Capturing the dynamics of systemic Renin‐Angiotensin‐Aldosterone System (RAAS) peptides heightens the understanding of the effect of benazepril in dogs

Mochel, Jonathan P.; Peyrou, Mathieu; Fink, Martin; Strehlau, G.; Mohamed, Rasha H.; Giraudel, J. M.; Ploeger, Bart; Danhof, Meindert

doi:10.1111/j.1365-2885.2012.01406.x

Cited by 21 publications

(17 citation statements)

References 27 publications

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“…This comprehensive assessment is beneficial, as looking at only 1 or 2 components of this system might be misleading. For example, assessment of only ACE activity during ACEI treatment might suggest very effective suppression, yet AngII and aldosterone do “break through” this treatment in some patients . Additional information regarding aldosterone metabolism and the assessment of RAAS activity in dogs and cats can be found in the Supporting Information of this review.…”

Section: Circulating and Tissue Raasmentioning

confidence: 99%

The renin‐angiotensin‐aldosterone system and its suppression

Ames

Atkins

Pitt

2019

Veterinary Internal Medicne

325

264

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Chronic activation of the renin‐angiotensin‐aldosterone system (RAAS) promotes and perpetuates the syndromes of congestive heart failure, systemic hypertension, and chronic kidney disease. Excessive circulating and tissue angiotensin II (AngII) and aldosterone levels lead to a pro‐fibrotic, ‐inflammatory, and ‐hypertrophic milieu that causes remodeling and dysfunction in cardiovascular and renal tissues. Understanding of the role of the RAAS in this abnormal pathologic remodeling has grown over the past few decades and numerous medical therapies aimed at suppressing the RAAS have been developed. Despite this, morbidity from these diseases remains high. Continued investigation into the complexities of the RAAS should help clinicians modulate (suppress or enhance) components of this system and improve quality of life and survival. This review focuses on updates in our understanding of the RAAS and the pathophysiology of AngII and aldosterone excess, reviewing what is known about its suppression in cardiovascular and renal diseases, especially in the cat and dog.

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Section: Circulating and Tissue Raasmentioning

confidence: 99%

The renin‐angiotensin‐aldosterone system and its suppression

Ames

Atkins

Pitt

2019

Veterinary Internal Medicne

325

264

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“…Because these hormones reflect different aspects of the pathophysiology of MMVD, response to treatment, or both, they might be regarded as functional markers. ACE‐Is suppress RAAS, although furosemide treatment cause RAAS activation even in the presence of an ACE‐I in MMVD dogs . Within treatment groups, plasma concentrations of AII and vasopressin decreased in the benazepril group compared with baseline, although this change was only significant for vasopressin.…”

Section: Discussionmentioning

confidence: 99%

Short‐Term Hemodynamic and Neuroendocrine Effects of Pimobendan and Benazapril in Dogs with Myxomatous Mitral Valve Disease and Congestive Heart Failure

Häggström

Lord

Höglund

et al. 2013

Veterinary Internal Medicne

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Background: Pimobendan and benazepril are frequently used with diuretics to treat dogs in congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD).Aim: To compare the short-term effects of pimobendan versus benazepril on pump function, heart size, and neuroendocrine profile in dogs with CHF caused by MMVD.Animals: Sixteen client-owned dogs. Material and methods: Seven-day prospective single-blinded study of dogs stabilized on furosemide monotherapy, randomized to pimobendan (0.4-0.6 mg/kg/day) or benazepril (0.25-1.0 mg/kg/day). Dogs had first-pass radionuclide angiocardiography, and heart size was measured by radiography and echocardiography. Circulating neuroendocrine hormones were measured.Results: Baseline variables did not differ between treatment groups. Greater decreases in the pimobendan than in the benazepril group were found for heart rate (P = .001), heart rate-normalized pulmonary transit time (P = .02), left atrial size (P = .03), and systolic and diastolic left ventricular diameters (P < .001 and P = .03, respectively) and volumes (P < .001 and P = .02, respectively), whereas ejection fraction increased more (P = .02) in the pimobendan group. Of the neuroendocrine hormones, only N-terminal proatrial natriuretic peptide (NT-ProANP) differed (P = .04) between groups. Within groups, plasma aldosterone increased (P = .01), and NT-proANP (P = .01) and NT-proB-type (P = .02) natriuretic peptide decreased in the pimobendan group, and NT-proANP (P = .02) and plasma vasopressin (P = .01) decreased in the benazepril group.Conclusions and Clinical Importance: Pimobendan improves short-term cardiac function more than benazepril in dogs with CHF caused by MMVD. Pimobendan treatment enables the heart to work at smaller end-systolic and diastolic dimensions while maintaining adequate forward stroke volume. Some of the treatment responses found in neuroendocrine profile might have therapeutic relevance.

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“…Although most of the preclinical investigations for dose selection of benazepril have used ACE activity as a surrogate marker of efficacy in dogs, recent literature suggests that this may not be a sensitive approach to properly assess the modulatory effect of ACE inhibitors on the RAAS ( Van de Wal et al 2006). Using a low-sodium diet (LSD) model of RAAS activation, our research shows that benazeprilat markedly influences the dynamics of the systemic RAAS following single and repeated oral administrations of benazepril at its recommended dose (0.25-1.0 mg/kg q24 h) in dogs (Mochel et al 2013b). In this study, treatment with benazepril triggered an apparent decrease in AII and ALD, together with a sustained elevation of RA, as a consequence of benazeprilat-induced interruption of the AII-renin negative feedback loop (Bussien et al 1986;Steele et al 2002).…”

Section: Benazepril Markedly Influences the Dynamics Of The Circulatimentioning

confidence: 94%

“…Based on our findings on the dynamics of the circulating RAAS under physiological (Mochel et al 2013a(Mochel et al , 2014a and RAAS-activated conditions (Mochel et al 2013b(Mochel et al , 2015, various strategies could in theory improve the therapeutic management of cardiovascular diseases in dogs. Essentially, one could think of:…”

Section: Benazepril Markedly Influences the Dynamics Of The Circulatimentioning

confidence: 96%

“…ACE inhibitors, like benazepril, act by preventing the formation of AII and the degradation of bradykinin, which acts as a potent vasodilator. Source: Mochel et al (2013b). Reprinted by permission of Wiley homeostasis via sodium, potassium, and hydrogen ion exchanges in the distal renal tubules and collecting ducts of Bellini (Quinn and Williams 1988).…”

Section: A Complex and Highly Regulated Machinerymentioning

confidence: 96%

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

Mochel

Danhof

2015

Reviews of Physiology, Biochemistry and Pharmacology Vol. 169

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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.

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Capturing the dynamics of systemic Renin‐Angiotensin‐Aldosterone System (RAAS) peptides heightens the understanding of the effect of benazepril in dogs

Cited by 21 publications

References 27 publications

The renin‐angiotensin‐aldosterone system and its suppression

The renin‐angiotensin‐aldosterone system and its suppression

Short‐Term Hemodynamic and Neuroendocrine Effects of Pimobendan and Benazapril in Dogs with Myxomatous Mitral Valve Disease and Congestive Heart Failure

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

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