Objectives: 2,3-butanedione monoxime (BDM) has been suggested as an additive to cardioplegic solutions, because it may reduce the energy cost associated with force production in heart muscle.
Methods: The present study investigated the effect of BDM (10 mM) on developed tension (DT), Ca(2+)-dependent myosin ATPase activity (MYO) and tension cost (myosin ATPase activity/ tension ratio), characterizing the cross-bridge detachment rate, of skinned fiber preparations (1% Triton X, 20 h, 4 degrees C) of human left ventricular failing myocardium (dilative cardiomyopathy, heart transplants, n=6) at increasing concentrations of Ca2+ (0.01-32 microM).
Results: BDM decreased Ca2+ sensitivity of DT [EC50 Ca2+, control: 1.3+/-0.2 microM, + BDM (10 mM): 4.5+/-0.3 microM] and MYO [EC50 Ca2+, control: 0.9+/-0.2 microM, + BDM (10 mM): 3.1+/-0.3 mM]. In addition, BDM reduced maximal DT [control: 26.0+/-1.9 mN/mm2, + BDM (10 mM): 8.1+/-1.1 mN/mm2] and MYO [control: 124+/-21 RM ADP/s, + BDM (10 mM): 62 9 microM ADP/s]. However, the influence of BDM on maximal DT (-69%) was more pronounced than on maximal MYO (-50%). The myosin ATPase activity/tension relation was significantly higher in the presence of BDM.
Conclusions: BDM exerts negative inotropic activity by reducing the number of force-generating cross-bridges, possibly by increasing the cross-bridge detachment rate as well as by reducing force generation per cross-bridge in human myocardium. As BDM reduces force generation more than ATPase activity, BDM may not necessarily reduce energy demand in human myocardium.