Interaction of DPI 201-106 with cardiac glycosides

Abstract

The interaction of the cardiotonic agent DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl(-2-hydroxypropoxy]-1H-indole -2- carbonitrile) with cardiac glycosides was investigated. In rabbit papillary muscles, all effects were normalized by using potentiating paired stimulation (PPS) as the 100% reference standard. Ouabain 1 microM alone increased the force of contraction (FC) by 66% +/- 6% (SEM) of PPS; 0.1 microM was ineffective. In the presence of 0.1 microM S-(-)-DPI 201-106, the active enantiomer of DPI 201-106, ouabain 0.1 and 1 microM increased FC by 41% +/- 11% and 119% +/- 19% of PPS, respectively. In anesthetized dogs, left ventricular dP/dtmax was increased by racemic DPI 201-106 0.2 mg/kg i.v. (+1987 +/- 660 mm Hg/s) and by ouabain 35 micrograms/kg i.v. (+560 +/- 40 mm Hg/s). The combined effect of DPI 201-106 and ouabain in similar doses was +2827 +/- 942 mm Hg/s. In digoxin-pretreated anesthetized cats, racemic DPI 201-106 was infused up to an accumulated dose of 12.22 mg/kg i.v. No signs of cardiotoxicity were observed in combination. In conclusion, the concomitant administration of DPI 201-106 and cardiac glycosides leads to enhanced positive inotropic effects in vitro and in vivo. The cardiotoxicity of glycosides was not increased by DPI 201-106.