Potentiation of beta-adrenergic inotropic response by pyruvate in failing human myocardium

Hermann, H; Zeitz, Oliver; Lehnart, Stephan E.; Keweloh, Boris; Datz, Nicolin; Hasenfuß, Gerd; Janssen, Paul M. L.

doi:10.1016/s0008-6363(01)00437-0

Cited by 23 publications

(15 citation statements)

References 34 publications

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“…Likewise, an increase in stimulation frequency increases the developed calcium transient and accelerates both calcium and force decline [27], [36]. In accordance with previous studies, we too observed that upon addition of pyruvate the calcium transient increases, but the decline of force does not increase, it actually is significantly slowed [3], [7], [8]. We demonstrated here that the increased SR calcium handling is not the primary underlying molecular mechanism for pyruvate’s inotropic effect.…”

Section: Discussionsupporting

confidence: 92%

“…Pyruvate’s effects in augmentingthe contractile strength of the heart have been shown to be consistent throughout several species including rat, rabbit, swine, and humans [4], [5], [6], [7]. It potentiates the effect of β-adrenergic drugs [8] and it has been infused intracoronary in humans experimentally to increase inotropic support [4], [9].…”

Section: Introductionmentioning

confidence: 98%

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The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity

et al. 2013

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Pyruvate is a metabolic fuel that is a potent inotropic agent. Despite its unique inotropic and antioxidant properties, the molecular mechanism of its inotropic mechanism is still largely unknown. To examine the inotropic effect of pyruvate in parallel with intracellular calcium handling under near physiological conditions, we measured pH, myofilament calcium sensitivity, developed force, and calcium transients in ultra thin rabbit heart trabeculae at 37 °C loaded iontophoretically with the calcium indicator bis-fura-2. By contrasting conditions of control versus sarcoplasmic reticulum block (with either cyclopiazonic acid and ryanodine or with thapsigargin) we were able to characterize and isolate the effects of pyruvate on sarcoplasmic reticulum calcium handling and developed force. A potassium contracture technique was subsequently utilized to assess the force-calcium relationship and thus the myofilament calcium sensitivity. Pyruvate consistently increased developed force whether or not the sarcoplasmic reticulum was blocked (16.8±3.5 to 24.5±5.1 vs. 6.9±2.6 to 12.5±4.4 mN/mm2, non-blocked vs. blocked sarcoplasmic reticulum respectively, p<0.001, n = 9). Furthermore, the sensitizing effect of pyruvate on the myofilaments was demonstrated by potassium contractures (EC50 at baseline versus 20 minutes of pyruvate infusion (peak force development) was 701±94 vs. 445±65 nM, p<0.01, n = 6). This study is the first to demonstrate that a leftward shift in myofilament calcium sensitivity is an important mediator of the inotropic effect of pyruvate. This finding can have important implications for future development of therapeutic strategies in the management of heart failure.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 98%

The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity

et al. 2013

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“…Application of pyruvate in this model improved both energetic and hemodynamic parameters [4]. Accordingly, application of pyruvate to human heart failure patients in vivo increased LV systolic and diastolic function [87,88], which was related to an increase of SR Ca 2+ load and thus, cytosolic Ca 2+ transient amplitude in vitro [82,89].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 84%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

218

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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“…Some of these concerns in regards to utilizing human samples have been discussed by others as well (Jweied, et al, 2007; Marston & de Tombe, 2008). Still, despite these difficulties, in vitro assessment of contraction in human cardiac tissue can be an important tool to study drugs or physiological processes (Hermann, et al, 2002; Janssen, et al, 1999; Janssen, et al, 2000; Pieske, et al, 1995; Rossman, et al, 2004). …”

Section: Verification Using Human Tissuementioning

confidence: 99%

Small and large animal models in cardiac contraction research: Advantages and disadvantages

Milani‐Nejad

Janssen

2014

Pharmacology & Therapeutics

371

310

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The mammalian heart is responsible for not only pumping blood throughout the body but also adjusting this pumping activity quickly depending upon sudden changes in the metabolic demands of the body. For the most part, the human heart is capable of performing its duties without complications; however, throughout many decades of use, at some point this system encounters problems. Research into the heart’s activities during healthy states and during adverse impacts that occur in disease states is necessary in order to strategize novel treatment options to ultimately prolong and improve patients’ lives. Animal models are an important aspect of cardiac research where a variety of cardiac processes and therapeutic targets can be studied. However, there are differences between the heart of a human being and an animal and depending on the specific animal, these differences can become more pronounced and in certain cases limiting. There is no ideal animal model available for cardiac research, the use of each animal model is accompanied with its own set of advantages and disadvantages. In this review, we will discuss these advantages and disadvantages of commonly used laboratory animals including mouse, rat, rabbit, canine, swine, and sheep. Since the goal of cardiac research is to enhance our understanding of human health and disease and help improve clinical outcomes, we will also discuss the role of human cardiac tissue in cardiac research. This review will focus on the cardiac ventricular contractile and relaxation kinetics of humans and animal models in order to illustrate these differences.

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Potentiation of beta-adrenergic inotropic response by pyruvate in failing human myocardium

Abstract: A combination of pyruvate and beta-adrenergic stimulation may be of therapeutic value in acute heart failure by reducing the concentrations of potential deleterious catecholamines that are currently necessary to maintain adequate tissue perfusion.

Cited by 23 publications

References 34 publications

The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity

The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity

Excitation-contraction coupling and mitochondrial energetics

Small and large animal models in cardiac contraction research: Advantages and disadvantages

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