Angiotensin
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2008-07-12T08:50:35Z
Gaius Cornelius
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'''Angiotensin''' causes blood vessels to constrict, and drives blood pressure up. It is part of the [[renin-angiotensin-aldosterone system|renin-angiotensin system]], which is a major target for drugs that lower blood pressure. Angiotensin also creates aldosterone, which causes the tubules of the kidneys to retain sodium and water, which also drives blood pressure up.
Angiotensin is an [[peptide|oligopeptide]] in the [[blood]] that causes [[vasoconstriction]], increased [[blood pressure]], and release of [[aldosterone]] from the [[adrenal cortex]]. It is a [[hormone]] and a powerful [[dipsogen]]. It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the [[liver]]. It plays an important role in the [[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 [[Cleveland Clinic]] and [[Ciba]] laboratories in Basel, Switzerland.<ref>{{cite journal |author=Basso N, Terragno NA |title=History about the discovery of the renin-angiotensin system |journal=Hypertension |volume=38 |issue=6 |pages=1246–9 |year=2001 |month=December |pmid=11751697 |doi= |url=http://hyper.ahajournals.org/cgi/pmidlookup?view=long&pmid=11751697}}</ref>
==Precursor, and types of angiotensin==
===Angiotensinogen===
Angiotensinogen is an [[Alpha globulin|α-2-globulin]] that is produced constitutively and released into the circulation mainly by the liver.
It is a member of the [[serpin]] family, although it is not known to inhibit other enzymes, unlike most serpins. Plasma angiotensinogen levels are increased by plasma [[corticosteroid]], [[estrogen]], [[thyroid]] [[hormone]], and angiotensin II levels.
Angiotensinogen is also known as renin substrate.
Human angiotensinogen is 118 amino acids long, but other species have angiotensinogen of varying sizes<ref>http://www.ncbi.nlm.nih.gov</ref>
===Angiotensin I===
'''Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu'''
[[Image:Renin-angiotensin-aldosterone system.png|thumb|475px|[[Renin-angiotensin-aldosterone system]]]]
Angiotensin I ([[CAS registry number|CAS]]# 11128-99-7) is formed by the action of [[renin]] on [[angiotensinogen]]. Renin is produced in the [[kidney]]s in response to both decreased intra-renal blood pressure at the [[juxtaglomerular cell]]s, or decreased delivery of Na+ and Cl- to the [[macula densa]]. If more Na+ is sensed, renin release is decreased.
Renin cleaves the [[peptide bond]] between the [[leucine]] (Leu) and [[valine]] (Val) residues on angiotensinogen, creating the ten [[amino acid]] peptide (des-Asp) angiotensin I ([[CAS registry number|CAS]]# 9041-90-1).
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 through removal of two terminal residues by the enzyme ''[[Angiotensin-converting enzyme]]'' (ACE, or ''kinase''), which is found predominantly in the [[capillary|capillaries]] of the lung.<ref>{{GeorgiaPhysiology|7/7ch09/7ch09p16}}</ref> ACE is actually found all over the body, but has its highest density in the lung due to the high density of capillary beds there. Angiotensin II acts as an [[endocrine system| endocrine]], [[autocrine signalling| autocrine]]/[[paracrine signalling| paracrine]], and [[intracrine]] hormone.
ACE is a target for inactivation by [[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 contraction by an IP3-dependent mechanism). [[ACE inhibitor]] drugs are major drugs against hypertension.
Other cleavage products of ACE, 7 or 9 amino acids long, are also known; they have differential affinity for [[angiotensin receptors]], although their exact role is still unclear. The action of angiotensin II itself is targeted by [[angiotensin II receptor antagonist]]s, which directly block [[Angiotensin receptor|angiotensin II AT<sub>1</sub> receptors]].
Angiotensin II is degraded to angiotensin III by angiotensinases that are located in red blood cells and the vascular beds of most tissues. It has a half-life in circulation of around 30 seconds, while 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 [[Vasoconstrictor|pressor]] activity of Angiotensin II, but 100% of the aldosterone-producing activity.
