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Mathematical modeling improves EC50 estimations from classical dose–response curves
Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. CVMD iMED DMPK AstraZeneca R&D, Mölndal, Sweden.
Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology. (AVIAN Behavioural Genomics and Physiology group)
Linköping University, Department of Biomedical Engineering. Linköping University, The Institute of Technology.
Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
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2015 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 282, no 5, 951-962 p.Article in journal (Refereed) Published
Abstract [en]

The beta-adrenergic response is impaired in failing hearts. When studying beta-adrenergic function in vitro, the half-maximal effective concentration (EC50) is an important measure of ligand response. We previously measured the in vitro contraction force response of chicken heart tissue to increasing concentrations of adrenaline, and observed a decreasing response at high concentrations. The classical interpretation of such data is to assume a maximal response before the decrease, and to fit a sigmoid curve to the remaining data to determine EC50. Instead, we have applied a mathematical modeling approach to interpret the full dose–response curvein a new way. The developed model predicts a non-steady-state caused by a short resting time between increased concentrations of agonist, which affect the dose–response characterization. Therefore, an improved estimate of EC50 may be calculated using steady-state simulations of the model. The model-based estimation of EC50 is further refined using additional time resolved data to decrease the uncertainty of the prediction. The resulting model-based EC50 (180–525 nM) is higher than the classically interpreted EC50 (46–191 nM). Mathematical modeling thus makes it possible to reinterpret previously obtained datasets, and to make accurate estimates of EC50 even when steady-state measurements are not experimentally feasible.

Place, publisher, year, edition, pages
2015. Vol. 282, no 5, 951-962 p.
Keyword [en]
adrenaline; cardiac b-adrenergic signaling; dynamic mathematical modeling; EC50; ordinary differential equations
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:liu:diva-114788DOI: 10.1111/febs.13194ISI: 000350650200010PubMedID: 25586512OAI: oai:DiVA.org:liu-114788DiVA: diva2:792454
Available from: 2015-03-04 Created: 2015-03-04 Last updated: 2017-12-04

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Nyman, ElinLindgren, IsaLundengård, KarinArbring, TheresiaAltimitas, JordiCedersund, Gunnar

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Nyman, ElinLindgren, IsaLundengård, KarinArbring, TheresiaAltimitas, JordiCedersund, Gunnar
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Department of Biomedical EngineeringFaculty of Science & EngineeringBiologyThe Institute of TechnologyDivision of Radiological SciencesFaculty of Health SciencesPhysics and ElectronicsDivision of Cell BiologyFaculty of Medicine and Health Sciences
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