Discovery
Angiotensin II is the active peptide hormone of the reninangiotensin system (RAS) with broad functions, including
a vasopressor effect and thirst stimulation. It is a drug target
for hypertension and renal diseases. In 1940, two groups of researchers separately discovered a potent vasoconstrictor by incubating plasma with
renin; the substance was named both “angiotonin” and
“hypertensin.” In 1958, they agreed to rename it
“angiotensin” (angio=blood vessel; tensin=tension).
Structure
Ang II is a linear peptide with no known secondary
modification. Ang II is produced by the subsequent cleavage of
angiotensinogen (AGT) by renin and angiotensin
I (Ang I) by ACE (See Renin Angiotensin System). Mr. 1046 of Ang II in humans. Freely soluble in water.
Gene, mRNA, and mRNA
AGT is located on chromosome 1q42.2 in humans. AGT
belongs to the SERPIN family A, member 8. AGT protein
sequences are highly variable but the functional domains
(Ang I) are relatively conserved among vertebrates. Ang I sequences were identified by the incubation of a renin source (kidney extract) and an angiotensinogen source (plasma). Lamprey Ang I with sequence
NRVYVHPFTL was first sequenced using peptide purification. However, the lamprey genome data suggested a
different Ang I sequence, and was later confirmed as the
native AGT. The purified teleost-type Ang I produced
in the buccal gland was suggested to be involved in endocrine mimicry to reduce host immunorejection.
Agonist
A nonpeptide ligand, L-162,313 was shown to bind to
AT1A, AT1B, and the AT2 receptor and act as an agonist
on AT1A and AT1B receptors in mice (34.9 and 23.3% of
the maximum response of Ang II, respectively). Early
studies used CGP42112A as the agonist for the AT2
receptor but compound 21, with little affinity for the
AT1 receptor, was recently developed as a specific agonist of the AT2 receptor in humans.
Antagonist
Saralasin ([Sar1
], [Ala8
]-Ang II) is a partial agonist of
angiotensin II receptors, though it is commonly mistaken
as a competitive antagonist. Antagonists including losartan, irbesartan, olmesartan, candesartan, and valsartan
are commonly used clinically as AT1 blockers. Two
AT2 receptor antagonists, PD123177 (discontinued) and
PD123319 (available), were developed to inhibit AT2
activities.
Biological functions
Ang II/AT1 axis mediates vasoconstriction, thirst,
release of vasopressin and aldosterone, renal sodium
reabsorption, fibrosis, inflammation, angiogenesis, vascular aging, and atherosclerosis. Ang II-induced effects
included blood pressure control; drinking; adrenergic
stimulation; modulation of the ion pump and transporter
activities in the gill, kidney, and intestine in fish; control
of the filtering nephron population in fish; and regulation of ventral skin absorption in amphibians. The injection of Ang II significantly increased ventral skin
drinking in the frog. Lamprey Ang II is a vasodepressor
instead of a vasopressor when injected intraarterially. The intracerebroventricular (ICV) injection of Ang II into
the trout increased the systemic blood pressure, heart
rate, and ventilation rate. The ICV injection of Ang II
elicits tachycardia in contrast to bradycardia when
injected peripherally. Central Ang II injection also
inhibits the vagal-mediated baro-reflex, indicating that
brain RAS is involved in the heart rate control.
The AT2 receptor is mostly embryonic. The expression
decreases in adults and is confined in certain tissues such
as the kidney. The effects of AT2 are often antagonistic to
AT1, and activation of the AT2 receptor usually indicates
a pathophysiological condition of AT1-mediated action
with potential harmful consequences. AT2 is abundantly
expressed in the spleen of the adult eel, which suggests an
immune-related function.
Description
It is known that tumor tissues including metastatic lymph nodes are composed of
newly growing vessels which lack blood flow autoregulation and are influenced only
secondarily by the responding somatic vessels. Human angiotensin II (AT II). a
vasopressor, was introduced in Japan to improve the efficacy of systemic
chemotherapy. In patients with various advanced cancers, i.v. infusion of AT II to
achieve a mean blood pressure of 1.5 times of baseline (but not over 150 mm Hg)
followed by a bolus injection of conventional cytotoxic agents increases blood flow
5-7 fold in tumor tissues and therefore, increases drug delivery to the target tissue
resulting in enhanced chemotherapeutic effects. This induced-hypertension
chemotherapy regimen can be performed safely with minimal side effects.
