Angiotensin: Difference between revisions

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{{PBB_Controls
{{Refimprove|date=March 2012}}
| update_page = yes
{{Infobox gene}}
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = no
| update_citations = yes
}}
{{GNF_Protein_box
| image = Angiotensins I and II comparison.png
| image_source = [[Space-filling model]]s of angiotensin I (left) and II (right). From {{PDB|1N9U}} and [http://www.pdb.org/pdb/explore.do?structureId=1N9V 1N9V].
| PDB =
| Name = Angiotensinogen (serpin peptidase inhibitor, clade A, member 8)
| HGNCid = 333
| Symbol = AGT
| AltSymbols =; ANHU; SERPINA8
| OMIM = 106150
| ECnumber = 
| Homologene = 14
| MGIid = 87963
| GeneAtlas_image1 = PBB_GE_AGT_202834_at_tn.png
| Function = {{GNF_GO|id=GO:0004867 |text = serine-type endopeptidase inhibitor activity}} {{GNF_GO|id=GO:0005179 |text = hormone activity}} {{GNF_GO|id=GO:0031702 |text = type 1 angiotensin receptor binding}} {{GNF_GO|id=GO:0031703 |text = type 2 angiotensin receptor binding}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0005625 |text = soluble fraction}}
| Process = {{GNF_GO|id=GO:0001543 |text = ovarian follicle rupture}} {{GNF_GO|id=GO:0001568 |text = blood vessel development}} {{GNF_GO|id=GO:0001658 |text = ureteric bud branching}} {{GNF_GO|id=GO:0001822 |text = kidney development}} {{GNF_GO|id=GO:0001998 |text = angiotensin mediated vasoconstriction during regulation of blood pressure}} {{GNF_GO|id=GO:0001999 |text = renal response to blood flow during renin-angiotensin regulation of blood pressure}} {{GNF_GO|id=GO:0002018 |text = renin-angiotensin regulation of aldosterone production}} {{GNF_GO|id=GO:0002019 |text = angiotensin mediated regulation of renal output}} {{GNF_GO|id=GO:0002035 |text = brain renin-angiotensin system}} {{GNF_GO|id=GO:0007160 |text = cell-matrix adhesion}} {{GNF_GO|id=GO:0007166 |text = cell surface receptor linked signal transduction}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0007565 |text = female pregnancy}} {{GNF_GO|id=GO:0008065 |text = establishment of blood-nerve barrier}} {{GNF_GO|id=GO:0008217 |text = blood pressure regulation}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0009409 |text = response to cold}} {{GNF_GO|id=GO:0030198 |text = extracellular matrix organization and biogenesis}} {{GNF_GO|id=GO:0030432 |text = peristalsis}} {{GNF_GO|id=GO:0040018 |text = positive regulation of body size}} {{GNF_GO|id=GO:0042445 |text = hormone metabolic process}} {{GNF_GO|id=GO:0042756 |text = drinking behavior}} {{GNF_GO|id=GO:0043410 |text = positive regulation of MAPKKK cascade}} {{GNF_GO|id=GO:0043524 |text = negative regulation of neuron apoptosis}} {{GNF_GO|id=GO:0045723 |text = positive regulation of fatty acid biosynthetic process}} {{GNF_GO|id=GO:0046622 |text = positive regulation of organ size}} {{GNF_GO|id=GO:0048143 |text = astrocyte activation}} {{GNF_GO|id=GO:0048659 |text = smooth muscle cell proliferation}} {{GNF_GO|id=GO:0051145 |text = smooth muscle cell differentiation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 183
    | Hs_Ensembl = ENSG00000135744
    | Hs_RefseqProtein = NP_000020
    | Hs_RefseqmRNA = NM_000029
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 1
    | Hs_GenLoc_start = 228904892
    | Hs_GenLoc_end = 228916666
    | Hs_Uniprot = P01019
    | Mm_EntrezGene = 11606
    | Mm_Ensembl = ENSMUSG00000031980
    | Mm_RefseqmRNA = NM_007428
    | Mm_RefseqProtein = NP_031454
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 8
    | Mm_GenLoc_start = 127442678
    | Mm_GenLoc_end = 127462983
    | Mm_Uniprot = Q3UTR7
  }}
}}
{{SI}}
{{CMG}}


