The Novel Cardiotonic Agent EMD 53 998 is a Potent “Calcium Sensitizer”

Beier, Norbert; Harting, J.; Jonas, R.; Klockow, Michael; Lues, Inge; Haeusler, G.

doi:10.1097/00005344-199107000-00004

Cited by 59 publications

(33 citation statements)

References 1 publication

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“…32 In the present study, 10 Ϫ4 mol/L pimobendan substantially shifted the pCatension curve to the left at SLs of 1.9 and 2.3 m, whereas in contrast to MgADP, pimobendan did not diminish the SLdependent shift of the pCa-tension relationship (Figure 2).…”

Section: Change In Hill Coefficient With Mgadpcontrasting

confidence: 40%

Effects of MgADP on Length Dependence of Tension Generation in Skinned Rat Cardiac Muscle

Fukuda

Kajiwara

Ishiwata

et al. 2000

Circulation Research

102

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Abstract-The effect of MgADP on the sarcomere length (SL) dependence of tension generation was investigated using skinned rat ventricular trabeculae. Increasing SL from 1.9 to 2.3 m decreased the muscle width by Ϸ11% and shifted the midpoint of the pCa-tension relationship (pCa 50 ) leftward by about 0.2 pCa units. MgADP (0.1, 1, and 5 mmol/L) augmented maximal and submaximal Ca 2ϩ -activated tension and concomitantly diminished the SL-dependent shift of pCa 50 in a concentration-dependent manner. In contrast, pimobendan, a Ca 2ϩ sensitizer, which promotes Ca 2ϩ binding to troponin C (TnC), exhibited no effect on the SL-dependent shift of pCa 50 , suggesting that TnC does not participate in the modulation of SL-dependent tension generation by MgADP. At a SL of 1.9 m, osmotic compression, produced by 5% wt/vol dextran (molecular weight Ϸ464 000), reduced the muscle width by Ϸ13% and shifted pCa 50 leftward to a similar degree as that observed when increasing SL to 2.3 m. This favors the idea that a decrease in the interfilament lattice spacing is the primary mechanism for SL-dependent tension generation. MgADP (5 mmol/L) markedly attenuated the dextran-induced shift of pCa 50 , and the degree of attenuation was similar to that observed in a study of varying SL. The actomyosin-ADP complex (AM.ADP) induced by exogenous MgADP has been reported to cooperatively promote myosin attachment to the thin filament. We hereby conclude that the increase in the number of force-generating crossbridges on a decrease in the lattice spacing is masked by the cooperative effect of AM.ADP, resulting in depressed SL-dependent tension generation. The full text of this article is available at http://www.circresaha.org. This intrinsic ability of the heart to alter cardiac output forms the basis for the Frank-Starling law of the heart. It is well established that twitch tension and Ca 2ϩ responsiveness in cardiac muscle preparations are enhanced as muscle length (ie, sarcomere length [SL]) is increased within the normal physiological range (SL from Ϸ1.8 to Ϸ2.3 m). 1-5 Although a number of studies have been conducted to account for the SL dependence of tension generation in living myocardium, its mechanism has not been completely elucidated. 6 However, at the myofilament level, there is an increasing amount of evidence suggesting that the SL dependence is primarily due to a change in the interfilament lattice spacing that accompanies the SL change. 7-9 A possible consequence of the decreased lattice spacing is an increase in the probability of myosin attachment to the thin filament, resulting in an increase in the number of force-generating crossbridges. 7,10,11 Ishiwata and Oosawa 12 proposed a model based on the Ca 2ϩ -dependent flexibility of the thin filament, in which they assumed that (1) the muscle volume (ie, the lattice volume) remains constant on a change in SL and that (2) there is a critical distance between the thick and thin filaments for tension generation. This model quantitatively explains both the stretch-induced increas...

