2009 - St. Petersburg - Russia

PAGE 2009: Applications- Endocrine
Sergej Ramusovic

A physiologically based pharmacodynamic model of the Renin-Angiotensin-Aldosterone-System

Ramusovic S (1), Willmann S (2), Läer S (1)

(1) University of Duesseldorf, Department of Clinical Pharmacy and Pharmacotherapy, Germany (2) Competence Center Systems Biology, Bayer Technology Services GmbH, 51368 Leverkusen, Germany

Objectives: Hypertension and blood pressure control are major cardiovascular targets to decrease morbidity and mortality in adult and paediatric patients. The Renin-Angiotensin-Aldosterone- (RAA-) System is an endocrinological cascade involved in blood pressure (BP) regulation. We aim at getting a better understanding of this system and of the drugs that interfere at the different levels of the RAAS. Therefore, we developed a physiologically based model describing central parts of the system at steady-state conditions and the dynamic disturbances of the system caused by its pharmacological blockade by enalapril.

Methods: A description of the RAA-System was obtained by literature review as were concentrations of the by-products of the cascade, Angiotensin I (Ang1) and Angiotensin II (Ang2), their half lives and the effects of enalapril application on them respectively [1]. The production of Ang 2 was modelled in terms of a subsequent proteolytic cascade including a negative feedback of Ang2 on renin production as indirect response model. So was the effect of enalapril application on Ang 2 levels. The model was built in MoBi 2.0 ® (Bayer Technology Services GmBH).

Results: The final model consisted of ten reaction steps with twenty two molecular species. Simulations for steady-state concentrations were comparable with literature data (simulation: 14.06 pM Ang1, 4.32 pM Ang2; literature: 14.93 pM Ang1, 4.73 pM Ang2 [1]). During ACE-Inhibition a maximum concentration of Ang1 and a minimum concentration of Ang2 (74.61 pM after 960 min and 0.8 pM after 240 min) comparable to literature data (86.4 pM after 960 min Ang1 and 1 pM after 240 min for Ang2 respectively [1]) were simulated. The concentration-time profiles of both by-products were described adequately by visual inspection.

Conclusions: A pharmacodynamic model including a relevant feedback mechanism to describe the time course of the RAAS components during ACE-Inhibition was developed. Due to its physiological nature, this model can be expanded to encompass further aspects of the RAA-System as well as it has the potential to become a part of a physiological model for blood pressure regulation.

References:
[1] Juillerat et al. Hypertension 1990; 5: 564-572




Reference: PAGE 18 (2009) Abstr 1558 [www.page-meeting.org/?abstract=1558]
Poster: Applications- Endocrine
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