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Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics.

ABSTRACT: Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin-angiotensin-aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension.

SUBMITTER: Mangiafico S

PROVIDER: S-EPMC3604644 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics.

Mangiafico Sarah S Costello-Boerrigter Lisa C LC Andersen Ingrid A IA Cataliotti Alessandro A Burnett John C JC

European heart journal 20120831 12

Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibi ...[more]

PMID: 22942338

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Project description:ObjectivesThe purpose of the present study was to translate our laboratory investigations to establish safety and efficacy of 8 weeks of chronic SC B-type natriuretic peptide (BNP) administration in human Stage C heart failure (HF).BackgroundB-Type natriuretic peptide is a cardiac hormone with vasodilating, natriuretic, renin-angiotensin inhibiting, and lusitropic properties. We have previously demonstrated that chronic cardiac hormone replacement with subcutaneous (SC) administration of BNP in experimental HF resulted in improved cardiovascular function.MethodsWe performed a randomized double-blind placebo-controlled proof of concept study comparing 8 weeks of SC BNP (10 μg/kg bid) (n = 20) with placebo (n = 20) in patients with ejection fraction <35% and New York Heart Association functional class II to III HF. Primary outcomes were left ventricular (LV) volumes and LV mass determined by cardiac magnetic resonance imaging. Secondary outcomes include LV filling pressure by Doppler echo, humoral function, and renal function.ResultsEight weeks of chronic SC BNP resulted in a greater reduction of LV systolic and diastolic volume index and LV mass index as compared with placebo. There was a significantly greater improvement of Minnesota Living with Heart Failure score, LV filling pressure as demonstrated by the reductions of E/e' ratio, and decrease in left atrial volume index as compared with placebo. Glomerular filtration rate was preserved with SC BNP, as was the ability to activate plasma 3',5'-cyclic guanosine monophosphate (p < 0.05 vs. placebo).ConclusionsIn this pilot proof of concept study, chronic protein therapy with SC BNP improved LV remodeling, LV filling pressure, and Minnesota Living with Heart Failure score in patients with stable systolic HF on optimal therapy. Renin-angiotensin was suppressed, and glomerular filtration rate was preserved. Subcutaneous BNP represents a novel, safe, and efficacious protein therapeutic strategy in human HF. Further studies are warranted to determine whether these physiologic observations can be translated into improved clinical outcomes and ultimately delay the progression of HF. (Cardiac Hormone Replacement With BNP in Heart Failure: A Novel Therapeutic Strategy; NCT00252187).

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Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics.

Publications

Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics.

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