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Section: Change In Hill Coefficient With Mgadpcontrasting

confidence: 40%

Effects of MgADP on Length Dependence of Tension Generation in Skinned Rat Cardiac Muscle

Fukuda

Kajiwara

Ishiwata

et al. 2000

Circulation Research

102

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“…'11,216-221) EMD 53998 has both a Ca 21 sensitizing action and a PDE III-inhibitory action ,21S) and it has been shown that the former action is due to the (+) enantiomer (EMD 57033) and the latter to the (-) enantiomer (EMD 57439) (Table II).111,219,221) In skinned cardiac muscle fibers, the pCa-tension relationship was shifted to the left and maximal tension was increased in the presence of EMD 53998. 215,217,218) In intact myocardial cells, contractile force or shortening was increased without or with only a small increase 11,220,221) or with a decrease 216) in the amplitude of Ca 21 transients. The small increase in peak Ca 21 transients was due mainly to inhibition of PDE III and the subsequent accumulation of cyclic AMP indeed by the (-) enantiomer BM 57439.18,220,22') Neither the (+) enantiomer EMD 57033 nor the (-) enantiomer EMD 57439 affected binding of Ca 2+ ions to troponin C in skinned fibers of canine heart.")…”

Section: Frank-starling Mechanismmentioning

confidence: 99%

Changes in Intracellular Ca2+ Mobilization and Ca2+ Sensitization as Mechanisms of Action of Physiological Interventions and Inotropic Agents in Intact Myocardial Cells.

Endoh

1998

Jpn Heart J

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“…This search has led to some thiadiazinone derivatives, which vary considerably in their potencies to sensitize myofilaments to Ca 2+ and to inhibit phosphodiesterase-III (PDE-III). One of these thiadiazinones is the racemic compound [±]-EMD 53998, the [-]-enantiomer of which inhibits phosphodiesterase-III with high affinity, whereas the Ca 2+ -sensitizing properties in addition to some low potency for PDE-III inhibition reside in the [+]-enantiomer (Beier et al 1991;Ventura et al 1992;White et al 1993;Lues et al 1993). Chemical modifications were subsequently directed at improving the potency for the Ca 2+ -sensitizing action while decreasing the potency for PDE-III inhibition.…”

Section: Introductionmentioning

confidence: 99%

Stereoselectivity of actions of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264

Ravens

Flüss

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The thiadiazinone derivative [+]-EMD 60263 ((+)-5-(l-(alpha-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4-tetrah ydroquinoline -6-yl)-6-methyl-3,6-dihydro-2H-1,3,4 -thiadiazine-2-on) is a Ca(2+)-sensitizing agent with only minor phosphodiesterase inhibitory activity. Our aim was to characterize the inotropic and electrophysiological effects of [+]-EMD 60263 and its enantiomer [-]-EMD 60264 in several cardiac muscle preparations. The Ca(2+)-sensitizing activity resided in the [+]-enantiomer only. [+]-EMD 60263 (3 microM) shifted the EC50 of Ca2+ for contractile activation of skinned fibers of pig heart from 2.41 microM to 0.73 microM, whereas [-]-EMD 60264 (30 microM) was ineffective. In Langendorff-perfused guinea pig hearts, [+]-EMD 60263 and [-]-EMD 60264 induced concentration-dependent positive and negative inotropic effects, respectively; both enantiomers reduced spontaneous heart rate but did not influence perfusion pressure. The maximum increase in force of human atrial trabeculae was 35% of pre-drug control with [+]-EMD 60263 in comparison to 113% with forskolin. In guinea-pig papillary muscles, [+]-EMD 60263 and [-]-EMD 60264 had opposite inotropic responses, however, both agents similarly prolonged action potential duration. Both enantiomers concentration-dependently blocked the rapidly activating component IKr of the delayed rectifier in guinea-pig myocytes. The block saturated at potentials positive to +30 mV, closely resembling the effects of the antiarrhythmic agent E-4031 which had been originally used to define IKr.

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The Novel Cardiotonic Agent EMD 53 998 is a Potent “Calcium Sensitizer”

Cited by 59 publications

References 1 publication

Effects of MgADP on Length Dependence of Tension Generation in Skinned Rat Cardiac Muscle

Effects of MgADP on Length Dependence of Tension Generation in Skinned Rat Cardiac Muscle

Changes in Intracellular Ca2+ Mobilization and Ca2+ Sensitization as Mechanisms of Action of Physiological Interventions and Inotropic Agents in Intact Myocardial Cells.

Stereoselectivity of actions of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264

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