THE CALCIUM SENSITIZER EMD-53998 ANTAGONIZES PHOSPHATE-INDUCED INCREASES IN ENERGY-COST OF ISOMETRIC TENSION IN CARDIAC SKINNED FIBERS

We have investigated whether a Ca2+-sensitizing substance, the thiadia zinone derivative EMD 53998, can alter the ratio of ATPase activity to force, i.e. the tension cost in skinned fibres of swine cardiac trabe cula in which the tension cost was increased by inorganic phosphate. I n the presence of 10 mM inorganic phosphate (P-i) and thapsigargin 20 mu M, EMD 53998 reduced the energy cost of isometric tension over the entire range of activating Ca2+ concentrations, resulting in a consist ent change in slope (similar to 20% decrease) of the ATPase/force rela tion. We confirmed that in the absence of added phosphate and at maxim al Ca2+ activation EMD 53998 had little if any effect on tension cost. We had previously reported that the effects of EMD 53998 and P-i on c alcium sensitivity and maximum isometric tension are mutually antagoni stic and our new energy data now support the proposal that EMD 53998 f unctionally antagonizes the effects of P-i on crossbridges. The decrea se in the slope of the relation between ATPase and force caused by EMD 53998 may be interpreted to reflect either a decrease in the rate of 'detachment' (g(app)) of crossbridges or an increase in average force per crossbridge, as predicted by classical crossbridge models. Since t he P-i release step of the crossbridge cycle is associated with the ra te of 'attachment' (f(app)) rather than g(app), we conclude that the d ecrease in tension cost with EMD 53998 most likely reflects an increas ed force per crossbridge. The mechanism of action for this Ca2+-sensit izing compound may then involve redistribution of crossbridge states a round the P-i release step, which may possibly be due to a lowered aff inity of crossbridges for phosphate.