Chronobiology of the renin-angiotensin-aldosterone system in dogs: relation to blood pressure and renal physiology

Abstract

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and volume homeostasis. Its contribution to the development of cardiovascular diseases has long been recognized. Extensive literature has shown that peptides of the RAAS oscillate with a circadian periodicity in humans, under strong influence of posture, sleep, and age. 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 (U_A:C) in relation to blood pressure (BP), sodium (U_Na, U_Na,fe), and potassium (U_K, U_K,fe) renal handling. Data derived from intensive blood and urine sampling, as well as continuous BP monitoring, were collected throughout a 24-h time period, and analyzed by means of nonlinear mixed-effects models. Differences between the geometric means of day and night observations were compared by parametric statistics. Our results show that variables of the renin cascade, BP, and urinary electrolytes oscillate with significant day-night differences in dogs. An approximately 2-fold (1.6–3.2-fold) change between the average day and night measurements was found for RA (p < 0.001), U_A:C (p = 0.01), U_K,fe (p = 0.01), and U_Na (p = 0.007). Circadian variations in BP, albeit small (less than 10 mm Hg), were statistically significant (p < 0.01) and supported by the model-based analysis. For all variables but U_Na and U_Na,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. The postprandial decrease in RA is assumed to be related to body fluid volume expansion secondary to water and sodium intake, whereas the reduction of U_A:C reflects aldosterone-stimulated secretion by the renin-angiotensin II pathway. U_Na and U_Na,fe peaked in the afternoon, about 7–8 h after food intake, which is consistent with the “impulse-response pattern” of sodium excretion described in previous publications. Finally, U_K and U_K,fe mirrored aldosterone-mediated potassium secretion in the kidney tubules. To describe the circadian variations of the various variables, two different mathematical representations were applied. A cosine model with a fixed 24-h period was found to fit the periodic variations of RA, U_A:C, U_K, U_K,fe, and BP well, whereas changes in U_Na and U_Na,fe were best characterized by a surge model. The use of nonlinear mixed effects allowed estimation of population characteristics that can influence the periodicity of the RAAS. Specifically, 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. (Author correspondence: [email protected])

• Chronotherapy
• Circadian periodicity
• Covariate
• Nonlinear mixed-effects modeling

Acknowledgments

The investigations on RAAS periodicity were conducted at the Centre de Recherche Sante Animale SA (CRA) of Novartis Animal Health, located in Saint-Aubin, Switzerland. The telemetry study was performed at Novartis Institutes of Biomedical Research, Novartis Pharma AG, Basel, Switzerland.

Notes

†Part of the results of these studies were presented in abstract form at the European Association for Veterinary Pharmacology and Toxicology (EAVPT), July 8–12, 2012, Noordwijkerhout, The Netherlands.

¹Because of limited tubular secretion and reabsorption (Guignard & Drukker, 1999; O’Connell et al., 1962), creatinine clearance can be used to provide estimates of the glomerular filtration rate (GFR) in dogs.