The Two Mechanisms of Action of Racemic Cardiotonic Emd 53998, Calcium Sensitization and Phosphodiesterase Inhibition, Reside in Different Enantiomers

SUMMARY The novel cardiotonic EMD 53 998 increases contractile force in vitro through both inhibition of phosphodiesterase III (PDE III) activity and increase in the responsiveness of the contractile proteins to calcium (“calcium sensitization”). Because EMD 53 998 is a racemate, the possibility arose that the two modes of action do not reside equally in the enantiomers. Therefore, the effects of the racemate and its two enantiomers [(+)EMD 57 033 and (-)EMD 57 439] were analyzed in guinea pig and rat cardiac tissue with respect to Ca2+ sensitization (Ca2+-induced force development in skinned cardiac myofibers and myofibrillar ATPase activity) and PDE III inhibition (isolated PDE isoenzymes and cyclic AMP level in isolated cardiac myocytes). In addition, the positive inotropic effects were compared in isometrically contracting papillary muscles. Enhancement of force of contraction (Fc) in submaximally activated skinned fibers showed a selectivity for the (+)enantiomer with EC50 = 1.7, 4.8, and