Last updated on June 18, 2019 at 21:34
The renin-angiotensin-aldosterone system
This system is better known as RAAS. It plays a central role in the control of Na+ excretion, sympathetic outflow, fluid volume and vascular tone.
Renin is produced by the juxtaglomerular apparatus in the kidney. It’s an enzyme that converts angiotensinogen produced by the liver into angiotensin I. Angiotensin I doesn’t have any important biological activity, so it’s converted into angiotensin II by the enzyme angiotensin-converting enzyme, also called ACE. ACE is a membrane-bound enzyme found on the surface of endothelial cells, especially in the lung.
Angiotensin II acts on two receptors, AT1 and AT2. They have opposite effects, although AT2 is much less active than AT1, so only AT1 is clinically important. AT1 has the following effects:
- Vasoconstriction, especially in the efferent arterioles of the glomeruli
- Increased noradrenaline release from the brain
- Increased proximal tubular reabsorption of Na+
- Stimulates secretion of aldosterone
- Stimulates growth of heart and vascular cells
Angiotensin II activates NF-κB, the famous inflammatory transcription factor. This stimulates inflammation, fibrosis and hypertrophy in the heart, which contributes to heart disease.
Angiotensin II is a very potent hypertensive molecule – it’s 40 times as potent as noradrenaline. It mainly constricts vessels in the skin, splanchnic organs and the kidney.
There are multiple points at which the RAAS can be inhibited:
- Renin release – inhibited by β antagonists
- Renin activity – inhibited by renin inhibitors
- ACE – inhibited by ACE inhibitors
- Angiotensin II receptors – inhibited by AT1-receptor antagonists
- Aldosterone receptors – inhibited by aldosterone-receptor antagonists
No RAAS-affecting drugs should be used in pregnant women.
RAAS plays an important role in cardiovascular disease, the major cause of mortality in the western world. By modifying RAAS can we decrease:
- Heart failure
- Myocardial infarction
- Progressive renal impairment
- Diabetic nephropathy
The only important renin inhibitor is aliskiren. It’s an orally active non-peptide molecule that binds to the active site of renin and blocks it.
It’s used to treat primary (essential) hypertension.
ACE inhibitors are often abbreviated as ACEI. They all end in -pril. The most important ones are captopril, enalapril, lisinopril and ramipril. They have many beneficial effects:
- Reduce sympathetic outflow
- Reduce total peripheral resistance
- Reduce aldosterone secretion
- Increase perfusion of the kidneys
- Reduce afterload and preload
- Reduce myocardial hypertrophy
- Reduce AVP (ADH) secretion
They’re the first line treatment of non-complicated hypertension, especially when there is also heart failure, diabetes or cardiovascular disease. It’s also used to treat symptomatic heart failure (where it’s usually given with beta blockers) and other conditions. They’re also renoprotective, meaning that they protect the kidney, due to the decreased vasoconstriction of the kidney.
- Hypotension – the initial depressor effect can be strong
- Dry cough – dose-independent, goes away after treatment. Probably due to accumulation of bradykinin
- Hyperkalaemia – especially in patients who take K+-sparing diuretics
- Skin rash
- Antacids – decrease their oral bioavailability
- K+-sparing diuretics and K+ supplements – may worsen a potential hyperkalaemia
Angiotensin II receptor antagonists
These antagonists block the AT1 receptor selectively, reversing the effects of angiotensin II. They all end in -sartan. The most important ones are losartan, valsartan, candesartan and irbesartan.
They have mostly the same effects and indications as ACEI, however they’re mostly used as alternatives in case ACEIs aren’t tolerated or ACEIs gives side effects.
They don’t cause dry cough. Angiooedema occurs much less commonly than for ACE inhibitors.
Aldosterone antagonists are used as diuretics and are covered in their own topic.
1. Calcium channel blockers
3. Diuretic drugs