Evidence for different receptor sites for the novel cardiotonic S-DPI 201-106, ATX II and veratridine on the cardiac sodium channel.

DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1 H-indole-2-carbonitrile, DPI) is a novel cardiotonic which prolongs the open state of the cardiac sodium channel. The interactions of the sea anemone toxin ATX II and of veratridine with the active enantiomer of (racemic) DPI, S-DPI, were investigated by making electrophysiologic measurements in guinea-pig papillary muscles. The prolongation of the action potential duration (APD) by S-DPI was potentiated in the presence of ATX II, suggesting that the two agents bound to different sites. Veratridine alone increased APD slowly over 4 h. S-DPI greatly accelerated and potentiated the effect of veratridine. Conversely, veratridine increased the efficacy of S-DPI but decreased its potency, both about 4-fold. All effects were TTX-sensitive. It is concluded that the three agents bind to different sites at the cardiac Na+ channel and that these sites are allosterically coupled.