Disease relevance of Emd-53998

• Cardiovascular profile of the calcium sensitizer EMD 57033 in open-chest anaesthetized pigs with regionally stunned myocardium [1].
• Beneficial effects of the Ca2+ sensitizer EMD 57033 in exercising pigs with infarction-induced chronic left ventricular dysfunction [2].
• Our results suggest that EMD 57033 represents a prototype of a new class of cardiotonic agents that might be potentially useful in the therapy of congestive heart failure [3].
• We have examined the effects of EMD 53998 and milrinone on contractility and calcium flux in a cell culture model of myocardial hypoxia [4].
• EMD 57033 enhances arrhythmias associated with increased wall-stress in the working rat heart [5].

High impact information on Emd-53998

• These changes were greater at slower heart rate or lower [Ca2+]o. The magnitude of increased VO2 with EMD 57033 was greater at 100 bpm than 150 bpm but unaffected by [Ca2+]o. We then investigated the influence of ejection on the response to EMD 57033 (n = 7) [6].
• On the other hand, it has been suggested that the agent EMD-53998 increases the Ca2+ sensitivity of the contractile proteins without affecting the intracellular Ca2+ transient in cardiac muscle [7].
• Effects of calcium and EMD-53998 on oxygen consumption in isolated canine hearts [7].
• EMD 57033 also stimulated the velocity of actin filament sliding on myosin heads adhered to nitrocellulose-coated glass coverslips [8].
• Intact canine ventricular myocytes responded to the positive enantiomer, EMD 57033, with an increase in the extent of shortening during twitch contractions without increasing the peak amplitude of the Ca2+ transient [8].

Chemical compound and disease context of Emd-53998

• Calcium sensitizer EMD 57033, but not the beta1-adrenoreceptor agonist dobutamine, increases mechanical efficiency in stunned myocardium [9].

Biological context of Emd-53998

• Force enhancement without changes in cross-bridge turnover kinetics: the effect of EMD 57033 [10].
• Detailed chemical shift mapping of the binding sites reveals that the regions encompassing helix G-loop IV-helix H are more affected by EMD 57033, while residues located on helix E-loop III-helix F and the linker between sites III and IV are more affected by cIp [11].
• EMD 57033 increased cardiac output (up to 27+/-8%) and LVdP/dt(max) (86+/-19%) [1].
• 4. In 11 resting MI, intravenous EMD 57033 (0.2 - 0.8 mg kg(-1) min(-1)) increased LVdP/dt(max) (57+/-5%) and stroke volume (26+/-6%) with no effect on heart rate, LV filling pressure, and myocardial O(2)-consumption, similar to N [2].
• In isolated rat hearts EMD 53998 (0.5 to 5 microM) had a dose-dependent effect to increase left ventricular systolic pressure [12].

Anatomical context of Emd-53998

• There was no effect of EMD 57439 on the relation between pCa and actomyosin Mg-ATPase activity of canine heart myofibrils [8].
• Previous studies have shown a small but significant negative lusitropic effect of the calcium sensitizer EMD 53998 in ferret papillary muscle, although this effect was considered to be outweighed by powerful augmentation of contractility [4].
• Negative lusitropy and abnormal calcium handling in hypoxic cardiac myocytes exposed to the calcium-sensitizer EMD 53998 [4].
• 2. Haemodynamic measurements of LV pressure, maximum rate of rise of LV pressure (LVdP/dtmax), cardiac output, mean arterial pressure, heart rate, pulmonary artery and pulmonary wedge pressures were made during infusion of solvent (control) and the calcium sensitizer EMD 57033 (0.6 mg min-1 kg-1) [13].
• The effect of the cardiotonic sensitizing drug EMD 57033 was studied in frog skinned skeletal muscle fibres at 12 degrees C to provide a baseline for skeletal muscle studies and for comparison with cardiac fibres [14].

Associations of Emd-53998 with other chemical compounds

• METHODS AND RESULTS: In 10 isolated, red blood cell-perfused rabbit hearts the effects of EMD 57033 (5.0 to 5.8 mumol/L) on left ventricular (LV) pressure and O2 consumption (VO2) were examined at heart rates of 100 and 150 beats per minute (bpm) and perfusate [Ca2+] ([Ca2+]o) of 2.5 and 1.0 mmol/L (isovolumic contractions) [6].
• The relationships between [Ca2+] and Tyr fluorescence of hcTnC and between [Ca2+] and bis-ANS fluorescence in the presence of hcTnC were substantially altered by EMD 57033 in the range of [Ca2+] where Ca2+/Mg2+ sites of hcTnC were titrated by Ca2+ [15].
• Steady-state [Ca2+]i-force relationship in intact twitching cardiac muscle: direct evidence for modulation by isoproterenol and EMD 53998 [16].
• In this work, we used 2D ¿(1)H, (15)N¿-HSQC NMR spectroscopy to monitor the binding of EMD 57033 to cTnC in the Ca(2+)-saturated state [11].
• Different effect of the Ca(2+) sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium [17].

Gene context of Emd-53998

• This is in contrast to their relative potencies to inhibit isolated myocardial phosphodiesterase III: EMD 54650 greater than EMD 53998 greater than EMD 54622 [18].
• The normalized extra-Ca2+-tension relation became shallow by EMD 57033 (EMD) (one of the Ca2+ sensitizers) and by an increase in Ca2+ concentration in the solution ([Ca2+]o) in a concentration-dependent manner [19].
• Effects of troponin-I extraction with vanadate and of the calcium sensitizer EMD 53998 on the rate of force generation in skinned cardiac muscle [20].
• The apparent TnI-isoform dependence of the effects elicited by EMD 53998 suggests that its actions are modulated by the regulatory proteins of the thin filament [21].
• In isolated 32P-labeled guinea pig ventricular cardiomyocytes, EMD 57033 increased the phosphorylation state of phospholamban as well as the inhibitory subunit of troponin, which are usually linked to reductions in contraction time [22].

Analytical, diagnostic and therapeutic context of Emd-53998

• These changes were significantly blunted in TG hearts and in NTG hearts perfused with EMD-57033 during reperfusion, with function returning to nearly baseline levels [23].
• In anesthetized rats, echocardiography showed that intra-duodenal administration of EMD 57033 increased left ventricular systolic function without affecting variables of diastolic filling in both groups [24].
• In isolated myocytes studied in the absence of electrical stimulation, EMD 53998 [12].
• Enantiomeric dissection of the effects of the inotropic agent, EMD 53998, in single cardiac myocytes [25].

References