Endocrine Abstracts

In cardiovascular-renal (CVR) pathology, the renin (REN)-angiotensin (A2) system (RAS) is central as key regulator of blood pressure BP (major CVR risk factor), and it is widely targeted by therapeutical agents. CVR regulations are utterly complex: realistic and integrated models are needed. However RAS is absent or crude in existing models: in the most integrative one (Guyton’s model GM), it is restricted to a simple factor acting on resistances and aldosterone: key elements are absent (e.g. REN). We integrated into GM realistic endocrine RAS modules: Plasma describing RAS actors; REN-producing JGA (juxtaglom. appar.) controlled by perfusion pressure and A2. We present such development (and late improvements).

Methods: Simulink used for modules; M2SL (simulation libr., Hernandez 2009) used for final, integrated GM+. JGA: controllers modulate REN secretion and REN-cells recruitment. Plasma: REN (Plasma REN Activ., PRA) & ACE kinetics, clearances are integrated to yield REN(t), A1(t) & A2(t). Parameters were optimized with Matlab tools: long-term for recruitment (5d, REN=f(Na intake)), and short-term for secretion (<24 h, REN or ACE inhib.; Nussberger2002). Cost function=simul.−exp. root mean-squared error, normalized to data range (nRMSE); final validation against independant data.

Results: Stand-alone JGA and Plasma were optimized, then GM+: 9 & 23% final error for long & short-term data, resp. Simulated baseline values for PRA, REN, A1 & A2 fell within ‘normal’ values; so was the case when driving the model with variable sodium intake (3 mmHg per 100 mEq/d). Short term simulations of A2 infusion (1 h, 3.0 ng/kg per min) reproduced (±40%), the BP rise (6–12 mmHg) and PRA decrease (40%) (Visser2008; Gordon2000). Simulating renal artery stenosis (PP=BP-30 mmHg) showed that PRA increased strongly (four-fold) and rapidly (minutes); the subsequent BP increase brought PRA down, and was associated with a (partial, 66%) compensatory return of PP toward its initial level, allowing for a partial restoration of filtration.

Conclusion: We developed and validated a realistic endocrine RAS, featuring plasma biochemistry & regulated renin production; the resulting, integrated CVR-RAS model exhibits proper physiological and pharmacological behavior, but still requires refinement, at all levels, to capture RAS physiological complexity (e.g. tissue RAS) and approach clinical needs.

Declaration of funding

This work was supported by the ANR (ANR-06-BYOS-7-03), by the INSERM, by the CNRS and by the CHU and the Faculty of Medicine of Poitiers. It was also partly supported by the GEMMS (Poitiers).