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Is too much neurohormonal blockade harmful?
Published in ILEANA PIÑA, SIDNEY GOLDSTEIN, MARK E DUNLAP, The Year in Heart Failure, 2005
Two trials have compared the effects oflow-dose versus high-dose ACE inhibitor in patients with moderate to severe heart failure, to test the hypothesis that more effective blockade of ACE may produce incremental benefits. The Assessment of Treatment with Lisinopril and Survival (ATLAS) randomized 3164 patients with New York Heart Association class II-IV heart failure to either low-dose (2.5-5.0 mglday, average 4.5 1.1 mg) or high-dose (32.5-35 mglday, average 33.2) lisinopril for a median of 45.7 months. The high-dose group had a non-significant, 8% decrease in mortality as compared with the low-dose group (P = 0.128). The risk of death or hospitalization was, however, 12% lower (P = 0.002) and hospitalizations for heart failure 24% lower (P = 0.002) in the high-dose group. The second study was much smaller and investigated a very high dose of enalapril (60 mglday, average 42 19.3 mg) compared with usual dose (average 17.9 4.3 mg/day) and could not find any benefit of high-dose ACE inhibitor 1291. This relative lack of beneficial effect with 'excessive' blockade of ACE could be related to the phenomenon of'angiotensin II and aldosterone escape' seen with ACE inhibitor use despite complete blockade of ACE. Indeed, Tang et al. I30I have shown that whereas high-dose enalapril (40 mg/day) caused a much greater suppression of serum ACE activity, levels of angiotensin and aldosterone remained elevated to the same extent in both the highand low-dose ACE inhibitor groups. Thus, high doses of ACE inhibitor produce only a minimal or no incremental benefit but are associated with more adverse side effects.
New treatments for hypertension
Published in H. Gavras, The Year in Hypertension 2004, 2004
CARMINE SAVOIA, ERNESTO L SCHIFFRIN
Drugs that inhibit other peptide systems such as the components of RAAS also represent an important new tool for cardiovascular protection. Angiotensin II stimulates the synthesis of aldosterone, which plays an independent role in cardiovascular damage, inflammation, and fibrosis. Although ACE inhibitors and angiotensin receptor blockers (ARBs or sartans) reduce aldosterone concentrations, aldosterone returns to baseline levels during chronic therapy with ACE inhibitors or ARBs (aldosterone escape). Elevated plasma aldosterone concentrations are associated with endothelial dysfunction, myocardial infarction, left ventricular hypertrophy, and death, and administration of the non-selective mineralocorticoid receptor (MR) antagonist spironolactone enhances the beneficial effect of ACE inhibition, particularly in heart failure. Despite the beneficial effect of spironolactone on mortality in patients with heart failure, the anti-androgenic side effects of spironolactone have limited its usefulness in the treatment of hypertension.
An overview of mineralocorticoid receptor antagonists as a treatment option for patients with heart failure: the current state-of-the-art and future outlook
Published in Expert Opinion on Pharmacotherapy, 2022
Marta Lorente-Ros, Jose S Aguilar-Gallardo, Aayush Shah, Bharat Narasimhan, Wilbert S. Aronow
While steroidal MRAs accumulate predominantly in the kidney, finerenone has equal distribution between heart and kidney, which potentially could contribute to improved cardiovascular outcomes and less effect on sodium–potassium balance [25]. Lastly, the concern for aldosterone escape with steroidal MRAs could theoretically be lower with non-steroidal MRAs. Aldosterone escape has been mostly attributed to increased potassium levels [5], which, theoretically, may be mitigated with non-steroidal MRAs, given the lesser effect on sodium-potassium channels and lower incidence of hyperkalemia [25]. However, to this date, the mechanisms behind the clinical benefits of non-steroidal MRAs are still under study. In addition, other non-steroidal MRAs may differ from finerenone, but pharmacological comparisons are not currently available.
Effects of eplerenone on cerebral aldosterone levels and brain lesions in spontaneously hypertensive rats
Published in Clinical and Experimental Hypertension, 2020
Xue Wang, Yuhai Zhu, Shuanglin Wang, Zhuoqun Wang, Haonan Sun, Yujie He, Wei Yao
Adverse cardiovascular effects may occur in response to aldosterone escape during chronic angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy (11), which are often used to treat hypertension. As a result, mineralocorticoid receptor antagonists have been increasingly used in patients with treatment-resistant hypertension. Several studies have shown that aldosterone receptor antagonism can protect organs and vasculature without significantly lowering blood pressure (BP), which is consistent with a major role for endogenous mineralocorticoids as mediators of cardiovascular injury (12). Blocking aldosterone receptors is an important goal in the clinical treatment of patients with heart or kidney dysfunction. As a selective aldosterone receptor blocker, eplerenone has advantages such as low sex hormone-related side effetcs and has exhibited therapeutic value in preventing cardiovascular disease and associated end organ damage (13). However, whether or not it has a role in protecting brain tissue remains unclear. Thus, hypothesizing that eplerenone could alleviate the brain damage caused by hypertension is tempting. The aim of the present study was to verify the relationship between cerebral aldosterone levels and brain tissue damage of spontaneously hypertensive rats (SHRs), and to determine the effects of eplerenone on BP and in protecting brain tissue.
Management of chronic kidney disease in type 2 diabetes: screening, diagnosis and treatment goals, and recommendations
Published in Postgraduate Medicine, 2022
Jay H. Shubrook, Joshua J. Neumiller, Eugene Wright
Aldosterone appears to play a role in the initiation and progression of CKD independent of arterial blood pressure and plasma angiotensin II level. Evidence suggests that continuous ACEi therapy does not necessarily result in sustained reduction of plasma aldosterone levels, which may remain high or even increase during long-term use (aldosterone escape) [44]. Aldosterone escape has been reported in up to 40% of patients with T2D with early nephropathy despite the use of ACEis, and has been associated with elevation in urinary albumin excretion or an enhanced decline in GFR in diabetic kidney disease (DKD) [45].