Description
Angiotensin II is a peptide hormone known best as a vasoconstrictor with central roles in chronic hypertension, heart failure, and stroke. It is an octapeptide typically generated by the removal of two residues from angiotensin I by angiotensin-converting enzyme (ACE). Angiotensin II is a ligand for at least two distinct receptors, AT
1 and AT
2, each evoking distinct signaling pathways and physiological responses. The development of antagonists for specific angiotensin II receptor subtypes represents a valuable alternative to ACE inhibitors.
Chemical Properties
White freeze-dried powder; soluble in water, soluble in methanol, ethanol and propylene glycol, insoluble in ethyl ether and chloroform; pH 5-8 in aqueous solution; stable in neutral solution, easily hydrolyzed when encountering strong acids and bases; amino acid sequence: aspartyl, argininyl, valerinyl, tyrosinyl, isoleucinyl, histidinyl, proline, phenylalanine.
Originator
Toa Eiyo (Japan)
Uses
Angiotensin II is a peptide hormone known best as a vasoconstrictor with central roles in chronic hypertension, heart failure, and stroke. It is an octapeptide typically generated by the removal of two residues from angiotensin I by angiotensin-converting enzyme (ACE). Angiotensin II is a ligand for at least two distinct receptors, AT1 and AT2, each evoking distinct signaling pathways and physiological responses. The development of antagonists for specific angiotensin II receptor subtypes represents a valuable alternative to ACE inhibitors.
Uses
A peptide involved in the regulation of blood pressure
Uses
Cardiopulmonary resuscitation - not yet an approved application
Definition
ChEBI: Ile(5)-angiotensin II is an angiotensin II that acts on the central nervous system (PDB entry: 1N9V). It has a role as a human metabolite. It is a tautomer of an Ile(5)-angiotensin II dizwitterion.
General Description
Functions in blood pressure maintenance. Stimulates the release of aldosterone from the adrenal gland. Has strong vasoconstrictive effects. Increases the entry of Ca
2+ in heart muscle via voltage-sensitive channels and activates myosin light chain kinase. Activates JAK2 in smooth muscle cells. Activates p125
FAK and a cytosolic 115-120 kDa calcium-dependent tyrosine kinase in rat epithelial cells. Also activates pp60c-src in vascular smooth muscle cells. Inhibits adenylate cyclase activity in spontaneously hypertensive rats.
Biochem/physiol Actions
Product does not compete with ATP.
Clinical Use
Renin antagonists, ACE inhibitors, and AT1 receptor
blockers have been used, in singular or multiple blockade, to treat hypertension and other RAS-related
diseases. High levels of Ang II are often related to hypertension,
renal failure, and cardiac fibrosis.
in vitro
Most of the known actions of Angiotensin II (Ang II) are mediated by AT 1 receptors, the AT 2 receptor contributes to the regulation of blood pressure and renal function. Angiotensin II raises blood pressure (BP) by a number of actions, the most important ones being vasoconstriction, sympathetic nervous stimulation, increased aldosterone biosynthesis and renal actions. Other Angiotensin II actions include induction of growth, cell migration, and mitosis of vascular smooth muscle cells, increased synthesis of collagen type I and III in fibroblasts, leading to thickening of the vascular wall and myocardium, and fibrosis. These actions are mediated by type 1 Ang II receptors (AT 1 ). At the cellular level, responsiveness to Angiotensin II is conferred by the expression of the two classes of angiotensin receptors (AT 1 and AT 2 ). The effects of Angiotensin II to increase blood pressure are mediated by AT1 receptors.
in vivo
To distinguish the AT 1 receptor population that is critical for the pathogenesis of hypertension, osmotic minipumps are implanted s.c. into each animal to infuse Angiotensin II (1,000 ng/kg/min) continuously for 4 weeks. Angiotensin II causes hypertension by activating AT 1 receptors in the kidney promoting sodium reabsorption.
storage
-20°C (desiccate)
