Modulation of cross-bridge interaction by 2,3-butanedione monoxime in human ventricular myocardium.

Abstract

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. 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). 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. 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.