The calcium sensitizer EMD 53998 antagonizes phosphate-induced increases in energy cost of isometric tension in cardiac skinned fibres.

We have investigated whether a Ca(2+)-sensitizing substance, the thiadiazinone derivative EMD 53998, can alter the ratio of ATPase activity to force, i.e. the tension cost in skinned fibres of swine cardiac trabecula in which the tension cost was increased by inorganic phosphate. In the presence of 10 mM inorganic phosphate (Pi) and thapsigargin 20 microM, EMD 53998 reduced the energy cost of isometric tension over the entire range of activating Ca2+ concentrations, resulting in a consistent change in slope (approximately 20% decrease) of the ATPase/force relation. We confirmed that in the absence of added phosphate and at maximal Ca2+ activation EMD 53998 had little if any effect on tension cost. We had previously reported that the effects of EMD 53998 and Pi on calcium sensitivity and maximum isometric tension are mutually antagonistic and our new energy data now support the proposal that EMD 53998 functionally antagonizes the effects of Pi on crossbridges. The decrease 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 the Pi release step of the crossbridge cycle is associated with the rate of 'attachment' (f(app)) rather than g(app), we conclude that the decrease in tension cost with EMD 53998 most likely reflects an increased force per crossbridge.(ABSTRACT TRUNCATED AT 250 WORDS)