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 (UA:C) in relation to blood pressure (BP), sodium (UNa, UNa,fe), and potassium (UK, UK,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), UA:C (p = 0.01), UK,fe (p = 0.01), and UNa (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 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. 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 UA:C reflects aldosterone-stimulated secretion by the renin-angiotensin II pathway. UNa and UNa,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, UK and UK,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, UA:C, UK, UK,fe, and BP well, whereas changes in UNa and UNa,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.

A prospective, randomized, double‐blind, placebo‐controlled pilot study of sacubitril/valsartan (Entresto) in dogs with cardiomegaly secondary to myxomatous mitral valve disease

“…Another limitation is the potential effects of chronobiology and diet on the RAAS and NP system. Circadian fluctuations of RAAS hormones and dietary sodium content could have affected our results, but intrapatient variables (feeding times, food types, sample collection times) were held constant for the duration of the study period 55, 56. Pooled urine samples also were used to minimize the potential effect of these variables on urinary aldosterone concentrations.…”

Effect of Breed on Plasma Endothelin‐1 Concentration, Plasma Renin Activity, and Serum Cortisol Concentration in Healthy Dogs

“…Another factor which could affect results is time‐to‐time variation. In dogs, circadian variation has been shown for serum cortisol45 and plasma renin activity,46 but has not been investigated for plasma ET‐1. In a small human study, time‐to‐time variation in ET‐1 was found 47.…”

Association between the AGTR1 A1166C polymorphism and risk of IgA nephropathy: a meta-analysis

“…Renin-angiotensin system (RAS) activity is an important modulator of blood pressure and plays a key role in renal diseases (Mochel et al, 2013). In the kidney, the RAS regulates renal cell growth and contributes to elevated transforming growth factor β production, leading to fibrosis (RuizOrtega and Egido, 1997).…”