Dual ACE/NEP Inhibitor Pills Lower Blood Pressure Through Two Mechanisms Simultaneously | Research

The takeaway

Orally active dual ACE/NEP inhibitors lowered blood pressure in hypertensive rats by simultaneously blocking angiotensin formation and protecting natriuretic peptides.

Dual mechanism, oral dosing
Single molecules inhibiting both ACE and NEP achieved oral bioavailability and blood pressure lowering in hypertensive rats

What the researchers found

Orally active dual ACE/NEP inhibitors lowered blood pressure in hypertensive rats through combined angiotensin blockade and natriuretic peptide protection.

Why it matters

Combining two blood pressure-lowering mechanisms in one pill could provide better treatment than either alone. This approach eventually led to drugs like sacubitril/valsartan (Entresto) for heart failure.

How the study worked

Researchers used rational drug design to create dual inhibitors, tested their ability to block both enzymes in vitro, measured oral bioavailability, and assessed blood pressure effects in experimentally hypertensive rats.

What this study cannot tell us

Animal study in rats. Oral bioavailability and efficacy in rats may not predict human pharmacology. Long-term safety not assessed.

How to read the evidence

Moderate — animal study with rational drug design approach. Multiple compounds tested with structure-activity relationships.

When this study was published

Published in 1994 (32 years ago). Led to the development of sacubitril/valsartan, approved 2015 for heart failure.

The bigger picture

This rational drug design approach eventually led to sacubitril/valsartan (Entresto), now standard for heart failure. The concept of protecting beneficial peptides while blocking harmful ones revolutionized cardiovascular medicine.

Questions still open

Could dual inhibitors replace separate ACE inhibitors and NEP inhibitors?
What advantages does dual inhibition offer over either mechanism alone?

Common questions

Why combine ACE and NEP inhibition?

ACE inhibitors block the production of angiotensin II (which raises blood pressure). NEP inhibitors protect natriuretic peptides (which lower blood pressure). Combining both provides complementary blood pressure lowering.

Did this lead to real drugs?

Yes — this concept led to sacubitril (an NEP inhibitor) combined with valsartan (an angiotensin blocker), marketed as Entresto, which is now a standard treatment for heart failure.

Read the original research

New dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme: rational design, bioavailability, and pharmacological responses in experimental hypertension.

Journal of medicinal chemistry, 37(8), 1070-83

View on PubMed ↗

Citation

Fournié-Zaluski, M C; Coric, P; Turcaud, S; Rousselet, N; Gonzalez, W; Barbe, B; Pham, I; Jullian, N; Michel, J B; Roques, B P. (1994). New dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme: rational design, bioavailability, and pharmacological responses in experimental hypertension.. Journal of medicinal chemistry, 37(8), 1070-83.