Angiotensin
Angiotensin term indicates three polypeptides deriving from angiotensinogen: angiotensin I inactive décapeptide, angiotensin II, vasoconstrictive octapeptide and angiotensin III, heptapeptide which induces aldosterone secretion.
Metabolism
Angiotensin II formation results from 3 pathways: the main pathway known for a long time, involves renin and angiotensin converting enzyme, another pathway of more recent knowledge, involves chymase which cleaves the same chemical bond as angiotensin converting enzyme and the last involves enzymes responsible of the direct transformation of angiotensinogen into angiotensin II.
Metabolism of angiotensin
- Angiotensinogen is a glycoprotein, of molecular weight of about 50 000 Da, synthesized by the liver which releases it into plasma. Its plasma concentration is generally sufficient to not limit the rate of angiotensin I formation. Other tissues, kidney (tubule), vessels (adventitious) and certain parts of the brain synthesize also angiotensinogen. The synthesis of angiotensinogen is increased by the intake of glucocorticoids and estrogens (contraceptive).
- Renin is an enzyme which cleaves angiotensin I from angiotensinogen. It is an aspartyl protease of glycoproteic nature which cleaves the chemical bond leucine-valin and detaches angiotensin I from angiotensinogen.
Renin is synthesized in the form of prorenin, by the juxtaglomerular part of the nephron which releases it into plasma where its half-life is approximately 15 minutes. Circulating renin can be taken up by tissues: liver, heart, vessels. These tissues can also synthesize it.
- Angiotensin converting enzyme, ACE, converts inactive angiotensin I into active angiotensin II and inactivates bradykinin. It is a zinc enzyme present in vascular endothelium, more particularly that of the pulmonary vessels, endocardium and brain. ACE is also present in plasma.
- Aminopepdidase A detaches aspartic acid from angiotensin II which is converted in angiotensin III.
- Chymase, an enzyme present in mastocytes of various organs among which the heart, catalyzes the transformation of angiotensin I into angiotensin II. It does not act on bradykinin. Its activity is not modified by ACE inhibitors.
- Other enzymes, like cathepsin, can catalyze angiotensin II formation directly from angiotensinogen.
The regulation of the system is assured essentially by renin.
Renin secretion is increased by several factors:
- decrease of arterial pressure
- decrease of plasma sodium concentration
- increase of catecholamines which act by beta adrenergic stimulation
- various drugs (general anesthetics, diuretics).
Renin secretion is decreased by certain drugs: beta--blockers and nonsteroidal anti-inflammatory drugs.
Little is known concerning the regulation of angiotensin II formation by the two other pathways.. They remain functional when the renin / ACE pathway is inhibited.
Effects
Angiotensin II causes its effects by stimulation of specific receptors called AT1 and AT2.
AT1 receptors are coupled to G proteins leading to activation of phospholipase C (hydrolysis of PIP2) or to inhibition of adenylcyclase and stimulation of MAP-kinase signaling pathway, leading to activation of proto-oncogenes c-fos and c-jun, particularly in heart and vascular smooth muscles. The stimulation of AT1 receptors is responsible for most effects of angiotensin II, in particular vasoconstriction, and angiogenesis necessary for tumoral growth.
The role of AT2 receptors is less known; their stimulation induces vasodilation by opening potassium channels and activating guanylate cyclase. They have antiproliferative effects, probably by activating protein phosphatases, which neutralizes kinase effects. The density of receptors AT2 is much higher in fetal tissues than in adult ones.
Peripheral effects
The effects of angiotensin II are primarily cardiovascular.
- Vasoconstrictive effect
Expressed in molar activity, the vasoconstrictive effect of angiotensin II is approximately 40 times more important than that of noradrenaline. Its vasoconstrictive effect (AT1) which is responsible of its hypertensive effect, is especially arteriolar (splanchnic, renal and cutaneous vessels) but also venous, what tends to reduce blood volume. The vasoconstrictive effect of angiotensin II is inhibited by specific antagonists.
In kidney, angiotensin elicits vasoconstriction of the efferent glomerular arteriole, which maintains an arterial pressure sufficient to ensure glomerular filtration, particularly in patients with stenosis of glomerular afferent arterioles. In these patients, suppression of the vasoconstriction induced by angiotensin II decreases arterial pressure under the threshold necessary for filtration and induces renal impairment.
- Cardiac effect
Angiotensin increases heart rate and contractility but, in vivo, when the vasoconstrictive effect elicits an arterial hypertension, a reflex bradycardia is observed.
Angiotensin II, in addition to the consequences of its hypertensive effect, directly induces changes in cardiovascular structure, hypertrophy and remodelling by growth factor-like actions. AT1 stimulation activates MAP-kinase and JAK/STAT signalling pathways. This activation leads to gene transcription and production of growth factors.
- Stimulation of aldosterone secretion
In very low doses insufficient to induce vasoconstrction, angiotensin II and III stimulate aldosterone synthesis and secretion and sodium retention.
- Another effect
In vitro, angiotensin II contracts smooth muscles: ileum, uterus, bronchi.
Central effects
Central effects of angiotensin were shown primarily by animal experimentation. Introduced into particular brain areas, angiotensin elicits:
- arterial hypertension by stimulation of the sympathetic system and noradrenaline release.
- dipsogenic effect: increase in thirst and water consumption;
- increase of vasopressin and ACTH secretion;
- increase of appetence for sodium.
The role of the brain renin-angiotensin system in human pathophysiology is not well known.
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