The renin-angiotensin-aldosterone system and its suppression

Abstract

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.

Keywords: angiotensin converting enzyme inhibitor; angiotensin receptor blocker; chronic kidney disease; heart failure; mineralocorticoid receptor blocker; proteinuric kidney disease; systemic hypertension.

Figure 1

The renin‐angiotensin‐aldosterone system (RAAS) scheme: factors that lead to the release of renin from the juxtaglomerular cells of the kidney and the “target organs” of AngII, for which the actions (both pathophysiologic and pathologic) are primarily mediated by the AT₁R. The actions of AngII at the AT₂R are thought to counter those of the AT₁R. The AT₂R is likely of greater importance in the developing fetus, yet might be upregulated in certain disease states in adults. Angiotensin II is also a major secretagogue for aldosterone, which acts via the MR to increase sodium retention in the kidney and also amplifies the pathophysiologic effects of AngII in the heart, kidney, and vasculature. AngI, angiotensin I; AngII, angiotensin II, AT₁R, angiotensin type‐1 receptor; AT₂R, angiotensin type‐2 receptor; CO, cardiac output; MR, mineralocorticoid receptor; SNS, sympathetic nervous system

Figure 2

The renin‐angiotensin‐aldosterone system peptide cascade (RAAS Fingerprint) is illustrated as a pedigree starting at angiotensin I. Each intersection represents a specific peptide fragment symbolized by colored spheres; enzymes involved in the reactions are annotated on connecting lines. Size of spheres and numbers beside them represent absolute concentrations of angiotensins (pg/mL, median values) in serum samples from 6 middle‐aged, healthy male Beagles; the concentrations were analyzed by mass spectrometry. Angiotensin (1,7) and (1,5) are breakdown products of both angiotensin I and II. The novel peptides angiotensin (1,12) and (1,25) may be directly derived from angiotensinogen and serve as precursors for angiotensin peptides such as AngII. Aldo, aldosterone; AngI, angiotensin I; AngII, angiotensin II; AngIII, angiotensin III; Ang IV, angiotensin IV; AP, aminopeptidase; AT₁R, angiotensin type‐1 receptor; NEP, neutral endopeptidase

Figure 3

Schematic representation of experiments carried out by Brilla and Weber7, 268, 269, 270, 271 using rats with varying kidney function and experimental hypertension. A, Normotensive control rat heart, aorta, renal arteries, kidneys, and normal angiotensin II and aldosterone production; B, unilateral renal ischemia (unilateral renal artery banding) model with infrarenal aortic banding; C, aldosterone infusion with high‐sodium diet; and D, infrarenal banding. Increased circulating angiotensin II, aldosterone, or both occur in models B and C, which are characterized by interstitial and perivascular fibrosis of both the hypertrophied left and non‐hypertrophied right ventricles. In model B, the angiotensin converting enzyme inhibitor, captopril, prevented interstitial and perivascular fibrosis in rats with renal ischemia, yet did not prevent this remodeling in rats with aldosterone infusion and high sodium diets (model C). When models B and C were treated with spironolactone before and after the induction of hypertension, the rats developed left ventricular hypertrophy as expected, yet had significantly less interstitial and perivascular myocardial fibrosis, when compared to untreated controls. ACEI, angiotensin converting enzyme inhibitor; Aldo, aldosterone; AngII, angiotensin II; LV, left ventricle; LVH, left ventricular hypertrophy; MRA, mineralocorticoid receptor antagonist; RV, right ventricle

Figure 4

The American College of Veterinary Internal Medicine (ACVIM) classification of cardiac disease. From at risk of heart failure to refractory heart failure173

