Mathematical modeling improves EC50 estimations from classical dose–response curves

Linköpings universitet, Institutionen för medicinsk teknik Linköpings universitet, Tekniska fakulteten Linköpings universitet, Biologi Linköpings universitet, Tekniska högskolan Linköpings universitet, Avdelningen för radiologiska vetenskaper Linköpings universitet, Hälsouniversitetet Linköpings universitet, Fysik och elektroteknik Linköpings universitet, Avdelningen för cellbiologi Linköpings universitet, Medicinska fakulteten CVMD iMED DMPK AstraZeneca R&D, Mölndal, Sweden 2015

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.

adrenaline; cardiac b-adrenergic signaling; dynamic mathematical modeling; EC50; ordinary differential equations; Radiology, Nuclear Medicine and Medical Imaging; Radiologi och bildbehandling; Article in journal; info:eu-repo/semantics/article; text

10.1111.febs.13194

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UPE oai:DiVA.org:liu-114788
0000-0002-4261-0291
0000-0001-9386-0568
doi:10.1111/febs.13194
PMID 25586512
ISI:000350650200010
1234638001

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