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It has been reported that Ang-(1-7) and Ang-(1-9) stimulate the secretion of atrial natriuretic peptide (ANP) via Mas receptor (Mas R) and Ang II type 2 receptor (AT2R), respectively. The effect of Ang-(1-5) on ANP secretion was investigated using isolated perfused beating rat atria. Ang-(1-5) stimulated high pacing frequency-induced ANP secretion in a dose-dependent manner. Ang-(1-5)-induced ANP secretion was attenuated by the pretreatment with an antagonist of Mas R (A-779) but not by an antagonist of AT1R (losartan) or AT2R (PD123,319). 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PMID:23446738 </body> </html> </notes> <annotation> <celldesigner:extension> <celldesigner:reactionType>STATE_TRANSITION</celldesigner:reactionType> <celldesigner:baseReactants> <celldesigner:baseReactant species="s12" alias="sa24"> <celldesigner:linkAnchor position="SW"/> </celldesigner:baseReactant> </celldesigner:baseReactants> <celldesigner:baseProducts> <celldesigner:baseProduct species="s36" alias="sa49"/> </celldesigner:baseProducts> <celldesigner:connectScheme connectPolicy="direct" rectangleIndex="0"> <celldesigner:listOfLineDirection> <celldesigner:lineDirection index="0" value="unknown"/> </celldesigner:listOfLineDirection> </celldesigner:connectScheme> <celldesigner:line width="1.0" color="ff000000"/> </celldesigner:extension> <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/"> <rdf:Description rdf:about="#re43"> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:pubmed:23446738"/> </rdf:Bag> </bqbiol:isDescribedBy> <bqbiol:isEncodedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:taxonomy:10116"/> </rdf:Bag> </bqbiol:isEncodedBy> </rdf:Description> </rdf:RDF> </annotation> <listOfReactants> <speciesReference metaid="CDMT00030" species="s12"> <annotation> <celldesigner:extension> <celldesigner:alias>sa24</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> </listOfReactants> <listOfProducts> <speciesReference metaid="CDMT00032" species="s36"> <annotation> <celldesigner:extension> <celldesigner:alias>sa49</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> </listOfProducts> </reaction> <reaction metaid="re45" id="re45" reversible="false"> <notes> <html xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body>Chromatographic purification and structural analysis by matrix-assisted laser desorption/ionisation time-of-flight/time-of-flight (MALDI-TOF/TOF) revealed an angiotensin octapeptide with the sequence Ala-Arg-Val-Tyr-Ile-His-Pro-Phe, which differs from Ang II in Ala1 instead of Asp1. Des[Asp1]-[Ala1]-Ang II, in the following named Angiotensin A (Ang A), is most likely generated enzymatically. In the presence of mononuclear leukocytes, Ang II is converted to Ang A by decarboxylation of Asp1. 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They demonstrate that alamandine can be formed in the rat heart after Ang-(1–7) perfusion with the use of selected reaction monitoring-mass spectrometry. This indicates that the cardiac tissue contains all necessary components to promote the decarboxylation of the Ang-(1–7) N-terminal aspartate amino acid residue. The sequence of alamandine is very similar to Ang-(1–7), differing only by the presence of an alanine residue in place of an aspartate residue in the amino terminus. 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Ang II and Ang III levels were evaluated from hypothalamus homogenates by HPLC. EC33 increased the half-life of Ang II 2.6-fold and completely blocked the formation of Ang III, whereas EC27 increased the half-life of Ang III 2.3-fold. These results demonstrate that APA and APN are involved in vivo in the metabolism of brain Ang II and Ang III, respectively. 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Ang II and Ang III levels were evaluated from hypothalamus homogenates by HPLC. EC33 increased the half-life of Ang II 2.6-fold and completely blocked the formation of Ang III, whereas EC27 increased the half-life of Ang III 2.3-fold. These results demonstrate that APA and APN are involved in vivo in the metabolism of brain Ang II and Ang III, respectively. 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PMID:32333398 ADAM17, the ACE2 sheddase, requires arginine and lysine residues within ACE2 amino acids 652 to 659 for receptor cleavage and competes with TMPRSS2 for ACE2 processing. PMID:24227843 Angiotensin II type 1 receptors promote ADAM17-mediated ACE2 shedding in the brain of hypertensive patients, leading to a loss in compensatory activity during neurogenic hypertension. 