J.P. Mochel and M. Danhof
Department of Pharmacology, Leiden-Academic Centre for Drug Research, 2300 Leiden, The Netherlands
Objectives: Similar to humans, activation of the renin-angiotensin-aldosterone system (RAAS) is one of the key neurohumoral responses to the reduced cardiac output observed in canine congestive heart failure (CHF). Results from our previous research [1] showed that variables of the RAAS and blood pressure (BP) oscillate with significant day–night differences in dogs. The manipulation of feeding schedules has been shown to influence the rhythmicity of several physiological variables (e.g liver glycogen and heart rate) but the impact of timed feeding on the chronobiology of the renin cascade remains controversial. The objective of this work was to evaluate the effect of food intake on the pharmacodynamics of renin activity (RA) and BP in dogs.
Methods: In a first experiment, blood samples for measurement of RA were drawn from 18 dogs fed a normal-sodium diet at either 07:00, 13:00 or 19:00 h. In a second study BP was recorded continuously from six telemetered beagle dogs fed a similar diet at 07:00 or 19:00 h. Data were collected throughout 24-h time periods and analyzed by means of NLME models in NONMEM 7.2 using a combination of periodic functions. Model selection was based on statistical significance between competing models using the OFV obtained from NONMEM, graphical evaluation and validity of parameter estimates. Residual error estimates from the mathematical models were used as supportive information for evaluation of lack of fit.
Results: Cosine and surge models were able to reproduce the time-variant changes of the experimental data with good accuracy, as suggested by the quality of the standard goodness-of-fit diagnostics and the individual predictions. Our data show that the timing of food intake exerts a synchronizing effect on RA and BP, such that a 6 to 12-h delay in the dogs’ feeding schedule triggers a shift of similar magnitude in the rhythm of these biomarkers.
Conclusions: Our results indicate that meal timing drives the periodicity of BP and RAAS-related variables in dogs. Activation of renin is a common neurohumoral feature of human and canine CHF [2]; information on the chronobiology of the RAAS in dogs therefore contributes to a better understanding of cardiovascular physiology in humans. Accumulating knowledge on the chronobiology of the RAAS and BP provides a strong scientific rationale for determining the optimum dosing time, thereby making the best usage of available cardioactive drugs.
References:
[1] Mochel JP, Fink M, Peyrou M, Desevaux C, Deurinck M, Giraudel JM, Danhof M. Chronobiology of the renin-angiotensin-aldosterone system in dogs: relation to blood pressure and renal physiology. Chronobiol Int. 2013;30(9):1144-59.
[2] Sisson DD. Neuroendocrine evaluation of cardiac disease. Vet Clin North Am Small Anim Pract. 2004;34(5):1105-26.
Reference: PAGE 25 () Abstr 5767 [www.page-meeting.org/?abstract=5767]
Poster: Drug/Disease modeling - Endocrine