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European Journal of Pharmacology Aug 2015The review describes DAA-I (des-aspartate-angiotensin-I) as a prototype of a novel class of drugs that acts as agonists on the angiotensin AT1 receptor or ARAs... (Review)
Review
The review describes DAA-I (des-aspartate-angiotensin-I) as a prototype of a novel class of drugs that acts as agonists on the angiotensin AT1 receptor or ARAs (angiotensin receptor agonists). DAA-I is a component of the renin angiotensin system. Earlier studies showed that it was rapidly metabolized to angiotensin III. However, when administered at doses below the Km of enzymes, DAA-I produces specific actions that antagonize the deleterious actions of angiotensin II. DAA-I exerts protective actions in animal models of eight human pathologies in which angiotensin II is implicated. The pathologies include cardiac hypertrophy, neointima growth and cardiovascular hypertrophy, myocardial-ischemia reperfusion injury, hyperglycemia and insulin resistance, chemical induced inflammation, and exercise-induced skeletal muscle inflammation. Binding of DAA-I to the angiotensin AT1 receptors releases prostaglandins, which could either function as autocrines/paracrines or second messengers and attenuate the deleterious actions of angiotensin II. It is possible that in in vivo DAA-I functions as a physiological antagonist to angiotensin II, and exogenous DAA-I is a novel class of angiotensin receptor drug that could rival the angiotensin receptor blockers.
Topics: Angiotensin I; Animals; Blood Pressure; Cardiomegaly; Humans; Hyperglycemia; Myocardial Reperfusion Injury; Receptor, Angiotensin, Type 1
PubMed: 25891368
DOI: 10.1016/j.ejphar.2015.04.004 -
Critical Care (London, England) Feb 2020In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe...
BACKGROUND
In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study.
METHODS
We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes.
RESULTS
Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30-676.00 pg/mL] vs 42 pg/mL [IQR 30.46-87.34 pg/mL] in controls; P < 0.0001) and median ANG I/II ratio (1.63 [IQR 0.98-5.25] vs 0.4 [IQR 0.28-0.64] in controls; P < 0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85-299.50 pg/mL] vs 97 pg/mL [IQR 35.27-181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P < 0.0001), lower ANG II levels (P < 0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P < 0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses.
CONCLUSIONS
Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.
Topics: Angiotensin I; Angiotensin II; Catecholamines; Female; Humans; Male; Shock
PubMed: 32028998
DOI: 10.1186/s13054-020-2733-x -
Biochemical Pharmacology Sep 2022Angiotensin-(1-9) [Ang-(1-9)] is a peptide of the non-canonical renin-angiotensin system (RAS) synthesized from angiotensin I by the monopeptidase angiotensin-converting... (Review)
Review
Angiotensin-(1-9) [Ang-(1-9)] is a peptide of the non-canonical renin-angiotensin system (RAS) synthesized from angiotensin I by the monopeptidase angiotensin-converting enzyme type 2 (ACE2). Using osmotic minipumps, infusion of Ang-(1-9) consistently reduces blood pressure in several rat hypertension models. In these animals, hypertension-induced end-organ damage is also decreased. Several pieces of evidence suggest that Ang-(1-9) is the endogenous ligand that binds and activates the type-2 angiotensin II receptor (AT2R). Activation of AT2R triggers different tissue-specific signaling pathways. This phenomenon could be explained by the ability of AT2R to form different heterodimers with other G protein-coupled receptors. Because of the antihypertensive and protective effects of AT2R activation by Ang-(1-9), associated with a short half-life of RAS peptides, several synthetic AT2R agonists have been synthesized and assayed. Some of them, particularly CGP42112, C21 and novokinin, have demonstrated antihypertensive properties. Only two synthetic AT2R agonists, C21 and LP2-3, have been tested in clinical trials, but none of them like an antihypertensive. Therefore, Ang-(1-9) is a promising antihypertensive drug that reduces hypertension-induced end-organ damage. However, further research is required to translate this finding successfully to the clinic.
Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Hypertension; Imidazoles; Peptidyl-Dipeptidase A; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Sulfonamides; Thiophenes
PubMed: 35870482
DOI: 10.1016/j.bcp.2022.115183 -
Journal of Hypertension May 2002
Review
Topics: Angiotensin I; Angiotensin II; Humans; Peptide Fragments
PubMed: 12011630
DOI: 10.1097/00004872-200205000-00004 -
Bioorganic Chemistry Dec 2022The renin-angiotensin system (RAS) is a key regulator of human arterial pressure. Several of its effects are modulated by angiotensin II, an octapeptide originating from...
