Chronobiology and Pharmacologic Modulation of the Renin–Angiotensin–Aldosterone System in Dogs: What Have We Learned?

Abstract

Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides in spontaneous cases of canine CHF. If such a link could be established, profiling of these biomarkers could support determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes.

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.…”

The Renin‐Angiotensin‐Aldosterone System in Greyhounds and Non‐Greyhound Dogs

“…This is consistent with the higher serum sodium concentrations observed in Greyhounds, suggesting that aldosterone secretion is downregulated. If ACE activity reflects angiotensin II production, this would suggest that direct renal effects of angiotensin II on tubular sodium reabsorption could be more important than those of aldosterone in maintaining the higher serum sodium concentrations in the Greyhounds . While chronic infusion of angiotensin II into the renal artery of Greyhounds results in increased systemic arterial pressure, baseline levels of angiotensin II have not been measured in this breed .…”

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies

“…According to a recent report from the National Academy of Medicine (64), only one out of ten oncology candidates that appear promising in preclinical mouse models are in fact effective and safe in human clinical trials. This overtly high attrition rate highlights the need for alternative models at the early stage of the Drug Research and Development lifecycle (65), as shown in other therapeutic areas (66)(67)(68)(69)(70)(71).…”