Overview

Triggers for renin release. Granular (juxtaglomerular) cells of the afferent arteriole release renin in response to three stimuli. These are reduced pressure in the afferent arteriole (an intrarenal baroreceptor), reduced NaCl reaching the macula densa, and increased renal sympathetic activity acting on β1 receptors.

The cascade. The liver makes angiotensinogen. Renin cuts it to the decapeptide angiotensin I. ACE, found mainly on the endothelium of the lung, converts angiotensin I to the octapeptide angiotensin II.

Actions of angiotensin II. Acting through AT1 receptors, angiotensin II constricts arterioles, which raises total peripheral resistance. It stimulates the adrenal zona glomerulosa to release aldosterone. Aldosterone increases ENaC channels and the Na⁺/K⁺-ATPase in the principal cells of the collecting duct, causing Na⁺ retention and K⁺ and H⁺ secretion.

Angiotensin II also increases Na⁺/H⁺ exchange in the proximal tubule. It constricts the efferent arteriole more than the afferent, which preserves glomerular filtration. It stimulates thirst and the release of ADH, and increases noradrenaline release from sympathetic nerves. Over the long term it promotes thickening and fibrosis of the heart and blood vessels.

ACE also breaks down bradykinin, a vasodilator. A counter-regulatory branch, in which ACE2 produces angiotensin-(1–7), causes vasodilation.

Opposing systems. The natriuretic peptides ANP and BNP promote sodium loss in the urine, dilate vessels and suppress renin and aldosterone.

Time course. The RAAS acts over minutes to hours. This sits between the seconds-long baroreflex and the days-long renal pressure natriuresis.

Function

Restores blood pressure and volume after haemorrhage, dehydration or salt depletion.
Maintains glomerular filtration rate when renal perfusion falls.
Regulates plasma K⁺ through aldosterone.

Clinical significance

RAAS pharmacology

ACE inhibitors such as ramipril can cause a dry cough and angio-oedema, because bradykinin builds up. They can also cause hyperkalaemia and are teratogenic. In bilateral renal artery stenosis they can cause acute kidney injury, because glomerular filtration depends on angiotensin II constricting the efferent arteriole. ARBs such as losartan block the AT1 receptor.

Mineralocorticoid receptor antagonists (spironolactone, eplerenone) reduce mortality in heart failure with reduced EF. ARNI (sacubitril/valsartan) combines an ARB with a neprilysin inhibitor, which raises natriuretic peptide levels.

Primary aldosteronism (Conn syndrome)

In primary aldosteronism, aldosterone is produced autonomously, most often by an adrenal adenoma or by hyperplasia of both adrenals. It causes hypertension, often with low potassium, a high aldosterone-to-renin ratio and suppressed renin. It is the commonest endocrine cause of secondary hypertension.

RAAS in heart failure

When cardiac output falls, the RAAS is activated chronically. The resulting salt retention, vasoconstriction and fibrosis worsen heart failure. Blocking these pathways is a cornerstone of treatment for HFrEF.

Compiled from standard anatomy and physiology references — see the Cardiovascular System sources. For education only; not medical advice.