Interaction of Cardiotonic Thiadiazinone Derivatives with Cardiac Troponin C

Pan, Bo‐Sheng; Johnson, Robert Garret

doi:10.1074/jbc.271.2.817

Cited by 61 publications

(37 citation statements)

References 47 publications

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“…The animals were instrumented with an LV microtipped pressure transducer, a coronary Doppler¯ow probe around the left anterior descending coronary artery, and distal to the probe an intracoronary catheter for infusion of Ca 2+ . In the myocardium perfused by the left anterior descending coronary artery ultrasonic crystals were implanted for the measurement of End-Systolic Elastance (E ES ), the directional coe cient of the LV end-systolic pressure segment relation, as a measure of regional myocardial contractile function (Krams et al, 1993); LV preload was varied by in¯ation of a balloon positioned in (Pan & Johnson, 1996), although modulation of the cooperative interaction between adjacent troponin-tropomyosin units along the thin ®laments or an e ect on the cross-bridge kinetics may also contribute Lues et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular effects of the novel Ca²⁺‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise

Stubenitsky

Weerd

Haitsma

et al. 1997

British J Pharmacology

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1 To date no study has described the cardiovascular e ects of increased myo®lament Ca 2+ responsiveness in awake animals both under resting conditions and during treadmill exercise. In the present study we therefore investigated the systemic, pulmonary and coronary haemodynamic actions of the Ca 2+ sensitizer EMD 57033 in 16 chronically instrumented awake pigs at rest and during treadmill exercise, and compared these to the haemodynamic actions of the Ca 2+ sensitizer/phosphodiesterase inhibitor pimobendan. 2 Under resting conditions EMD 57033 (0.2, 0.4 and 0.8 mg kg 71 min 71 , i.v.) produced dosedependent increases in LVdP/dt max (up to 65+17% (mean +s.e.mean), P40.05) and stroke volume (up to 20+3%, P40.05), with an increase in heart rate only after the highest dose (22+5%, P40.05), while mean aortic blood pressure and LVdP/dt min were not altered. EMD 57033 had also no e ect on pulmonary vascular resistance, but produced dose-dependent decreases in systemic vascular resistance (32+4%, P40.05), and coronary vascular resistance (44+2%, P40.05). These e ects were essentially unchanged when animals were pretreated with non-selective b-adrenoceptor blockade, indicating that phosphodiesterase inhibition did not contribute to the positive inotropic actions of EMD 57033. 3 During exercise at 2, 3, and 4 km h 71 , the positive inotropic actions of EMD 57033 gradually waned at higher levels of exercise. This may have been caused by the exercise-induced increase in b-adrenergic activity, because after pretreatment with propranolol the positive inotropic actions of EMD 57033 were preserved at all levels of exercise. In contrast, the positive inotropic and chronotropic e ects of pimobendan were ampli®ed during exercise, but were abolished (at rest) or markedly attenuated (during exercise) after pretreatment with propranolol. 4 The responses to EMD 57033 during exercise after combined a-and b-adrenergic receptor blockade were not di erent from those after b-adrenergic receptor blockade alone, indicating that the positive inotropic actions of EMD 57033 were not mediated via or did not depend on intact a-adrenergic receptor activity. 5 In conclusion, EMD 57033 increases left ventricular myocardial contractility in awake pigs. During exercise this e ect is partially o set by the increased b-adrenergic activity, with no e ect of a-adrenergic activity, suggesting that EMD 57033 may be most e ective in patients with severe loss of b-adrenergic responsiveness.

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Section: Discussionmentioning

confidence: 99%

Cardiovascular effects of the novel Ca²⁺‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise

Stubenitsky

Weerd

Haitsma

et al. 1997

British J Pharmacology

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“…Evidence that EMD 57033 binds to the C-domain of cTnC has come from both direct binding measurements [81] and NMR chemical shift changes [64,82]. This indicates that EMD 57033 has a different mechanism of action than bepridil, TFP, W7, anapoe, and levosimendan.…”

Section: Emd 57033mentioning

confidence: 99%

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

Robertson

Sykes

2008

Biochemical and Biophysical Research Communications

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Over the forty years since its discovery, many studies have focused on understanding the role of troponin as a myofilament based molecular switch in regulating the Ca 2+ -dependent activation of striated muscle contraction. Recently, studies have explored the role of cardiac troponin as a target for cardiotonic agents. These drugs are clinically useful for treating heart failure, a condition in which the heart is no longer able to pump enough blood to other organs. These agents act via a mechanism that modulates the Ca 2+ -sensitivity of troponin; such a mode of action is therapeutically desirable because intracellular Ca 2+ concentration is not perturbed, preserving the regulation of other Ca 2+ -based signaling pathways. This review describes molecular details of the interaction of cardiac troponin with a variety of cardiotonic drugs. We present recent structural work that has identified the docking sites of several cardiotonic drugs in the troponin C -troponin I interface and discuss their relevance in the design of troponin based drugs for the treatment of heart disease.

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“…4, the concentration of protein-bound Ca 2ϩ can be neglected compared with that of added Ca 2ϩ , so that the latter is equal to the free Ca 2ϩ concentration. Titration of Exposed Hydrophobicity-The Ca 2ϩ -and Mg 2ϩ -dependent changes in hydrophobic matrices of S100A2 or derivatives were followed by monitoring the fluorescence properties of 4,4Ј-dianilino-1,1Ј-binaphtyl-5,5Ј-disulfonic acid (bis-ANS) as described by Pan and Johnson (38). Solutions of 40 M bis-ANS and 2 M metal-free proteins (after the addition of 25 mM EGTA) were excited at 390 nm, and the emission spectrum was recorded with slits of 5 nm.…”

Section: Camentioning

confidence: 99%

Binding of Ca2+ and Zn2+ to Human Nuclear S100A2 and Mutant Proteins

Franz¹,

Durussel²,

Cox³

et al. 1998

Journal of Biological Chemistry

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Interaction of Cardiotonic Thiadiazinone Derivatives with Cardiac Troponin C

Cited by 61 publications

References 47 publications

Cardiovascular effects of the novel Ca²⁺‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise

Cardiovascular effects of the novel Ca²⁺‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

Binding of Ca2+ and Zn2+ to Human Nuclear S100A2 and Mutant Proteins

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Interaction of Cardiotonic Thiadiazinone Derivatives with Cardiac Troponin C

Cited by 61 publications

References 47 publications

Cardiovascular effects of the novel Ca2+‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise

Cardiovascular effects of the novel Ca2+‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

Binding of Ca2+ and Zn2+ to Human Nuclear S100A2 and Mutant Proteins

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Cardiovascular effects of the novel Ca²⁺‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise

Cardiovascular effects of the novel Ca²⁺‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise