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A Computational Model of the Circulating Renin-Angiotensin System and Blood Pressure Regulation

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Abstract

The renin-angiotensin system (RAS) is critical in sodium and blood pressure (BP) regulation, and in cardiovascular-renal (CVR) diseases and therapeutics. As a contribution to SAPHIR project, we present a realistic computer model of renin production and circulating RAS, integrated into Guyton’s circulatory model (GCM). Juxtaglomerular apparatus, JGA, and Plasma modules were implemented in C ++/M2SL (Multi-formalism Multi-resolution Simulation Library) for fusion with GCM. Matlab© optimization toolboxes were used for parameter identification. In JGA, renin production and granular cells recruitment (GCR) are controlled by perfusion pressure (PP), macula densa (MD), angiotensin II (Ang II), and renal sympathetic activity (RSNA). In Plasma, renin and ACE (angiotensin-converting enzyme) activities are integrated to yield Ang I and II. Model vs. data deviation is given as normalized root mean squared error (nRMSE; n points). Identification: JGA and Plasma parameters were identified against selected experimental data. After fusion with GCM: (1) GCR parameters were identified against Laragh’s PRA-natriuresis nomogram; (2) Renin production parameters were identified against two sets of data ([renin] transients vs. ACE or renin inhibition). Finally, GCR parameters were re-identified vs. Laragh’s nomogram (nRMSE 8%, n = 9). Validation: (1) model BP, PRA and [Ang II] are within reported ranges, and respond physiologically to sodium intake; (2) short-term Ang II infusion induces reported rise in BP and PRA. The modeled circulating RAS, in interaction with an integrated CVR, exhibits a realistic response to BP control maneuvers. This construction will allow for modelling hypertensive and CVR patients, including salt-sensitivity, polymorphisms, and pharmacotherapeutics.

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Abbreviations

ACE:

Angiotensin converting enzyme, ACE-1 (EC 3.4.15.1)

AGT:

Angiotensinogen

Ang I (/II):

Angiotensin I (/II)

ATP:

Adenosine triphosphate

AT1-R:

Ang II type 1 receptor

BRENDA:

BRaunschweig ENzyme DAtabase (http://www.brenda-enzymes.org/)

cAMP:

Cyclic adenosine monophosphate

GC:

Renin-secreting granular cells

GCM:

Guyton’s circulatory model

JGA:

Juxta-glomerular apparatus

MAP:

Mean arterial pressure

MD:

Macula densa

M2SL:

Multi-formalism Multi-resolution Simulation Library

NID:

Na input rate variable in Guyton’s circulatory model

PP:

Perfusion pressure

PRA:

Plasma renin activity

RAS:

Renin-angiotensin system

RAAS:

Renin-angiotensin-aldosterone system

Renin:

(EC 3.4.23.15)

RSNA:

Renal sympathetic nerve activity

SAPHIR [project]:

A systems approach for physiological integration of renal, cardiac and respiratory functions

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Acknowledgments

This work was supported by the CNRS (PH), the INSERM (PH and FG), the Faculty of Medicine and Pharmacy (University of Poitiers; PH and FG), and the Research-Hospital Center (CHU) of Poitiers. As a component of the SAPHIR project (FG), this work was supported by the ANR (decision #ANR-06-BYOS-0007-03). We wish to thank Drs V. LeRolle & A. Hernandez (LTSI/INSERM U642), and Dr J. Fontecave-Jallon (PRETA Team, TIMC-IMAG) for help with the M2SL versions of GCM. We wish to thank Pr. J. DiBona and acknowledge his kind and helpful comments about RSNA.

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  1. Inserm U927, CHU La Milétrie, 2 rue de la Milétrie, BP 577, 86000, Poitiers, France

    François Guillaud & Patrick Hannaert

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  1. François Guillaud
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  2. Patrick Hannaert
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Correspondence to Patrick Hannaert.

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Guillaud, F., Hannaert, P. A Computational Model of the Circulating Renin-Angiotensin System and Blood Pressure Regulation. Acta Biotheor 58, 143–170 (2010). https://doi.org/10.1007/s10441-010-9098-5

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