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


Angiotensin is an [[peptide|oligopeptide]] and 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 Specialty Chemicals|Ciba]] laboratories in Basel, Switzerland.<ref name="pmid11751697">{{cite journal | vauthors = Basso N, Terragno NA | title = History about the discovery of the renin-angiotensin system | journal = Hypertension | volume = 38 | issue = 6 | pages = 1246–9 | date = Dec 2001 | pmid = 11751697 | doi = 10.1161/hy1201.101214 }}</ref>


==Overview==
== Precursor and types ==
'''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 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 first isolated at the [[Cleveland Clinic]].


==Precursor, and types of angiotensin==
=== Angiotensinogen ===
===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 consist of 453 [[amino acid]] residues.
Angiotensinogen (AGT) is an [[Alpha globulin|α-2-globulin]] 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.


===Angiotensin I===
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'''
:Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-...


[[Image:Renin-angiotensin-aldosterone system.png|thumb|left|475px|[[Renin-angiotensin-aldosterone system]]]]
=== Angiotensin I ===


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


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).
[[Image:Renin-angiotensin-aldosterone system.png|thumb|[[Renin–angiotensin–aldosterone system]]|480x480px]]


Angiotensin I appears to have no biological activity and exists solely as a precursor to angiotensin II.
Angiotensin I ([[CAS registry number|CAS]]# 11128-99-7) is formed by the action of [[renin]] on [[angiotensinogen]]. Renin cleaves the [[peptide bond]] between the [[leucine]] (Leu) and [[valine]] (Val) residues on angiotensinogen, creating the [[Peptide#Notes on terminology |decapeptide]] (ten amino acid) (des-Asp) angiotensin I. Renin is produced in the [[kidney]]s in response to renal sympathetic activity, decreased intrarenal blood pressure (<90mmHg systolic blood pressure<ref>{{cite web|title=JAMA Article Jan 2012|url=http://jama.ama-assn.org/content/280/13/1168.full}}</ref> ) at the [[juxtaglomerular cell]]s, or decreased delivery of Na+ and Cl- to the [[macula densa]].<ref name="isbn0-07-146633-9">{{cite book |veditors=Loscalzo J, Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL | title = Harrison's principles of internal medicine | edition = | publisher = McGraw-Hill Medical | location = | year = 2008 | origyear = | pages = | quote = | isbn = 0-07-146633-9 |vauthors=Williams GH, Dluhy RG | chapter = Chapter 336: Disorders of the Adrenal Cortex | url = | accessdate = }}</ref>  If a reduced NaCl concentration<ref>{{cite journal | vauthors = Skott O, Briggs JP | year = 1987 | title = Direct demonstration of macula densa-mediated renin secretion | url = | journal = Science | volume = 237 | issue = | pages = 1618–1620 }}</ref> in the distal tubule is sensed by the macula densa, renin release by juxtaglomerular cells is increased. This sensing mechanism for macula densa-mediated renin secretion appears to have a specific dependency on chloride ions rather than sodium ions. Studies using isolated preparations of [[thick ascending limb]] with [[Glomerulus (kidney)|glomerulus]] attached in low NaCl perfusate were unable to inhibit renin secretion when various sodium salts were added but could inhibit renin secretion with the addition of [[chloride]] salts.<ref>Kirchner K.A., Kotchen T.A., Galla J.H., and Luke R.G.: Importance of chloride for acute inhibition of renin by sodium chloride. Am J Physiol 1978; 235: pp. F444-450</ref> This, and similar findings obtained in vivo,<ref>Kim S.M., Mizel D., Huang Y.G., Briggs J.P., and Schnermann J.: Adenosine as a mediator of macula densa-dependent inhibition of renin secretion. Am J Physiol Renal Physiol 2006; 290: pp. F1016-1023</ref> has led some to believe that perhaps "the initiating signal for MD control of renin secretion is a change in the rate of NaCl uptake predominantly via a luminal [[Na-K-Cl cotransporter|Na,K,2Cl co-transporter]] whose physiological activity is determined by a change in luminal Cl concentration."<ref>"Function of the Juxtaglomerular Apparatus: Control of Glomerular Hemodynamics and Renin Secretion" Jürgen B. Schnermann and Hayo Castrop, in Seldin and Giebisch's The Kidney, Chapter 23, 757-801</ref>


