Why Combining Blood Pressure Drugs That Target the Same System May Not Work Better | Research

The takeaway

Combining RAS inhibitors changed angiotensin peptide profiles in complex ways but did not consistently improve blood pressure beyond single-drug therapy in hypertensive rats.

Modest additional benefit
Dual RAS blockade provided only small blood pressure improvements over single-agent lisinopril despite changing multiple angiotensin peptide levels

What the researchers found

Lisinopril produced the strongest antihypertensive effect; dual RAS blockade created complex angiotensin peptide profile changes but only modest additional blood pressure reduction in this low-RAS model.

Why it matters

Understanding why combined RAS blockade fails to improve outcomes despite better blood pressure control is critical for developing safer and more effective antihypertensive strategies.

The numbers in context

SHR (spontaneously hypertensive rats). Tested lisinopril, olmesartan, aliskiren, and dual combinations. Lisinopril and olmesartan increased Ang I and Ang 1-7. Lisinopril suppressed Ang II while olmesartan increased it. Aliskiren reduced Ang II and Ang 1-7.

How the study worked

Preclinical study in spontaneously hypertensive rats (SHR) measuring hemodynamics and circulating and tissue angiotensin peptide levels during single and dual RAS inhibitor treatment.

Who was studied

Spontaneously hypertensive rats

What this study cannot tell us

Animal study in spontaneously hypertensive rats, which may not fully replicate human RAS physiology. The low-RAS setting of SHR may limit applicability to high-RAS forms of hypertension.

How to read the evidence

Preclinical animal study providing mechanistic insight. While it explains clinical observations, direct translation to human treatment decisions requires caution.

When this study was published

Published in 2025, adding modern peptide profiling data to the long-standing question of dual RAS blockade efficacy.

The bigger picture

This research explains at the peptide level why the clinical strategy of dual RAS blockade — which seemed logical on paper — has failed in practice. The angiotensin peptide system is more complex than simply blocking more receptors.

Questions still open

Would results differ in high-RAS models of hypertension where angiotensin levels are elevated?
Could tissue-specific peptide changes explain the adverse outcomes seen in clinical dual RAS blockade trials?

Common questions

Why do doctors not usually combine blood pressure drugs from the same class?

Clinical trials showed that combining RAS inhibitors (like ACE inhibitors with ARBs) did not improve patient outcomes and sometimes increased side effects like kidney problems and high potassium. This study helps explain why — the peptide changes are complex and unpredictable.

What is the renin-angiotensin system?

The RAS is a hormone system that regulates blood pressure and fluid balance. Angiotensin II is its main effector, causing blood vessels to constrict and raising blood pressure. Many common blood pressure drugs work by blocking different steps in this system.

Read the original research

Combined RAS Modulation: The Effect on Plasma and Tissue Angiotensin Peptide Levels.

Physiological research, 74(Suppl 2), S205-S218

View on PubMed ↗

Citation

Paulis, L; Rajkovicova, R; Repova, K; Gubo, G; Barta, A; Poglitsch, M; Domenig, O; Andelova, N; Ferko, M; Pechanova, O; Simko, F. (2025). Combined RAS Modulation: The Effect on Plasma and Tissue Angiotensin Peptide Levels.. Physiological research, 74(Suppl 2), S205-S218.