In the face of high or even normal total body sodium, a high aldosterone level is therefore inappropriate. Further discussion of the interplay among aldosterone, sodium status, metabolic state, inflammation, and oxidative stress can be found in the Supporting Information. Angiotensin converting enzyme inhibitors are widely used in the treatment of cardiovascular and renal diseases in multiple species.
Drugs in this class inhibit ACE and not only decrease formation of AngII, but also decrease the degradation of the vasodilatory compound bradykinin. The pharmacokinetic properties of ACEI are complex and their disposition during repeated dosing cannot be characterized by a classical noncompartmental model. Although circulating ACE activity is significantly suppressed at these recommended dosages, clinical trials are required to determine efficacy and if there are outcome differences between ACEI.
The clinical relevance of these differences, however, is not known. As ACE is anchored to the cell membrane such that its catalytic site faces the extracellular space, , differences in lipophilicity should be less important, except in the case of certain centrally acting ACEI. Chymase has a greater catalytic efficiency than ACE and is thought to serve as the primary generator of AngII in the tissues however, and likely contributes to apparent inefficacy of ACEI.
As previously discussed, novel approaches to target tissue RAAS management is likely to be part of future pharmacotherapeutic strategies. These adverse effects are rarely, if at all, recognized in dogs and cats. Whether ARBs are superior to ACEI in dogs and cats with either cardiovascular or renal disease is not known, though the early experience with telmisartan in cats with hypertension, chronic kidney disease CKD , and proteinuria suggests that this may be the case see below. Spironolactone and eplerenone are synthetic steroidal MRA.
In the dog, spironolactone is quickly absorbed through the gastrointestinal tract into the plasma and is then converted to several active metabolites. Spironolactone is relatively inexpensive and is the most frequently used MRA in veterinary medicine.
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Inhibition of the neutral endopeptidase, neprilysin, decreases the breakdown of endogenous vasoactive peptides, including natriuretic peptides, bradykinin and adrenomedullin. When the neprilysin inhibitor, sacubitril, was combined with an ACEI, the frequency of angioedema and cough in people was unacceptably high.
This combination was evaluated in a large human clinical trial, where it was superior to ACE inhibition alone in reducing the risk of death and hospitalization for patients with heart failure with reduced ejection fraction HFrEF. Studies in humans have shown the benefits of ACEI in the treatment of systolic heart failure, associated with moderate to severe and mild to moderate clinical signs.
Of these, only enalapril and benazepril, and to a lesser degree imidapril and ramipril, have been extensively studied.
A subsequent European study comparing pimobendan and the ACEI, benazepril, showed modest survival benefit in those receiving pimobendan. Only the 4th panel was composed exclusively of dogs with MMVD. Although the third graph contains data from a retrospective study of dogs treated with benazepril versus those left untreated in ACVIM Stage B1.
Panel 1. Placebo plus standard treatment, dashed line. Enalapril plus standard treatment, solid line. Panel 2. Benazepril plus standard treatment, solid line. Panel 3. Both studies demonstrated comparable survival and quality of life scores between imidapril and the control ACEI. Panel 4.
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. Standard treatment plus spironolactone, solid line. Panel 5. Placebo, dashed line. Enalapril, solid line. Panel 6. Panel 7. Although retrospective, this study demonstrates a delay in the onset of CHF in the treatment group.
Enalapril was dosed at 0. The treatment group received enalapril at an average dosage of 0. This raises the question of pharmacogenomic differences among dog breeds. Further study is necessary to determine whether differences in RAAS phenotypes impact the response to RAAS suppressive treatment and the natural history of cardiac disease in this breed. In dogs with experimentally created mitral regurgitation, captopril treatment led to a fall in total peripheral resistance index, decrease in regurgitant fraction, and increase in forward ejection fraction as compared to untreated controls.
This study showed that the inodilator pimobendan significantly prolonged the preclinical period in this cohort of dogs. These significantly positive results have led to the recommendation in recent guidelines that MRA be used as a standard therapy in the treatment of HFrEF.
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The changes in patient neurohormonal profiles during chronic spironolactone treatment were monitored in a subset of patients in the RALES trial. As there was a survival benefit associated with spironolactone, the impact of these hormone increases are likely mitigated by antagonism of the MR.
This was followed by an increase in average plasma aldosterone concentration, above baseline levels, 6 months after initiation of treatment. The role of spironolactone in the treatment of heart failure, caused by ventricular diastolic dysfunction with preserved ejection fraction HFpEF is an area of ongoing research. Pathological activation of the RAAS and, in particular, hyperaldosteronism are implicated in the pathologic ventricular remodeling and diastolic myocardial dysfunction in hypertrophic cardiomyopathy HCM in humans.