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


'''Asp-Arg-Val-Tyr-Ile-His-Pro-Phe''' | His-Leu
=== Angiotensin II ===


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.
:Asp-Arg-Val-Tyr-Ile-His-Pro-Phe


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.
Angiotensin I  is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzyme ''[[angiotensin-converting enzyme]]'' (ACE), primarily through ACE within the lung (but also present in [[endothelial cells]], kidney epithelial cells, and the brain).  Angiotensin II acts on the CNS to increase ADH production, and also acts on venous and arterial vessels' smooth muscle to cause vasoconstriction. Angiotensin II also increases [[Aldosterone]] secretion, therefore, it acts as an [[endocrine system|endocrine]], [[autocrine signalling|autocrine]]/[[paracrine signalling|paracrine]], and [[intracrine]] hormone.


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]].
ACE is a target of [[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 [[Na/H+ exchanger|Na/H<sup>+</sup> exchanger]] in the [[proximal tubule]]s of the kidney to stimulate Na reabsorption and H<sup>+</sup> excretion which is coupled to bicarbonate reabsorption. This ultimately results in an increase in blood volume, pressure, and pH.<ref>{{cite book|last=Le|first=Tao|title=First Aid for the Basic Sciences. Organ Systems|year=2012|publisher=McGraw-Hill|page=625}}</ref> Hence, [[ACE inhibitor]]s are major anti-hypertensive drugs.


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.
Other cleavage products of ACE, seven 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 AII itself is targeted by [[angiotensin II receptor antagonist]]s, which directly block [[Angiotensin receptor|angiotensin II AT<sub>1</sub> receptors]].


===Angiotensin III===
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.


Asp | '''Arg-Val-Tyr-Ile-His-Pro-Phe'''
=== Angiotensin III ===


Angiotensin III has 40% of the [[Vasoconstrictor|pressor]] activity of Angiotensin II, but 100% of the aldosterone-producing activity.
:Asp | Arg-Val-Tyr-Ile-His-Pro-Phe


===Angiotensin IV===
Angiotensin III has 40% of the [[Vasoconstrictor|pressor]] activity of angiotensin II, but 100% of the aldosterone-producing activity.
Increases [[mean arterial pressure]].


Arg | '''Val-Tyr-Ile-His-Pro-Phe'''
=== Angiotensin IV ===


Angiotensin IV is a hexapeptide which, like angiotensin III, has some lesser activity.
:Arg | Val-Tyr-Ile-His-Pro-Phe
==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===
Angiotensin IV is a hexapeptide that, like angiotensin III, has some lesser activity.
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">Skurk T, Lee YM,Hauner H. "Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture." ''Hypertension.'' 2001 May;37(5):1336-40. PMID 11358950</ref><ref name="Gesualdo">Gesualdo L, et al. "Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells." ''Kidney Int.'' 1999 Aug;56(2):461-70. PMID 10432384</ref>
== Effects == <!--Renin-angiotensin_system has a link to here-->
:''See also [[Renin-angiotensin system#Effects]]''
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 " <ref name="adipose review">{{cite journal | vauthors = Yvan-Charvet L, Quignard-Boulangé A | title = Role of adipose tissue renin-angiotensin system in metabolic and inflammatory diseases associated with obesity | journal = Kidney International | volume = 79 | issue = 2 | pages = 162–8  | date = Jan 2011 | pmid = 20944545 | doi = 10.1038/ki.2010.391 }}</ref>
 
=== Cardiovascular ===
 
They are potent direct [[vasoconstrictor]]s, constricting arteries and veins and increasing blood pressure. This effect is achieved through activation of the [[Angiotensin II receptor type 1|GPCR AT1]], which signals through a [[Gq alpha subunit|Gq protein]] to activate Phospholipase C, and subsequently increase intracellular calcium.<ref>{{Cite journal|title = Cellular Mechanism of Vasoconstriction Induced by Angiotensin II It Remains To Be Determined|url = http://circres.ahajournals.org/content/93/11/1015|journal = Circulation Research|date = 2003-11-28|issn = 0009-7330|pmid = 14645130|pages = 1015–1017|volume = 93|issue = 11|doi = 10.1161/01.RES.0000105920.33926.60|language = en|first = Hideo|last = Kanaide|first2 = Toshihiro|last2 = Ichiki|first3 = Junji|last3 = Nishimura|first4 = Katsuya|last4 = Hirano}}</ref>
 
Angiotensin II has prothrombotic potential through adhesion and aggregation of [[platelets]] and stimulation of [[plasminogen activator inhibitor 1|PAI-1]] and [[plasminogen activator inhibitor 2|PAI-2]].<ref name="skurk">{{cite journal | vauthors = 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 | date = May 2001 | pmid = 11358950 | doi = 10.1161/01.HYP.37.5.1336 | url = http://hyper.ahajournals.org/cgi/pmidlookup?view=long&pmid=11358950 }}</ref><ref name="Gesualdo">{{cite journal | vauthors = Gesualdo L, Ranieri E, Monno R, Rossiello MR, Colucci M, Semeraro N, Grandaliano G, Schena FP, Ursi M, Cerullo G | title = Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells | journal = Kidney International | volume = 56 | issue = 2 | pages = 461–70 | date = Aug 1999 | pmid = 10432384 | doi = 10.1046/j.1523-1755.1999.00578.x }}</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.
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.{{Citation needed|date=March 2012}}
 
=== Neural ===


===Neural effects===
Angiotensin II increases [[thirst]] sensation ([[dipsogen]]) through the [[subfornical organ]] 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.{{Citation needed|date=November 2017}}
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===
=== Adrenal ===
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]].
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===
=== Renal ===
Angiotensin II has a direct effect on the proximal tubules to increase Na<sup>+</sup> [[absorption]]. Although it slightly inhibits [[glomerular filtration]] by indirectly (through sympathetic effects) and directly stimulating [[mesangial cell]] constriction, its overall effect is to increase the [[glomerular filtration rate]] by increasing the renal perfusion pressure via efferent renal arteriole constriction. Angiotensin II causes the release of prostaglandins from the kidneys.
Angiotensin II has a direct effect on the proximal tubules to increase Na<sup>+</sup> [[absorption (chemistry)|reabsorption]]. 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 hydrostatic pressure and maintain [[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 [[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.


