Jonathan P. Mochel (1,2), Martin Fink (2), Mathieu Peyrou (3), Cyril Desevaux (4), Mark Deurinck (5), Jérôme M. Giraudel (6), and Meindert Danhof (1)
(1) Department of Pharmacology, Leiden-Academic Centre for Drug Research, 2300 Leiden, The Netherlands. (2) Department of Modeling and Simulation, Novartis Campus St. Johann, 4002 Basel, Switzerland. (3) Department of Therapeutics Research, Novartis Centre de Recherche Sante Animale SA, 1566 St-Aubin, Switzerland. (4) Department of Pre-Clinical Safety, Novartis Centre de Recherche Sante Animale SA, 1566 St-Aubin, Switzerland. (5) Department of Pre-clinical Safety, Novartis Institutes of Biomedical Research, 4002 Basel, Switzerland. (6) Yarrandoo Research and Development Centre, Novartis Animal Health Australasia Pty Limited, 2178 Kemps Creek, Australia.
Objectives: Although observations of time-variant changes in the renin cascade are available in dogs, no detailed chronobiological investigation has been conducted so far. The present studies were designed to explore the circadian variations of plasma renin activity (RA) and urinary aldosterone to creatinine ratio (UA:C) in relation to blood pressure (BP), sodium (UNa, UNa,fe), and potassium (UK, UK,fe) renal handling.
Methods: Data derived from intensive blood and urine sampling, as well as continuous BP monitoring were collected throughout a 24-hour time period, and analyzed by means of NLME models, using NONMEM version 7.2[1]. Covariate search was performed using the stepwise covariate model building tool of Perl-speaks-NONMEM[2]. Model selection was based on statistical significance between competing models using OFV, graphical evaluation and validity of parameter estimates. Differences between the geometric means of day and night observations were further compared by parametric statistics.
Results: Our results show that the RAAS, BP and urinary electrolytes oscillate with significant day-night differences around the clock in dogs. An approximately 2-fold change between the average day and night measurements was found for RA (p<.001), UA:C (p:.02), UK (p<.001), and UNa (p:.007). For all endpoints but UNa and UNa,fe the levels were higher at night than during the day. The data also indicate that blood pressure oscillates in parallel to the RAAS, such that, as opposed to healthy humans BP does not drop at night in dogs. A cosine model with a fixed 24-hour period was found to fit the variations of RA, UA:C, UK, UK,fe, and BP well, while changes in UNa and UNa,fe were best characterized by a surge model. Sodium intake was found to interact with the tonic and the phasic secretion of renin, suggesting that varying feeding time could also impact the chronobiology of the renin cascade.
Conclusions: This research offers the first chronobiological characterization of the RAAS and BP in dogs. Cosine and surge models were able to describe and predict the time-variant changes of the experimental data with high accuracy, as shown by the quality of the standard goodness-of-fit diagnostics. Additional investigations on the chronobiology of the RAAS and BP are required in diseased dogs under ACEI to determine whether it is possible to improve drug therapy of RAAS-related diseases with bedtime administration as compared with morning dosing.
References:
[1] Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Mats Karlsson, Niclas Jonsson and Andrew Hooker, 2008.
Reference: PAGE 22 () Abstr 2663 [www.page-meeting.org/?abstract=2663]
Poster: Endocrine