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PMID:17630322 Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. The authors report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy. In cultured rat CFs, Ang II treatment enhanced exosome release via the activation of Ang II receptor types 1 (AT1R) and 2 (AT2R), whereas lipopolysaccharide, insulin, endothelin (ET)-1, transforming growth factor beta (TGFbeta)1 or hydrogen peroxide did not. PMID:26497614 ANG (1-7) acts primarily via the G protein-coupled receptor MAS1, and forms ANG (1-5), which signals via MRGPRD. ANG (1-7) can also act via the AGTR2 receptor but with much lower affinity than ANG II. PMID:32333398 Ang A has the same affinity to the AT1 receptor as Ang II, but a higher affinity to the AT2 receptor. 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The ACE2 homologue ACE, by contrast, cleaves the decapeptide AngI into the octapeptide AngII. Thus, ACE2 counterbalances the function of ACE and negatively regulates AngII production. To test whether Spike-Fc injections indeed affect the function of the renin-angiotensin system, AngII levels in the lungs of acid- and Spike-Fc–treated mice were analyzed. Acid aspiration increased AngII levels in the lungs of wild-type mice. Notably, the authors observed a further, significant increase in AngII levels in the lung tissue of mice treated with Spike-Fc. PMID:16007097 Adipocytes express all components of the renin-angiotensin system, and the renin-angiotensin system is involved in obesity and insulin resistance. The aim of this study was to investigate plasma Ang II in obese patients with type 2 diabetes mellitus (T2D) and the change during weight loss. Fifty Japanese obese subjects with T2D were enrolled. 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PMID:17630322 Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. The authors report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy in rats. In cultured CFs, Ang II treatment enhanced exosome release via the activation of Ang II receptor types 1 (AT1R) and 2 (AT2R), whereas lipopolysaccharide, insulin, endothelin (ET)-1, transforming growth factor beta (TGFbeta)1 or hydrogen peroxide did not. PMID:26497614 Both, ANG II and ANG IV act primarily via the angiotensin II receptor type 1 (AGTR1). PMID:32333398 Ang A has the same affinity to the AT1 receptor as Ang II, but a higher affinity to the AT2 receptor. 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In addition, this confirms the previous observation that chymase (rather than ACE) is the main hydrolyzing enzyme responsible for Ang II generation from Ang-(1-12) in the adult rat heart. PMID:27465904 Since angiotensin-(1-12) [Ang-(1-12)] is a non-renin dependent alternate precursor for the generation of cardiac Ang peptides in rat tissue, the authors investigated the metabolism of Ang-(1-12) by plasma membranes (PM) isolated from human atrial appendage tissue from nine patients undergoing cardiac surgery for primary control of atrial fibrillation. PM was incubated with highly purified Ang-(1-12) for 1 h with or without renin-angiotensin system (RAS) inhibitors [lisinopril for angiotensin converting enzyme (ACE), SCH39370 for neprilysin (NEP), MLN-4760 for ACE2 and chymostatin for chymase]. In the absence of all RAS inhibitor, Ang-(1-12) was converted into Ang I (2%), Ang II (69%), Ang-(1-7) (5%), and Ang-(1-4) (2%). 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PMID:30934934 A human neutrophil protease, initially termed neutral peptide-generating protease, has been shown to cleave angiotensin II directly from angiotensinogen and has been identified as leukocyte cathepsin G. When purified neutrophils were disrupted by nitrogen cavitation and fractionated by differential centrifugation, 44 and 24% of the angiotensin II-generating activity was in the lysosomal and undisrupted cell fractions, respectively. The angiotensin II-generating protease of human neutrophils has been identified as cathepsin G on the basis of subcellular localization, substrate specificity, physicochemical characteristics, and antigenic identity. 