The Two Mechanisms of Action of Racemic Cardiotonic EMD 53998, Calcium Sensitization and Phosphodiesterase Inhibition, Reside in Different Enantiomers

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

doi:10.1097/00005344-199306000-00006

Cited by 75 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%

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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%

“…EMD 57439, a pure PDE III inhibitor) and (+) EMD 53998 (i.e. EMD 57033), a Ca 2+ sensitiser with minimal PDE III inhibitory actions in vitro (Ventura et al, 1992;Lues et al, 1993). Data on the cardiovascular actions of EMD 57033 in vivo are lacking.…”

Section: Introductionmentioning

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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“…It has been found to increase the Ca 2+ -sensitivity of both myofibrillar ATPase and force development by skinned muscle fibers [71,72]. In vivo studies have also demonstrated that EMD 57033 enhances cardiac contractile function without affecting Ca 2+ -homeostasis [73][74][75][76][77].…”

Section: Emd 57033mentioning

confidence: 98%

“…EMD 57033 is the (+)-enantiomer of a racemate. The (-)-enantiomer, EMD 57439, exhibits no Ca 2+ -sensitizing activity but acts as a pure phosphodiesterase III inhibitor [71,72]. The drawback in the development of EMD 57033 as a Ca 2+ -sensitizer is because of observations that whereas treatment with EMD 57033 results in consistent positive inotropic effects, its effect on relaxation is impaired in some heart muscle preparations [72,78].…”

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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“…These agents are clearly not pure Ca2+ sensitizers. They inhibited phosphodiesterase activity, thereby increasing CAMP content in myocardial cells (18) and enhancing the phosphorylation state of typical targets for CAMPdependent phosphorylation, such as PLB (19). It was important, therefore, to determine whether Ca" sensitizers devoid of any phosphodiesterase inhibitory properties could be developed.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Profile of CGP 48506, A New Positive Inotropic Agent

Neumann

Zimmermann

1997

Cardiovascular Drug Reviews

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Key Words: Benzodiazocine-Calcium-sensitizing agents-Phosphodiesterase inhibitionPositive inotropy.The purpose of this review is to summarize the studies on the mechanism(s) of action of a new cardiotonic agent, CGP 48506. Cardiotonic drugs are expected to alleviate symptoms of heart failure and reduce mortality of patients suffering from this disease. To put the positive inotropic mechanism(s) of action of CGP 48506 into perspective, some important and well investigated positive inotropic mechanisms are described. The methods used to distinguish the inotropic mechanism(s) of action of CGP 48506 from those of other drugs are briefly discussed. The concept of Ca2+ sensitization by drugs is delineated. Potential advantages and disadvantages of Ca2+ sensitizers for the treatment of heart failure are mentioned. Evidence is presented that CGP 48506 acts primarily as a Ca2+ sensitizer. Data on the effect of CGP 48506 in animal as well as human cardiac preparations indicate that CGP 48506 is a novel and effective positive inotropic agent.

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The Two Mechanisms of Action of Racemic Cardiotonic EMD 53998, Calcium Sensitization and Phosphodiesterase Inhibition, Reside in Different Enantiomers

Cited by 75 publications

References 0 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

Pharmacological Profile of CGP 48506, A New Positive Inotropic Agent

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The Two Mechanisms of Action of Racemic Cardiotonic EMD 53998, Calcium Sensitization and Phosphodiesterase Inhibition, Reside in Different Enantiomers

Cited by 75 publications

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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

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

Pharmacological Profile of CGP 48506, A New Positive Inotropic Agent

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Product

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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