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. (shrink)

Hypoxia hampers ATP production and threatens cell survival. Since cellular energetics tightly controls cell responses and fate, ATP levels and dynamics are of utmost importance. An integrated mathematical model of ATP synthesis by the mitochondrial oxidative phosphorylation/electron transfer chain system has been recently published :e36, 2005). This model was validated under static conditions. To evaluate its performance under dynamical situations, we implemented and simulated it . Inner membrane potential and [NADH] were used as indicators of mitochondrial function. Root mean squared (...) error was used to compare simulations and experiments :39155–39165, 2003). Steady-state experimental data were reproduced within 2–6%. Model dynamics were evaluated under: baseline, activation of NADH production, addition of ADP, addition of inorganic phosphate, oxygen exhaustion. In all phases, except the last one, ΔΨ and [NADH] as well as oxygen consumption, were reproduced . Under anoxia, simulated ΔΨ markedly depolarized . In conclusion, the model reproduces dynamic data as long as oxygen is present. Anticipated improvement by the inclusion of ATP consumption and explicit Krebs cycle are under evaluation. (shrink)

Sickle cell haemoglobin polymerization reduces erythrocyte deformability, causing deleterous vaso-occlusions. The double-nucleation model states that polymers grow from HbS aggregates, the nuclei, in solution , onto existing polymers . When linearized at initial HbS concentration, this model predicts early polymerization and its characteristic delay-time :591–610, 611–631, 1985). Addressing its relevance for describing complete polymerization, we constructed the full, non-linearized model . Here, we compare the simulated outputs to experimental progress curves . Within 10% from start, average root mean square deviation (...) between simulated and experimental curves is 0.04 ± 0.01 . Conversely, for complete progress curves, averaged rms is 0.48 ± 0.04. This figure is improved to 0.13 ± 0.01 by adjusting heterogeneous pathway parameters : the nucleus stability , and the fraction of polymer surface available for nucleation , from 5e−7, to 13 . Similar results are obtained at 37°C. We conclude that the physico-chemical description of heterogeneous nucleation warrants refinements in order to capture the whole HbS polymerization process. (shrink)