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The authors report the identification and characterization of the major Ang II-forming, neutral serine proteinase, from left ventricular tissues of the human heart. A 115,150-fold purification from human cardiac membranes yielded a purified protein with an Mr of 30,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Based upon its amino-terminal sequence, the major human cardiac Ang II-forming proteinase appears to be a novel member of the chymase subfamily of chymotrypsin-like serine proteinases. Human heart chymase was completely inhibited by the serine proteinase inhibitors, soybean trypsin inhibitor, phenylmethylsulfonyl fluoride, and chymostatin. It was partially inhibited by p-tosyl-L-phenylalanine chloromethyl ketone, but was not inhibited by p-tosyl-L-lysine chloromethyl ketone, and aprotinin. Also, human heart chymase was not inhibited by inhibitors of the other three classes of proteinases. Human heart chymase has a high specificity for the conversion of Ang I to Ang II and the Ang I-carboxyl-terminal dipeptide His-Leu. Human heart chymase did not degrade several peptide hormones, including Ang II, bradykinin, and vasoactive intestinal peptide, nor did it form Ang II from angiotensinogen. The high substrate specificity of human heart chymase for Ang I distinguishes it from other Ang II-forming enzymes including Ang I converting enzyme, tonin, kallikrein, cathepsin G, and other known chymases. 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The amino acid composition of the isolated pressor substance (residues/mol) was: Asp, 1.03; Val, 1.03; Ile, 1.00; Tyr, 0.69; Phe, 1.04; His, 0.91; Arg, 0.86; Pro, 0.86. This composition was identical with that of angiotensin. Since the reaction mixture was not contaminated with common proteolytic enzymes, such as trypsin, chymotrypsin, renin, cathepsin D and proangiotensin-converting enzyme, and other enzymes activated by kallikrein, it is clear that hog kallikrein directly produces angiotensin in vitro. 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Pre-incubation with losartan (LOS), an antagonist of ATR1 prevented the effect of ANGII on ISC. 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ANG (1-7) can also act via the AGTR2 receptor but with much lower affinity than ANG II. PMID:32333398 The study investigated whether a vasodepressor effect of Ang-(1-7) could be unmasked acutely in conscious spontaneously hypertensive rats (SHR) against a background of angiotensin II type 1 (AT1) receptor blockade. Mean arterial pressure (MAP) and heart rate were measured over a 5-day protocol in various groups of rats randomized to receive the following drug combinations: saline, AT1 receptor (AT1R) antagonist candesartan (0.01 or 0.1 mg/kg IV) alone, Ang-(1-7) (5 pmol/min) alone, candesartan plus Ang-(1-7), and candesartan plus Ang-(1-7) and angiotensin II type 2 (AT2) receptor (AT2R) antagonist PD123319 (50 microg/kg per minute). In Wistar-Kyoto (WKY) rats, saline, Ang-(1-7), or candesartan alone caused no significant alteration in MAP, whereas Ang-(1-7) coadministered with candesartan caused a marked, sustained reduction in MAP. A similar unmasking of a vasodepressor response to Ang-(1-7) during AT1R blockade was observed in SHR. Moreover, the AT(2)R antagonist PD123319 markedly attenuated the enhanced depressor response evoked by the Ang-(1-7)/candesartan combination in SHR and WKY rats. In separate experiments, the bradykinin type 2 receptor antagonist HOE 140 (100 microg/kg IV) or the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (1 mg/kg IV) abolished the depressor effect of Ang-(1-7) in the presence of candesartan. Collectively, these results suggest that Ang-(1-7) evoked a depressor response during AT1R blockade via activation of AT2R, which involves the bradykinin-NO cascade. 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PMID:29351514 Angiotensin (Ang)-(1-7) has cardiovascular protective effects and is the opponent of the often detrimental Ang II within the renin-angiotensin system. The study aimed to identify a second messenger stimulated by Ang-(1-7) allowing confirmation as well as discovery of the heptapeptide's receptors. Ang-(1-7) elevates cAMP concentration in primary cells, such as endothelial or mesangial cells. Using cAMP as readout in receptor-transfected human embryonic kidney (HEK293) cells, the study provided pharmacological proof that Mas is a functional receptor for Ang-(1-7). Moreover, the authors identified the G-protein-coupled receptor MrgD as a second receptor for Ang-(1-7). 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