The Renin–Angiotensin–Aldosterone System (RAAS): The Body's Pressure Thermostat
Why does a common blood-pressure pill give some people a nagging dry cough? The answer is a single hormone cascade that the body uses to defend its blood pressure — and that four of the most important drug classes in medicine are built to block. Follow the chain from kidney to blood vessel and you'll understand hypertension, heart failure, and kidney protection all at once.
A patient started on a new blood-pressure tablet comes back a few weeks later, annoyed: a persistent, tickling dry cough has kept him awake for nights, and nothing soothes it. His doctor recognizes it instantly and switches his drug — the cough vanishes within days. That cough is a fingerprint, and it points straight to a hormone cascade the drug was blocking. To understand it — and why the same cascade is a target in hypertension, heart failure, and kidney disease — we follow the chain from the kidney outward.
The cascade, step by step
So the RAAS raises blood pressure two ways at once — squeezing the vessels AND expanding the fluid volume — mapping perfectly onto the BP = output × resistance equation from the last article. It's a brilliant survival system for a real drop in pressure (bleeding, dehydration), but in chronic hypertension and heart failure it runs harmfully high, which is exactly why blocking it is so useful.
Four ways to block it
Because each step is a target, four major drug classes interrupt the cascade at different points. ACE inhibitors (the '-pril' drugs, like lisinopril) block the converting enzyme, so less angiotensin II forms. ARBs (the '-sartan' drugs, like losartan) block angiotensin II's receptor instead. Aldosterone antagonists (spironolactone, eplerenone) block the final hormone at the kidney. And direct renin inhibitors (aliskiren) block the very first step. All of them lower blood pressure by relaxing vessels and shedding salt and water — and, importantly, by preventing the harmful long-term remodeling of the heart and kidneys, which is why they also protect in heart failure, after a heart attack, and in kidney disease.
Back to our patient. ACE doesn't only make angiotensin II — it also breaks down bradykinin, a molecule that irritates the airways. When an ACE inhibitor blocks the enzyme, bradykinin builds up, and in some people that causes the classic dry cough (and, rarely, dangerous swelling called angioedema). ARBs don't touch bradykinin — they block the receptor downstream — so switching to a '-sartan' keeps the blood-pressure benefit without the cough. The cough was bradykinin's fingerprint all along.
- RAAS cascade: renin → angiotensin I → (ACE) → angiotensin II → aldosterone.
- Angiotensin II constricts vessels AND (via aldosterone) retains salt & water — raising BP two ways.
- Blockers: ACE inhibitors (-pril), ARBs (-sartan), aldosterone antagonists, renin inhibitors.
- ACE also degrades bradykinin — its buildup causes the ACE-inhibitor cough (and rare angioedema).
- RAAS blockers protect the heart & kidneys by blocking harmful remodeling, not just lowering BP.
RAAS blockade is about more than blood pressure. Angiotensin II and aldosterone don't just raise pressure — they drive scarring and thickening (remodeling) of the heart and blood vessels, and damage the kidney's filters. That's why ACE inhibitors and ARBs are cornerstones not only of hypertension but of heart failure, post-heart-attack care, and protecting the kidneys in diabetes — they slow the disease, not just the number. One cascade, blocked, helps four different conditions.
- Blaming the ACE-inhibitor cough on infection. It's bradykinin — switch to an ARB.
- Combining an ACE inhibitor with an ARB routinely. Double RAAS block risks kidney injury & high potassium.
- Forgetting RAAS blockers raise potassium (they cut aldosterone) — watch levels.
- Using ACE inhibitors/ARBs in pregnancy. They are teratogenic — avoid.
The dry cough of ACE inhibitors is caused by:
- RAAS: renin → angiotensin I → (ACE) → angiotensin II → aldosterone, raising BP two ways.
- Blocked by ACE inhibitors (-pril), ARBs (-sartan), aldosterone antagonists, renin inhibitors.
- ACE also degrades bradykinin → the ACE-inhibitor cough and rare angioedema (ARBs avoid this).
- RAAS blockers protect the heart & kidneys and raise potassium; avoid in pregnancy.
- Katzung BG. Basic & Clinical Pharmacology — Drugs acting on the renin-angiotensin-aldosterone system.
- Brunton LL, et al. Goodman & Gilman's The Pharmacological Basis of Therapeutics — Renin & angiotensin.
- Rang HP, Dale MM, et al. Rang & Dale's Pharmacology — The renin-angiotensin system.
- Guyton & Hall Textbook of Medical Physiology — The renin-angiotensin-aldosterone system.
- Whalen K. Lippincott Illustrated Reviews: Pharmacology — ACE inhibitors & ARBs.