{|class="wikitable"
{|class="wikitable"
|+ Renal effects of Angiotensin II
|+ Direct Renal effects of angiotensin II (not including [[aldosterone]] release)
|-
|-
!Target
!Target
!Action
!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>
!Mechanism<ref name="isbn1-4160-2328-3">{{cite book |vauthors=Boulpaep EL, Boron WF | title = Medical Physiology: a Cellular and Molecular Approach | edition = | publisher = Elsevier Saunders | location = St. Louis, Mo | year = 2005 | origyear = | pages = 771 | quote = | isbn = 1-4160-2328-3 | oclc = | doi = | url = | accessdate = }}</ref>
|-
|-
![[Renal artery]] & <BR> [[afferent arterioles]]  
![[renal artery]] & <BR> [[afferent arterioles]]  
| [[vasoconstriction]] || [[Voltage-dependent calcium channel|VDCC]]s --> [[calcium|Ca<sup>2+</sup>]] influx
| [[vasoconstriction]] (weaker) || [[Voltage-dependent calcium channel|VDCC]]s → [[calcium|Ca<sup>2+</sup>]] influx
|-
|-
! [[efferent arteriole]]  
! [[efferent arteriole]]  
| [[vasoconstriction]] || (probably) activate [[Angiotensin_type_I_receptor#at1|Angiotensin receptor 1]] --> Activation of [[gq alpha subunit|G<sub>q</sub>]] --> &uarr;[[phospholipase C|PLC]] activity --> &uarr;[[Inositol triphosphate|IP<sub>3</sub>]] and [[diacylglycerol|DAG]] --> activation of [[Inositol triphosphate receptor|IP<sub>3</sub> receptor]] in [[sarcoplasmic reticulum|SR]] --> &uarr;intracellular Ca<sup>2+</sup>  
| [[vasoconstriction]] (stronger) || (probably) activate [[Angiotensin 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  
![[mesangial cell]]s  
| contraction --> &darr;filtration area ||  
| contraction → ↓filtration area ||  
* activation of [[gq alpha subunit|G<sub>q</sub>]] --> &uarr;[[phospholipase C|PLC]] activity --> &uarr;[[Inositol triphosphate|IP<sub>3</sub>]] and [[diacylglycerol|DAG]] --> activation of [[Inositol triphosphate receptor|IP<sub>3</sub> receptor]] in [[sarcoplasmic reticulum|SR]] --> &uarr;intracellular Ca<sup>2+</sup>
* 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
*[[Voltage-dependent calcium channel|VDCC]]s → [[calcium|Ca<sup>2+</sup>]] influx
|-
![[proximal tubule]]
| increased Na<sup>+</sup> reabsorption ||
* adjustment of [[Starling forces]] in peritubular capillaries to favour increased reabsorption
** efferent and afferent arteriole contraction → decreased hydrostatic pressure in peritubular capillaries
** efferent arteriole contraction → increased filtration fraction → increased colloid osmotic pressure in peritubular capillaries
* increased [[sodium–hydrogen antiporter]] activity
|-
|-
! [[Tubuloglomerular feedback]]  
! [[tubuloglomerular feedback]]  
| Increased sensitivity || Responsiveness increase of [[afferent arteriole]] to signals from [[macula densa]]
| increased sensitivity || increase in [[afferent arteriole]] responsiveness to signals from [[macula densa]]
|-
|-
! [[renal medulla|medullary]] blood flow  
! [[renal medulla|medullary]] blood flow  
| Reduction ||
| reduction ||
|-
|-
|}
|}


==See also==
== See also ==
* [[ACE inhibitor]]
* [[ACE inhibitor]]
* [[Angiotensin receptor]]
* [[Angiotensin receptor]]
* [[Angiotensin II receptor antagonist]]
* [[Angiotensin II receptor antagonist]]
* [[Captopril]]
* [[Perindopril]]
* [[Renin inhibitor]]


