THE CA2-53998 ANTAGONIZES THE EFFECT OF 2,3-BUTANEDIONE MONOXIME ON SKINNED CARDIAC-MUSCLE FIBERS( SENSITIZER EMD)

The effects of 2,3-butanedione monoxime (BDM) and yl]-6-methyl-3,6-dih ydro-2H-1,3,4-thiadiazin-2-one (EMD 53998) on cardiac muscle were stud ied in skinned muscle fibres from the right ventricle of the porcine h eart. BDM decreases the Ca2+ sensitivity (pCa(50) for 50% activation) and it exerts a dose-dependent inhibitory effect on force in troponin I (TnI)-depleted (unregulated) cardiac skinned muscle fibres (IC50 sim ilar to 20 mM) thereby mimicking the effect of the TnI inhibitory pept ide (cTnI 137-148, corresponding to the cardiac TnI inhibitory region) and that of inorganic phosphate (P-i). This inhibitory action can be antagonized by the calcium-sensitizing cardiotonic thiadiazinone deriv ative EMD 53998 that increases the IC50 to about 30 mM. In skinned fib res, BDM (10 mM) also increased the ratio of ATPase activity to isomet ric force (tension cost), whereas EMD 53998 (20 mu M) decreased it. We propose that BDM antagonizes EMD 53998 because both compounds affect the Pi release step of the crossbridge cycle in an antagonistic manner .