The renin-angiotensin system (RAS) is a key regulator of human arterial pressure. Several of its effects are modulated by angiotensin II, an octapeptide originating from the action of angiotensin-I converting enzyme (ACE) on the decapeptide angiotensin-I. ACE possess two active sites (nACE and cACE) that have their own kinetic and substrate specificities. ACE inhibitors are widely used as the first-line treatment for hypertension and other heart-related diseases, but because they inactivate both ACE domains, their use is associated with serious side effects. Thus, the search for domain-specific ACE inhibitors has been the focus of intense research. Angiotensin (1-7), a peptide that also belongs to the RAS, acts as a substrate of nACE and an inhibitor of cACE. We have synthetized 15 derivatives of Ang (1-7), sequentially removing the N-terminal amino acids and modifying peptides extremities, to find molecules with improved selectivity and inhibition properties. Ac-Ang (2-7)-NH is a good ACE inhibitor, resistant to cleavage and with improved cACE selectivity. Molecular dynamics simulations provided a model for this peptide's selectivity, due to Val and Tyr interactions with ACE subsites. Val has an important interaction with the S subsite, since its removal greatly reduced peptide-enzyme interactions. Taken together, our findings support ongoing studies using insights from the binding of Ac-Ang (2-7)-NH to develop effective cACE inhibitors.
Topics: Humans; Peptidyl-Dipeptidase A; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Peptides
PubMed: 36306699
DOI: 10.1016/j.bioorg.2022.106204 -
Hypertension (Dallas, Tex. : 1979) Jun 2014
Review
Topics: Angiotensin I; Animals; Humans; Models, Cardiovascular; Peptide Fragments; Receptors, Angiotensin; Renin-Angiotensin System; Vasodilation
PubMed: 24664288
DOI: 10.1161/HYPERTENSIONAHA.113.01274 -
Methods in Molecular Biology (Clifton,... 2017The renin-angiotensin system (RAS) is a complex circulating and tissue-based system. There are multiple pathways for the formation and degradation of peptides. In order... (Review)
Review
The renin-angiotensin system (RAS) is a complex circulating and tissue-based system. There are multiple pathways for the formation and degradation of peptides. In order to understand the functions of the system, characterization of angiotensin peptides (products and substrates) is important. Radioimmunoassays with the requisite specificity and sensitivity have been developed to allow for the characterization and quantification of circulating and tissue angiotensins. Here, we describe the appropriate methods for collecting the tissue and blood, the extractions steps required to partially purify and remove larger molecular weight-interfering proteins from tissue and plasma, and the radioimmunoassay of three of the peptides of this system (Ang I, Ang II, and Ang-(1-7)), as well as the verification of immunoreactive identity for Ang II and Ang-(1-7) by combined high-performance liquid chromatography-RIA analysis.
Topics: Angiotensin I; Angiotensin II; Animals; Chromatography, High Pressure Liquid; Humans; Peptide Fragments; Radioimmunoassay; Renin-Angiotensin System
PubMed: 28116709
DOI: 10.1007/978-1-4939-6625-7_7 -
Circulation Research Apr 2013
Topics: Angiotensin I; Animals; Antihypertensive Agents; Drug Discovery; Humans; Male; Oligopeptides; Peptide Fragments; Renin-Angiotensin System
PubMed: 23580768
DOI: 10.1161/CIRCRESAHA.113.301246 -
Nihon Rinsho. Japanese Journal of... Mar 1995
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Current Hypertension Reports Apr 2003Angiotensinogen (AGT) can be schematically considered to consist of a combination of an angiotensin I (Ang I) function, located at the N-terminal end, and the presence... (Review)
Review
Angiotensinogen (AGT) can be schematically considered to consist of a combination of an angiotensin I (Ang I) function, located at the N-terminal end, and the presence of a serpin (serine protease inhibitor) structure at the opposite end. des(Ang I)AGT, which accounts for more than 97% of the molecule, apparently has no function. Several serpins (antithrombin, maspin, pigment epithelial-derived factor, and kallistatin) have been recently shown to exert an antiangiogenic activity, suggesting a common mechanism of endothelial cell proliferation and migration. AGT and its renin-cleaved product, des(Ang I)AGT, are also angiogenesis inhibitors, both in vitro and in vivo at concentrations within the range of those observed in plasma. This property most likely results from the structure analogy of AGT with serpins. The pathologic relevance of this new function is still not known, but AGT produced by glial cells may play a role in the stabilization of the blood-brain barrier. These new data must be considered in light of the overall action of the renin-angiotensin system in angiogenesis.
Topics: Angiogenesis Inhibitors; Angiotensin I; Angiotensinogen; Animals; Humans; Neovascularization, Physiologic; Peptide Fragments
PubMed: 12642015
DOI: 10.1007/s11906-003-0072-3