==References==
== References ==
{{reflist|2}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
* {{cite journal | vauthors = de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T | title = International union of pharmacology. XXIII. The angiotensin II receptors | journal = Pharmacological Reviews | volume = 52 | issue = 3 | pages = 415–472  | date = Sep 2000 | pmid = 10977869 | last5 = Unger | first5 = T }}
*''Brenner & Rector's The Kidney'', 7th ed., Saunders, 2004.
*''Brenner & Rector's The Kidney'', 7th ed., Saunders, 2004.
*''Mosby's Medical Dictionary'', 3rd Ed., CV Mosby Company, 1990.
*''Mosby's Medical Dictionary'', 3rd Ed., CV Mosby Company, 1990.
*''Review of Medical Physiology'', 20th Ed., William F. Ganong, McGraw-Hill, 2001.
*''Review of Medical Physiology'', 20th Ed., William F. Ganong, McGraw-Hill, 2001.
{{PBB_Further_reading
*''Clinical Physiology of Acid-Base and Electrolyte Disorders'', 5th ed., Burton David Rose & Theodore W. Post McGraw-Hill, 2001
| citations =
* {{cite journal | vauthors = 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  | date = Aug 1993 | pmid = 8230088 | doi =  }}
*{{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 | vauthors = Weir MR, Dzau VJ | title = The renin-angiotensin-aldosterone system: a specific target for hypertension management | journal = American Journal of Hypertension | volume = 12 | issue = 12 Pt 3 | pages = 205S–213S  | date = Dec 1999 | pmid = 10619573 | doi = 10.1016/S0895-7061(99)00103-X }}
*{{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 | vauthors = Berry C, Touyz R, Dominiczak AF, Webb RC, Johns DG | title = Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 281 | issue = 6 | pages = H2337–65  | date = Dec 2001 | pmid = 11709400 | 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 | vauthors = Sernia C | title = A critical appraisal of the intrinsic pancreatic angiotensin-generating system | journal = JOP : Journal of the Pancreas | volume = 2 | issue = 1 | pages = 50–5  | date = Jan 2001 | pmid = 11862023 | 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 | vauthors = Varagic J, Frohlich ED | title = Local cardiac renin-angiotensin system: hypertension and cardiac failure | journal = Journal of Molecular and Cellular Cardiology | volume = 34 | issue = 11 | pages = 1435–42  | date = Nov 2002 | pmid = 12431442 | doi = 10.1006/jmcc.2002.2075 }}
*{{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 | vauthors = Wolf G | title = Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis | journal = Antioxidants & Redox Signaling | volume = 7 | issue = 9–10 | pages = 1337–45 | year = 2006 | pmid = 16115039 | doi = 10.1089/ars.2005.7.1337 }}
*{{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 | vauthors = Cazaubon S, Deshayes F, Couraud PO, Nahmias C | title = [Endothelin-1, angiotensin II and cancer] | journal = Médecine Sciences : M/S | volume = 22 | issue = 4 | pages = 416–22  | date = Apr 2006 | pmid = 16597412 | doi = 10.1051/medsci/2006224416 }}
*{{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 | vauthors = Ariza AC, Bobadilla NA, Halhali A | title = [Endothelin 1 and angiotensin II in preeeclampsia] | journal = Revista De Investigación Clínica; Organo Del Hospital De Enfermedades De La Nutrición | volume = 59 | issue = 1 | pages = 48–56 | year = 2007 | pmid = 17569300 | 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}}
{{refend}}


==External links==
== External links ==
{{commons category|Angiotensin}}
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=I04.953 I04.953]
* {{MeshName|Angiotensins}}
* {{MeshName|Angiotensins}}
* {{UCSC gene info|AGT}}


{{Cardiovascular physiology}}
{{Cardiovascular physiology}}
{{Neuropeptides}}
{{Neuropeptides}}
{{Autacoids}}
{{Autacoids}}
{{Angiotensin receptor modulators}}
{{Authority control}}


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[[Category:Cardiovascular system]]
[[Category:Angiology]]
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[[Category:physiology]]
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Revision as of 23:38, 19 November 2017

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

Angiotensin is an oligopeptide and 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.[1]

Precursor and types

Angiotensinogen

Angiotensinogen (AGT) is an α-2-globulin 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 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-...
Renin–angiotensin–aldosterone system

Angiotensin I (CAS# 11128-99-7) is formed by the action of renin on angiotensinogen. Renin cleaves the peptide bond between the leucine (Leu) and valine (Val) residues on angiotensinogen, creating the decapeptide (ten amino acid) (des-Asp) angiotensin I. Renin is produced in the kidneys in response to renal sympathetic activity, decreased intrarenal blood pressure (<90mmHg systolic blood pressure[2] ) at the juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa.[3] If a reduced NaCl concentration[4] in the distal tubule is sensed by the macula densa, renin release by juxtaglomerular cells is increased. This sensing mechanism for macula densa-mediated renin secretion appears to have a specific dependency on chloride ions rather than sodium ions. Studies using isolated preparations of thick ascending limb with glomerulus attached in low NaCl perfusate were unable to inhibit renin secretion when various sodium salts were added but could inhibit renin secretion with the addition of chloride salts.[5] This, and similar findings obtained in vivo,[6] has led some to believe that perhaps "the initiating signal for MD control of renin secretion is a change in the rate of NaCl uptake predominantly via a luminal Na,K,2Cl co-transporter whose physiological activity is determined by a change in luminal Cl concentration."[7]