===Angiotensin IV===
Arg | '''Val-Tyr-Ile-His-Pro-Phe'''
Angiotensin IV is a hexapeptide which, like angiotensin III, has some lesser activity.
==Effects== <!--Renin-angiotensin_system has a link to here-->
:''See also [[Renin-angiotensin_system#Effects]]''
Angiotensins II, III & IV have a number of effects throughout the body:
===Cardiovascular effects===
It is a potent direct [[vasoconstrictor]], constricting arteries and veins and increasing blood pressure.
Angiotensin II has prothrombotic potential through adhesion and aggregation of [[platelets]] and production of [[plasminogen activator inhibitor 1|PAI-1]] and [[plasminogen activator inhibitor 2|PAI-2]].<ref name="skurk">{{cite journal |author=Skurk T, Lee YM, Hauner H |title=Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture |journal=Hypertension |volume=37 |issue=5 |pages=1336–40 |year=2001 |month=May |pmid=11358950 |doi= |url=http://hyper.ahajournals.org/cgi/pmidlookup?view=long&pmid=11358950}}</ref><ref name="Gesualdo">{{cite journal |author=Gesualdo L, Ranieri E, Monno R, ''et al'' |title=Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells |journal=Kidney Int. |volume=56 |issue=2 |pages=461–70 |year=1999 |month=August |pmid=10432384 |doi=10.1046/j.1523-1755.1999.00578.x |url=}}</ref>
When cardiac cell growth is stimulated, a local (autocrine-paracrine) renin-angiotensin system is activated in the cardiac myocte, 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 A1 adrenoreceptors.
===Neural effects===
Angiotensin II increases [[thirst]] sensation ([[dipsogen]]) through the [[subfornical organ]] (SFO) of the brain, decreases the response of the [[baroreceptor reflex]], and increases the desire for [[table salt|salt]]. It increases secretion of [[vasopressin|ADH]] in the [[posterior pituitary]] and secretion of [[corticotropin|ACTH]] in the anterior pituitary. It also potentiates the release of [[norepinephrine]] by direct action on postganglionic [[sympathetic nervous system|sympathetic]] fibers.
===Adrenal effects===
Angiotensin II acts on the [[adrenal cortex]], causing it to release [[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 [[menstrual cycle]].
===Renal effects===
Angiotensin II has a direct effect on the proximal tubules to increase Na<sup>+</sup> [[absorption]]. It has a complex and variable effect on [[glomerular filtration]] and [[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 hydrostat pressure and maintain [[glomerular filtration rate]]. A number of other mechanism 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 as a sensitizer to [[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 completing mechanisms on glomerular filtration will vary with the physiological and pharmaclogical environment.
{|class="wikitable"
|+ Renal effects of Angiotensin II
|-
!Target
!Action
!Mechanism<ref name=boron771> Unless else specified in table, then ref is: {{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |location= |year= |pages= |isbn=1-4160-2328-3 |oclc= |doi=}} Page 771 </ref>
|-
![[Renal artery]] & <BR> [[afferent arterioles]]
| [[vasoconstriction]] || [[Voltage-dependent calcium channel|VDCC]]s --> [[calcium|Ca<sup>2+</sup>]] influx
|-
! [[efferent arteriole]]
| [[vasoconstriction]] || (probably) activate [[Angiotensin_type_I_receptor#at1|Angiotensin receptor 1]] --> Activation of [[gq alpha subunit|G<sub>q</sub>]] --> ↑[[phospholipase C|PLC]] activity --> ↑[[Inositol triphosphate|IP<sub>3</sub>]] and [[diacylglycerol|DAG]] --> activation of [[Inositol triphosphate receptor|IP<sub>3</sub> receptor]] in [[sarcoplasmic reticulum|SR]] --> ↑intracellular Ca<sup>2+</sup>
|-
![[mesangial cell]]s
| contraction --> ↓filtration area ||
* activation of [[gq alpha subunit|G<sub>q</sub>]] --> ↑[[phospholipase C|PLC]] activity --> ↑[[Inositol triphosphate|IP<sub>3</sub>]] and [[diacylglycerol|DAG]] --> activation of [[Inositol triphosphate receptor|IP<sub>3</sub> receptor]] in [[sarcoplasmic reticulum|SR]] --> ↑intracellular Ca<sup>2+</sup>
*[[Voltage-dependent calcium channel|VDCC]]s --> [[calcium|Ca<sup>2+</sup>]] influx
|-
! [[Tubuloglomerular feedback]]
| Increased sensitivity || Responsiveness increase of [[afferent arteriole]] to signals from [[macula densa]]
|-
! [[renal medulla|medullary]] blood flow
| Reduction ||
|-
|}
==See also==
* [[ACE inhibitor]]
* [[Angiotensin receptor]]
* [[Angiotensin II receptor antagonist]]
==References==
{{reflist}}
==Further reading==
{{refbegin | 2}}
*''Brenner & Rector's The Kidney'', 7th ed., Saunders, 2004.
