials was taken as an estimate for INa. Racemic DPI (3 X 10(-6) mol/l) 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 Vmax depression induced by racemic DPI became attenuated due to hyperpolarization and finally tended to disappear at about -90 mV, while at the same time INa modification became increasingly accentuated. An increase in holding potential caused the non-decaying portion of the macroscopic INa 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.