The renin-angiotensin-aldosterone system (RAAS) plays an important role in regulating blood volume and systemic vascular resistance, which together influence cardiac output and arterial pressure. As the name implies, there are three important components to this system: 1) renin, 2) angiotensin, and 3) aldosterone. Renin, which is primarily released by the kidneys, stimulates the formation of angiotensin in blood and tissues, which in turn stimulates the release of aldosterone from the adrenal cortex.
Renin is a proteolytic enzyme that is released into the circulation primarily by the kidneys. Its release is stimulated by:
- sympathetic nerve activation (acting through β1-adrenoceptors)
- renal artery hypotension (caused by systemic hypotension or renal artery stenosis)
- decreased sodium delivery to the distal tubules of the kidney.
When renin is released into the blood, it acts upon a circulating substrate, angiotensinogen, that undergoes proteolytic cleavage to form the decapeptide angiotensin I. Vascular endothelium, particularly in the lungs, has an enzyme, angiotensin converting enzyme (ACE), that cleaves off two amino acids to form the octapeptide, angiotensin II (AII), although many other tissues in the body (heart, brain, vascular) also can form AII.
AII has several very important functions:
- Constricts resistance vessels (via AII [AT1] receptors) thereby increasing systemic vascular resistance and arterial pressure
- Stimulates sodium transport (reabsorption) at several renal tubular sites, thereby increasing sodium and water retention by the body
- Acts on the adrenal cortex to release aldosterone, which in turn acts on the kidneys to increase sodium and fluid retention
- Stimulates the release of vasopressin (antidiuretic hormone, ADH) from the posterior pituitary, which increases fluid retention by the kidneys
- Stimulates thirst centers within the brain
- Facilitates norepinephrine release from sympathetic nerve endings and inhibits norepinephrine re-uptake by nerve endings, thereby enhancing sympathetic adrenergic function
- Stimulates cardiac hypertrophy and vascular hypertrophy
The renin-angiotensin-aldosterone pathway is not only regulated by the mechanisms that stimulate renin release, but it is also modulated by natriuretic peptides (ANP and BNP) released by the heart. These natriuretic peptides acts as an important counter-regulatory system.
Therapeutic manipulation of this pathway is very important in treating hypertension and heart failure. ACE inhibitors, AII receptor blockers and aldosterone receptor blockers, for example, are used to decrease arterial pressure, ventricular afterload, blood volume and hence ventricular preload, as well as inhibit and reverse cardiac and vascular hypertrophy.