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Snelder N, Ploeger BA, Luttringer O, et al. Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling. Br J Pharmacol. 2014;171(22):5076-92doi: 10.1111/bph.12824.
Snelder, N., Ploeger, B. A., Luttringer, O., Rigel, D. F., Fu, F., Beil, M., Stanski, D. R., & Danhof, M. (2014). Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling. British journal of pharmacology, 171(22), 5076-92. https://doi.org/10.1111/bph.12824
Snelder, N, et al. "Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling." British journal of pharmacology vol. 171,22 (2014): 5076-92. doi: https://doi.org/10.1111/bph.12824
Snelder N, Ploeger BA, Luttringer O, Rigel DF, Fu F, Beil M, Stanski DR, Danhof M. Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling. Br J Pharmacol. 2014 Nov;171(22):5076-92. doi: 10.1111/bph.12824. Epub 2014 Sep 05. PMID: 24962208; PMCID: PMC4253457.
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Br J Pharmacol. 2014 Nov;171(22):5076-92. doi: 10.1111/bph.12824. Epub 2014 Sep 05.

Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling.

British journal of pharmacology

N Snelder, B A Ploeger, O Luttringer, D F Rigel, F Fu, M Beil, D R Stanski, M Danhof

Affiliations

  1. Division of Pharmacology, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.

PMID: 24962208 PMCID: PMC4253457 DOI: 10.1111/bph.12824

Abstract

BACKGROUND AND PURPOSE: Previously, a systems pharmacology model was developed characterizing drug effects on the interrelationship between mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR). The present investigation aims to (i) extend the previously developed model by parsing CO into heart rate (HR) and stroke volume (SV) and (ii) evaluate if the mechanism of action (MoA) of new compounds can be elucidated using only HR and MAP measurements.

EXPERIMENTAL APPROACH: Cardiovascular effects of eight drugs with diverse MoAs (amiloride, amlodipine, atropine, enalapril, fasudil, hydrochlorothiazide, prazosin and propranolol) were characterized in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats following single administrations of a range of doses. Rats were instrumented with ascending aortic flow probes and aortic catheters/radiotransmitters for continuous recording of MAP, HR and CO throughout the experiments. Data were analysed in conjunction with independent information on the time course of the drug concentration following a mechanism-based pharmacokinetic-pharmacodynamic modelling approach.

KEY RESULTS: The extended model, which quantified changes in TPR, HR and SV with negative feedback through MAP, adequately described the cardiovascular effects of the drugs while accounting for circadian variations and handling effects.

CONCLUSIONS AND IMPLICATIONS: A systems pharmacology model characterizing the interrelationship between MAP, CO, HR, SV and TPR was obtained in hypertensive and normotensive rats. This extended model can quantify dynamic changes in the CVS and elucidate the MoA for novel compounds, with one site of action, using only HR and MAP measurements. Whether the model can be applied for compounds with a more complex MoA remains to be established.

© 2014 The British Pharmacological Society.

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