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Blocking the Enzyme That Destroys Heart-Protective Peptides Makes Them Work Much Better

RPEP-002471992Seymour, A A; Asaad, M M; Abboa-Offei, B E; Rovnyak, P L; Fennell, S; Rogers, W L
Animal StudyModerate evidence
The takeaway

An NEP inhibitor dramatically boosted the blood pressure-lowering and kidney effects of brain natriuretic peptide in both rats and monkeys.

Markedly potentiated

NEP inhibition dramatically enhanced BNP's blood pressure-lowering and natriuretic effects in two species

What the researchers found

NEP inhibitor SQ 28,603 markedly potentiated BNP-32 responses in SHR and monkeys. BNP was more resistant to NEP degradation than ANP. Cyclic GMP responses also potentiated.

Why it matters

This research laid groundwork for drugs like sacubitril (Entresto) that protect natriuretic peptides from degradation. These drugs are now standard heart failure treatment.

How the study worked

Conscious spontaneously hypertensive rats and cynomolgus monkeys received BNP or ANP with or without NEP inhibitor SQ 28,603. Blood pressure, natriuresis, and cyclic GMP were measured.

What this study cannot tell us

Animal study in two species. Doses and routes differ from clinical use. SHR model is one type of hypertension.

How to read the evidence

Moderate — animal study in two species (rats and monkeys) with consistent results. Cross-species validation strengthens confidence.

When this study was published

Published in 1992 (34 years ago). This early work contributed to sacubitril/valsartan (approved 2015), now a cornerstone of heart failure treatment.

The bigger picture

This research directly led to the development of sacubitril/valsartan (Entresto), now a standard treatment for heart failure. By protecting the body's own heart-protective peptides from destruction, these drugs represent a paradigm shift in cardiovascular medicine.

Questions still open

  • Could NEP inhibitors benefit hypertension patients without heart failure?
  • Are there other beneficial peptides that NEP inhibition could protect?

Common questions

What is NEP and why does blocking it help?
NEP (neutral endopeptidase) is an enzyme that breaks down natriuretic peptides — the body's natural heart-protective molecules. Blocking NEP lets these peptides last longer and work more effectively, lowering blood pressure and reducing fluid overload.
How did this lead to modern heart failure drugs?
This research showed that protecting BNP from enzymatic destruction dramatically boosted its cardiovascular benefits. This principle became sacubitril, which is combined with valsartan in the drug Entresto — now a standard treatment for heart failure.

Read the original research

Potentiation of brain natriuretic peptides by SQ 28,603, an inhibitor of neutral endopeptidase 3.4.24.11, in monkeys and rats.

The Journal of pharmacology and experimental therapeutics, 262(1), 60-70

View on PubMed ↗

Citation

Seymour, A A; Asaad, M M; Abboa-Offei, B E; Rovnyak, P L; Fennell, S; Rogers, W L. (1992). Potentiation of brain natriuretic peptides by SQ 28,603, an inhibitor of neutral endopeptidase 3.4.24.11, in monkeys and rats.. The Journal of pharmacology and experimental therapeutics, 262(1), 60-70.