*''Mosby's Medical Dictionary'', 3rd Ed., CV Mosby Company, 1990.
*''Review of Medical Physiology'', 20th Ed., William F. Ganong, McGraw-Hill, 2001.
*''Clinical Physiology of Acid-Base and Electrolyte Disorders'', 5th ed., Burton David Rose & Theodore W. Post McGraw-Hill, 2001
{{PBB_Further_reading
| citations =
*{{cite journal | author=Lees KR, MacFadyen RJ, Doig JK, Reid JL |title=Role of angiotensin in the extravascular system |journal=Journal of human hypertension |volume=7 Suppl 2 |issue= |pages= S7–12 |year= 1993 |pmid= 8230088 |doi= }}
*{{cite journal | author=Weir MR, Dzau VJ |title=The renin-angiotensin-aldosterone system: a specific target for hypertension management |journal=Am. J. Hypertens. |volume=12 |issue= 12 Pt 3 |pages= 205S–213S |year= 2000 |pmid= 10619573 |doi= }}
*{{cite journal | author=Berry C, Touyz R, Dominiczak AF, ''et al.'' |title=Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=281 |issue= 6 |pages= H2337–65 |year= 2002 |pmid= 11709400 |doi= }}
*{{cite journal | author=Sernia C |title=A critical appraisal of the intrinsic pancreatic angiotensin-generating system |journal=JOP |volume=2 |issue= 1 |pages= 50–5 |year= 2002 |pmid= 11862023 |doi= }}
*{{cite journal | author=Varagic J, Frohlich ED |title=Local cardiac renin-angiotensin system: hypertension and cardiac failure |journal=J. Mol. Cell. Cardiol. |volume=34 |issue= 11 |pages= 1435–42 |year= 2003 |pmid= 12431442 |doi= }}
*{{cite journal | author=Wolf G |title=Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis |journal=Antioxid. Redox Signal. |volume=7 |issue= 9-10 |pages= 1337–45 |year= 2006 |pmid= 16115039 |doi= 10.1089/ars.2005.7.1337 }}
*{{cite journal | author=Cazaubon S, Deshayes F, Couraud PO, Nahmias C |title=[Endothelin-1, angiotensin II and cancer] |journal=Med Sci (Paris) |volume=22 |issue= 4 |pages= 416–22 |year= 2006 |pmid= 16597412 |doi= }}
*{{cite journal | author=Ariza AC, Bobadilla NA, Halhali A |title=[Endothelin 1 and angiotensin II in preeeclampsia] |journal=Rev. Invest. Clin. |volume=59 |issue= 1 |pages= 48–56 |year= 2007 |pmid= 17569300 |doi= }}
}}
{{refend}}
==External links==
* {{MeshName|Angiotensins}}
{{Cardiovascular physiology}}
{{Neuropeptides}}
{{Autacoids}}
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[[Category:Peptide hormones]]
[[Category:Cardiovascular system]]
[[Category:Endocrinology]]
[[Category:physiology]]
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