Angiotensin

Angiotensin is a is_associated_with::peptide hormone that causes is_associated_with::vasoconstriction and a subsequent increase in is_associated_with::blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of is_associated_with::aldosterone, another hormone, from the is_associated_with::adrenal cortex. is_associated_with::Aldosterone promotes sodium retention in the distal nephron, in the kidney, which also drives blood pressure up.

Angiotensin is an oligopeptide and is a is_associated_with::hormone and a powerful is_associated_with::dipsogen. It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the is_associated_with::liver. It plays an important role in the is_associated_with::renin-angiotensin system. Angiotensin was independently isolated in Indianapolis and Argentina in the late 1930s (as 'angiotonin' and 'hypertensin', respectively) and subsequently characterised and synthesized by groups at the is_associated_with::Cleveland Clinic and Ciba laboratories in Basel, Switzerland.

Angiotensinogen
Angiotensinogen is an α-2-globulin produced constitutively and released into the circulation mainly by the liver. It is a member of the is_associated_with::serpin family, although it is not known to inhibit other enzymes, unlike most serpins. Plasma angiotensinogen levels are increased by plasma is_associated_with::corticosteroid, is_associated_with::estrogen, is_associated_with::thyroid is_associated_with::hormone, and angiotensin II levels.

Angiotensinogen is also known as renin substrate. Human angiotensinogen is 453 amino acids long, but other species have angiotensinogen of varying sizes. The first 12 amino acids are the most important for activity.


 * Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-...

Angiotensin I

 * Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu | Val-Ile-...



Angiotensin I (CAS# 11128-99-7) is formed by the action of is_associated_with::renin on is_associated_with::angiotensinogen. Renin cleaves the is_associated_with::peptide bond between the is_associated_with::leucine (Leu) and is_associated_with::valine (Val) residues on angiotensinogen, creating the ten-is_associated_with::amino acid peptide (des-Asp) angiotensin I. Renin is produced in the is_associated_with::kidneys in response to renal sympathetic activity, decreased intrarenal blood pressure (<90mmHg systolic blood pressure ) at the is_associated_with::juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the is_associated_with::macula densa. If less Na+ is sensed by the macula densa, renin release by juxtaglomerular cells is increased.

Angiotensin I appears to have no biological activity and exists solely as a precursor to angiotensin II.

Angiotensin II

 * Asp-Arg-Val-Tyr-Ile-His-Pro-Phe | His-Leu

Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzyme is_associated_with::angiotensin-converting enzyme (ACE), primarily through ACE within the lung (but also present in is_associated_with::endothelial cells and kidney epithelial cells). ACE found in other tissues of the body has no physiological role (ACE has a high density in the lung, but activation here promotes no vasoconstriction, angiotensin II is below physiological levels of action). Angiotensin II acts as an endocrine, autocrine/paracrine, and is_associated_with::intracrine hormone.

ACE is a target for inactivation by is_associated_with::ACE inhibitor drugs, which decrease the rate of Angiotensin II production. Angiotensin II increases blood pressure by stimulating the Gq protein in vascular smooth muscle cells (which in turn activates an IP3-dependent mechanism leading to a rise in intracellular calcium levels and ultimately causing contraction). In addition, angiotensin II acts at the is_associated_with::Na/H exchanger in the is_associated_with::proximal tubules of the kidney to stimulate Na reabsorption and H excretion which is coupled to bicarbonate reabsorption. This ultimately results in an increase in blood volume, pressure, and pH. Hence, is_associated_with::ACE inhibitors are major anti-hypertensive drugs.

Other cleavage products of ACE, seven or 9 amino acids long, are also known; they have differential affinity for is_associated_with::angiotensin receptors, although their exact role is still unclear. The action of AII itself is targeted by is_associated_with::angiotensin II receptor antagonists, which directly block angiotensin II AT1 receptors.

Angiotensin II is degraded to angiotensin III by angiotensinases located in red blood cells and the vascular beds of most tissues. It has a half-life in circulation of around 30 seconds, whereas, in tissue, it may be as long as 15–30 minutes.

Angiotensin III

 * Asp | Arg-Val-Tyr-Ile-His-Pro-Phe

Angiotensin III has 40% of the pressor activity of angiotensin II, but 100% of the aldosterone-producing activity. Increases is_associated_with::mean arterial pressure.

Angiotensin IV

 * Arg | Val-Tyr-Ile-His-Pro-Phe

Angiotensin IV is a hexapeptide that, like angiotensin III, has some lesser activity.

Effects

 * See also is_associated_with::Renin-angiotensin_system

Angiotensins II, III and IV have a number of effects throughout the body:

Adipic
Angiotensins "modulate fat mass expansion through upregulation of adipose tissue lipogenesis ... and downregulation of lipolysis "

Cardiovascular
They are potent direct is_associated_with::vasoconstrictors, constricting arteries and veins and increasing blood pressure.

Angiotensin II has prothrombotic potential through adhesion and aggregation of is_associated_with::platelets and stimulation of PAI-1 and PAI-2. When cardiac cell growth is stimulated, a local (autocrine-paracrine) renin-angiotensin system is activated in the cardiac myocyte, which stimulates cardiac cell growth through protein kinase C. The same system can be activated in smooth muscle cells in conditions of hypertension, atherosclerosis, or endothelial damage. Angiotensin II is the most important Gq stimulator of the heart during hypertrophy, compared to endothelin-1 and α1 adrenoreceptors.

Neural
Angiotensin II increases is_associated_with::thirst sensation (is_associated_with::dipsogen) through the is_associated_with::subfornical organ of the brain, decreases the response of the is_associated_with::baroreceptor reflex, and increases the desire for salt. It increases secretion of ADH in the is_associated_with::posterior pituitary and secretion of ACTH in the anterior pituitary. It also potentiates the release of is_associated_with::norepinephrine by direct action on postganglionic sympathetic fibers.

Adrenal
Angiotensin II acts on the is_associated_with::adrenal cortex, causing it to release is_associated_with::aldosterone, a hormone that causes the kidneys to retain sodium and lose potassium. Elevated plasma angiotensin II levels are responsible for the elevated aldosterone levels present during the luteal phase of the is_associated_with::menstrual cycle.

Renal
Angiotensin II has a direct effect on the proximal tubules to increase Na+ reabsorption. It has a complex and variable effect on is_associated_with::glomerular filtration and is_associated_with::renal blood flow depending on the setting. Increases in systemic blood pressure will maintain renal perfusion pressure; however, constriction of the afferent and efferent glomerular arterioles will tend to restrict renal blood flow. The effect on the efferent arteriolar resistance is, however, markedly greater, in part due to its smaller basal diameter; this tends to increase glomerular capillary hydrostatic pressure and maintain is_associated_with::glomerular filtration rate. A number of other mechanisms can affect renal blood flow and GFR. High concentrations of Angiotensin II can constrict the glomerular mesangium, reducing the area for glomerular filtration. Angiotensin II is a sensitizer to is_associated_with::tubuloglomerular feedback, preventing an excessive rise in GFR. Angiotensin II causes the local release of prostaglandins, which, in turn, antagonize renal vasoconstriction. The net effect of these competing mechanisms on glomerular filtration will vary with the physiological and pharmacological environment.