Reduction of myocardial cross-bridge turnover rate in presence of EMD 53998, a novel Ca2+-sensitizing agent

Abstract

We have studied the effect of EMD 53998 (5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydrochinolin-6-yl)-6-me thyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one) on cross-bridge turnover rate at varying Ca2+ concentrations. Cross-bridge cycling rate was estimated both by adenosine triphosphatase measurements and determination of mechanical characteristics of constantly activated fibres, which is assumed to reflect cross-bridge kinetics. The results indicate that the turnover rate of myocardial cross-bridges was reduced in the presence of EMD 53998 at low Ca2+ concentrations (pCa greater than or equal to 6.25), but not at higher Ca2+ concentrations (pCa less than or equal to 5.85).

Pharmacology of Levosimendan: A New Myofilament Calcium Sensitizer

“…Myofilament Ca2+ sensitizers, including pimobendan (7,13,56), sulmazole (62), and EMD 53998 (6,11,29), augment Ca2+ binding to the Ca2'-specific regulatory site of cardiac troponin C, leading to prolonged systolic interaction of actin and myosin filaments (31). These agents also partially inhibit vascular smooth muscle and cardiac phosphodiesterases (PDEs) (7,12,35,59), resulting in systemic and pulmonary vasodilation, further augmentation of contractile function, and direct positive lusitropic (relaxation) effects (50).…”

Calcium‐Sensitizing Drugs: Positive Inotropy by Enhanced Sensitivity of the Contractile Apparatus to Calcium

“…Prolongation of relaxation time was even more pronounced in hypoxic myocytes, possibly as a direct consequence of increased cytoplasmic calcium loading under these conditions (127). The absence of contractile economy in intact heart preparations contrasts with data using cardiac muscle strips, were economization of contraction cost was reported with both the racemic mixture (44,65,106) and the calcium-sensitizing (+)-isomer (34,77). The reason for this discrepancy remains unclear.…”

EMD 57033: A Novel Ca2+ Sensitizing Agent

“…In general, EMD 53998 enhanced maximal ATPase activity (89). In apparent contrast, this racemate reduced ATPase activity in skinned porcine cardiac fibers, but this effect was seen only at low Ca2+ concentrations (61). Other studies showed that the (+)-enantiomer of EMD 53998 (EMD 57033) stimulated the actomyosin ATPase in cardiac myofibrils (27,87) and in a concentration-dependent manner in skinned fibers (63).…”

“…In skinned myocardial fibers, EMD 53998 reduced tension cost at low Ca2+ concentrations (pCa 2 6.25) but not at higher concentrations (pCa =s 5.85) (61). On the other hand, the drug was reported to increase energy efficiency of intact papillary muscles (59).…”

“…Almost the entire spectrum of experimental models is presented. In skinned porcine ventricular fibers (4, 39,61) and in strips from failing human hearts (74), EMD 53998 increased Ca2 + sensitivity and shifted the pCa-force relationship to the left in a dose-dependent manner.…”