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

Angiotensin II

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

Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE), primarily through ACE within the lung (but also present in endothelial cells, kidney epithelial cells, and the brain). Angiotensin II acts on the CNS to increase ADH production, and also acts on venous and arterial vessels' smooth muscle to cause vasoconstriction. Angiotensin II also increases Aldosterone secretion, therefore, it acts as an endocrine, autocrine/paracrine, and intracrine hormone.

ACE is a target of 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 Na/H+ exchanger in the 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.[8] Hence, 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 angiotensin receptors, although their exact role is still unclear. The action of AII itself is targeted by 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 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 Renin-angiotensin system#Effects

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 " [9]

Cardiovascular

They are potent direct vasoconstrictors, constricting arteries and veins and increasing blood pressure. This effect is achieved through activation of the GPCR AT1, which signals through a Gq protein to activate Phospholipase C, and subsequently increase intracellular calcium.[10]

Angiotensin II has prothrombotic potential through adhesion and aggregation of platelets and stimulation of PAI-1 and PAI-2.[11][12]

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.[citation needed]

Neural

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

Adrenal

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

Angiotensin II has a direct effect on the proximal tubules to increase Na+ reabsorption. 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 hydrostatic pressure and maintain 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 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.

Direct Renal effects of angiotensin II (not including aldosterone release)
Target Action Mechanism[13]
renal artery &
afferent arterioles 		vasoconstriction (weaker) VDCCs → Ca2+ influx
efferent arteriole vasoconstriction (stronger) (probably) activate Angiotensin receptor 1 → Activation of Gq → ↑PLC activity → ↑IP3 and DAG → activation of IP3 receptor in SR → ↑intracellular Ca2+
mesangial cells contraction → ↓filtration area
proximal tubule increased Na+ reabsorption
  • adjustment of Starling forces in peritubular capillaries to favour increased reabsorption
    • efferent and afferent arteriole contraction → decreased hydrostatic pressure in peritubular capillaries
    • efferent arteriole contraction → increased filtration fraction → increased colloid osmotic pressure in peritubular capillaries
  • increased sodium–hydrogen antiporter activity
tubuloglomerular feedback increased sensitivity increase in afferent arteriole responsiveness to signals from macula densa
medullary blood flow reduction