Figure 5

Seven renin‐angiotensin‐aldosterone system (RAAS) suppression clinical trials, 6 of which are of placebo‐controlled, double‐blind, multicenter design, are redrawn from the original publications.37, 182, 183, 184, 185, 186, 190, 191, 192, 210 All studies were funded by pharmaceutical companies. The first 4 Kaplan‐Meier curves represent trials involving dogs in congestive heart failure (the American College of Veterinary Internal Medicine [ACVIM], Stage C2; congestive heart failure [CHF]), caused by myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM). Only the 4th panel was composed exclusively of dogs with MMVD. All studies in panels 5 through 7 were made up entirely of dogs with asymptomatic MMVD (ACVIM Stage B). Panels 1 and 2 depict prospective double‐blind clinical trials, involving enalapril. Although the third graph contains data from a retrospective study of dogs treated with benazepril versus those left untreated in ACVIM Stage B1. Symptomatic (panels 1 through 4) Panel 1. The LIVE trial was 1 of the first placebo‐controlled double‐blind clinical trials in veterinary cardiology. Significant improvement in survival (death or removal from study) was documented in a population of dogs in CHF (ACVIM, Stage C2), caused by MMVD or DCM, when treated with enalapril plus standard treatment, as compared to placebo plus standard treatment. Placebo plus standard treatment, dashed line. Enalapril plus standard treatment, solid line. Panel 2. The BENCH Trial compared benazepril to placebo in dogs with CHF caused by MMVD or DCM, and demonstrated significant benefit in survival (time to death or removal from the study for worsening clinical signs), and quality of life, in the dogs receiving benazepril. Placebo plus standard treatment, dashed line. Benazepril plus standard treatment, solid line. Panel 3. The FIRST (placebo‐controlled, double‐blind) and EFFIC trials (open label) respectively compared imidapril (solid line) or ramipril (not shown) to an established angiotensin converting enzyme inhibitor (ACEI), enalapril (dashed line), in treating dogs with MMVD or DCM, NYHA Stage 2‐4. Data are shown only for the 12‐month placebo‐controlled FIRST trial. Both studies demonstrated comparable survival and quality of life scores between imidapril and the control ACEI. Panel 4. The CEVA Spironolactone Trial compared spironolactone plus standard treatment (including benazepril) to placebo, in a prospective double‐blind trial involving dogs in ISACH International Small Animal Health Council (ISACHC) classification, II and III, caused by MMVD. In general, these dogs were in relatively mild heart failure. Similar to the RALES trial, significant survival benefit was realized by the dogs receiving spironolactone along with standard treatment. Placebo plus standard treatment, dashed line. Standard treatment plus spironolactone, solid line. Asymptomatic (panels 5 through 7) Panel 5. The SVEP trial involved an approximate 50:50 distribution of dogs with ACVIM Stage B1 and Stage B2, (asymptomatic), with treated dogs receiving enalapril, at a dosage of 0.37 mg/kg/d.190 Of these 229 dogs (all Cavalier King Charles Spaniels), approximately 45% reached the defined endpoint, onset of CHF. The 2% benefit seen in the number of days dogs remained in the study, free of CHF, between placebo‐ and enalapril‐treated dogs was not significant (log‐rank test, P = .85). Placebo, dashed line. Enalapril, solid line. Panel 6. The VETPROOF compared enalapril to placebo, in a double‐blind placebo‐controlled trial of dogs in ACVIM B2. The graph depicting the combined endpoint of survival (all‐cause death and CHF‐free survival), expressed as a Kaplan‐Meier curve, for 124 dogs that met entry requirements is presented. Median times to this combined endpoint in the treatment and placebo groups were 851 and 534 days (59% difference of 317 days [10.6 months] in heart failure and survival benefit), respectively (P = .05). The primary endpoint (time to onset of CHF) was prolonged by enalapril versus placebo, but was not significant (P = .06). However, the numbers of dogs not in CHF were significantly different between groups on days 500 and 1000, as were the curves delineating all‐cause mortality. Placebo, dashed line. Enalapril, solid line. Panel 7. Kaplan‐Meier survival curves of dogs treated with benazepril (solid line) or untreated (placebo, dashed line), after the initial diagnosis of ISACHC class Ia (ACVIM Stage B1) MMVD, with moderate‐to‐severe mitral regurgitation, demonstrated with echocardiography. Although retrospective, this study demonstrates a delay in the onset of CHF in the treatment group. This raises the possibility that ACEI may be of benefit even before cardiac remodeling is evident and supports the use of ACEI in MMVD, before the onset of congestive heart failure