This study did not result in a significant survival benefit or reduction in hospitalization for heart failure. Significantly fewer cats receiving spironolactone reached the primary endpoint cardiovascular death , compared to those receiving placebo. Also, no cat receiving spironolactone experienced ulcerative facial dermatitis. Because of a small sample size and disparities in disease severity between the 2 groups at baseline, the authors concluded that these results are promising, yet additional studies evaluating spironolactone in cats with HCM and heart failure are warranted.
The role of hyperaldosteronism in dogs with hypertension, secondary to pituitary dependent hyperadrenocorticism, is unclear, - as HTN often persists despite medical treatment and control of the hyperadrenocorticism. In cats, HTN is usually secondary to renal disease, endocrine disease, or both.
In this species, HTN is a common cause of left ventricular hypertrophy, diastolic dysfunction, and other target organ damage. Plasma aldosterone concentrations and the aldosterone to renin ratio in azotemic hypertensive cats have been shown to be significantly elevated, as compared to normotensive cats.
A recent clinical field study showed that telmisartan was tolerated and lowered mean arterial blood pressure when compared to placebo in cats with HTN that was either idiopathic or secondary to CKD or hyperthyroidism. Finally, circulating RAAS activation in cats is not always associated with the development of hypertension, as demonstrated in studies of cats with hyperthyroidism and CKD. Proteinuria, a marker of kidney injury, is likely a predictor of increased risk for disease progression, and might play a causal role in progression of glomerular disease.
In people, the combination of ACEI and ARB is usually more effective at reducing proteinuria in various forms of kidney disease than either treatment alone.
The reduction in proteinuria does not, however, always translate to improved renal outcomes need for dialysis, increasing creatinine, and fall in estimated glomerular filtration rate [GFR] and is sometimes associated with increased incidence of hyperkalemia and acute kidney injury when compared to monotherapy.
Combination RAAS suppression and the addition of an MRA to standard pharmacotherapy has not been studied in dogs and cats with naturally occurring renal disease. The benefit of RAAS suppressive treatment in canine proteinuric CKD, including idiopathic glomerulonephritis, has been demonstrated in experimental models and small clinical studies. This difference was significant at 3 months, yet not at 6 months.
Furthermore, treated dogs had lower urine protein to creatinine ratios UP:C and significantly lower renal tubular and glomerular lesion scores. The magnitude of proteinuria in dogs newly diagnosed with CKD appears to be related to prognosis, as a reduction in proteinuria may prolong survival. Controlled studies are needed to evaluate the effect of these combinations.
Importantly, proteinuria has been shown to predict progression of azotemia and is negatively associated with survival in cats with chronic renal disease and with HTN. As with dogs, combination RAAS blockade has not been evaluated in cats. Finally, benazepril has been shown to lower blood urea nitrogen, serum creatinine concentration, and blood pressure in cats with polycystic kidney disease. We have learned through clinical experience with ACEIs that their negative impact on kidney function is minimal, even in the face of severe heart failure.
When azotemia is observed, ACEIs are usually being administered in conjunction with diuretics, sodium restriction, and sometimes vasodilators, often with resultant hypotension. Typically, diuretic cessation or reduction in dosage results in the improvement or resolution of azotemia. A safety analysis of dogs involved in the study of Bernay and colleagues showed that those receiving spironolactone, in addition to standard treatment including an ACEI , were not at higher risk for adverse events such as death from renal disease and abnormalities in serum sodium, potassium, urea nitrogen, and creatinine , when compared with dogs receiving placebo and standard treatment.
Importantly, dogs receiving spironolactone in addition to conventional treatment for heart failure loop diuretic, ACEI, and pimobendan did not have a greater incidence of hyperkalemia.
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In a study of Doberman pinschers with occult DCM, significant increases in serum potassium concentration versus individual baseline values were seen in dogs receiving both spironolactone and an ACEI. Overall, regular monitoring of serum electrolytes and renal values is prudent in all animals receiving vasodilators and diuretics, including spironolactone and ACEI.
Finally, spironolactone in combination with an ACEI appears to be safe, when used to treat dogs with naturally occurring, asymptomatic MMVD, as well those with occult DCM, without preexisting azotemia. Sustained RAAS activation adversely affects the heart, vessels, and kidneys.