See also

References

  1. ↑ Basso N, Terragno NA (Dec 2001). "History about the discovery of the renin-angiotensin system". Hypertension. 38 (6): 1246–9. doi:10.1161/hy1201.101214. PMID 11751697.
  2. ↑ "JAMA Article Jan 2012".
  3. ↑ Williams GH, Dluhy RG (2008). "Chapter 336: Disorders of the Adrenal Cortex". In Loscalzo J, Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL. Harrison's principles of internal medicine. McGraw-Hill Medical. ISBN 0-07-146633-9.
  4. ↑ Skott O, Briggs JP (1987). "Direct demonstration of macula densa-mediated renin secretion". Science. 237: 1618–1620.
  5. ↑ Kirchner K.A., Kotchen T.A., Galla J.H., and Luke R.G.: Importance of chloride for acute inhibition of renin by sodium chloride. Am J Physiol 1978; 235: pp. F444-450
  6. ↑ Kim S.M., Mizel D., Huang Y.G., Briggs J.P., and Schnermann J.: Adenosine as a mediator of macula densa-dependent inhibition of renin secretion. Am J Physiol Renal Physiol 2006; 290: pp. F1016-1023
  7. ↑ "Function of the Juxtaglomerular Apparatus: Control of Glomerular Hemodynamics and Renin Secretion" Jürgen B. Schnermann and Hayo Castrop, in Seldin and Giebisch's The Kidney, Chapter 23, 757-801
  8. ↑ Le, Tao (2012). First Aid for the Basic Sciences. Organ Systems. McGraw-Hill. p. 625.
  9. ↑ Yvan-Charvet L, Quignard-Boulangé A (Jan 2011). "Role of adipose tissue renin-angiotensin system in metabolic and inflammatory diseases associated with obesity". Kidney International. 79 (2): 162–8. doi:10.1038/ki.2010.391. PMID 20944545.
  10. ↑ Kanaide, Hideo; Ichiki, Toshihiro; Nishimura, Junji; Hirano, Katsuya (2003-11-28). "Cellular Mechanism of Vasoconstriction Induced by Angiotensin II It Remains To Be Determined". Circulation Research. 93 (11): 1015–1017. doi:10.1161/01.RES.0000105920.33926.60. ISSN 0009-7330. PMID 14645130.
  11. ↑ Skurk T, Lee YM, Hauner H (May 2001). "Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture". Hypertension. 37 (5): 1336–40. doi:10.1161/01.HYP.37.5.1336. PMID 11358950.
  12. ↑ Gesualdo L, Ranieri E, Monno R, Rossiello MR, Colucci M, Semeraro N, Grandaliano G, Schena FP, Ursi M, Cerullo G (Aug 1999). "Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells". Kidney International. 56 (2): 461–70. doi:10.1046/j.1523-1755.1999.00578.x. PMID 10432384.
  13. ↑ Boulpaep EL, Boron WF (2005). Medical Physiology: a Cellular and Molecular Approach. St. Louis, Mo: Elsevier Saunders. p. 771. ISBN 1-4160-2328-3.

Further reading

  • de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (Sep 2000). "International union of pharmacology. XXIII. The angiotensin II receptors". Pharmacological Reviews. 52 (3): 415–472. PMID 10977869.
  • 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
  • Lees KR, MacFadyen RJ, Doig JK, Reid JL (Aug 1993). "Role of angiotensin in the extravascular system". Journal of Human Hypertension. 7 Suppl 2: S7–12. PMID 8230088.
  • Weir MR, Dzau VJ (Dec 1999). "The renin-angiotensin-aldosterone system: a specific target for hypertension management". American Journal of Hypertension. 12 (12 Pt 3): 205S–213S. doi:10.1016/S0895-7061(99)00103-X. PMID 10619573.
  • Berry C, Touyz R, Dominiczak AF, Webb RC, Johns DG (Dec 2001). "Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide". American Journal of Physiology. Heart and Circulatory Physiology. 281 (6): H2337–65. PMID 11709400.
  • Sernia C (Jan 2001). "A critical appraisal of the intrinsic pancreatic angiotensin-generating system". JOP : Journal of the Pancreas. 2 (1): 50–5. PMID 11862023.
  • Varagic J, Frohlich ED (Nov 2002). "Local cardiac renin-angiotensin system: hypertension and cardiac failure". Journal of Molecular and Cellular Cardiology. 34 (11): 1435–42. doi:10.1006/jmcc.2002.2075. PMID 12431442.
  • Wolf G (2006). "Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis". Antioxidants & Redox Signaling. 7 (9–10): 1337–45. doi:10.1089/ars.2005.7.1337. PMID 16115039.
  • Cazaubon S, Deshayes F, Couraud PO, Nahmias C (Apr 2006). "[Endothelin-1, angiotensin II and cancer]". Médecine Sciences : M/S. 22 (4): 416–22. doi:10.1051/medsci/2006224416. PMID 16597412.
  • Ariza AC, Bobadilla NA, Halhali A (2007). "[Endothelin 1 and angiotensin II in preeeclampsia]". Revista De Investigación Clínica; Organo Del Hospital De Enfermedades De La Nutrición. 59 (1): 48–56. PMID 17569300.

External links

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