{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T19:40:09Z","timestamp":1793475609934,"version":"4.5.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>The renin-angiotensin system comprises a biochemical cascade that hydrolyzes angiotensinogen into several different bioactive peptides, which can activate different receptors, promoting plenty of specific effects. This study aimed to evaluate the presence of the putative product of alamandine, the pentapeptide Ala-(1-5) (alamandine-[1-5]), in the circulation and its biological activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>To accomplish this, we have used mass spectrometry (Matrix-assisted Laser Desorption\/Ionization Time-of-Flight\/Time-of-Flight mass spectrometry [MALDI\/TOF\/TOF], Liquid Chromatography-Tandem Mass Spectrometry [LC-MS\/MS]) and several methodologies, including isolated blood vessels, isolated perfused hearts, isolated cardiomyocytes, blood pressure recording in freely moving normotensive and spontaneously hypertensive rats, high-resolution echocardiography, central administration (intracerebroventricular infusion and microinjection in the insular cortex), cell culture (endothelial cells and G-protein\u2013coupled receptors-transfected Chinese Hamster Ovary cells), and wild-type and Mas (Mas receptor proto-oncogene), MrgD (Mas-related G-protein\u2013coupled receptor subtype D), or AT2 (angiotensin II type 2) receptor-deficient mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We show that Ala-(1-5) is present in the circulation of healthy humans and rodents and promotes many biological central and peripheral actions. A major role for ACE (angiotensin-converting enzyme) activity in the formation of Ala-(1-5) from alamandine in the circulation was observed using plasma samples from angiotensinogen-knockout mice. Ala-(1-5) increases baroreflex sensitivity and produces a long-lasting (\u22486 hours) antihypertensive effect in spontaneously hypertensive rats, associated with a significant reduction in cardiac output. Additionally, Ala-(1-5) decreases inotropism in isolated perfused hearts and reduces contractility in cardiomyocytes. In Chinese Hamster Ovary cells-transfected cells, Ala-(1-5) can bind and stimulate NO production through all receptors from the renin-angiotensin system protective arm (Mas, MrgD, and AT\n                      <jats:sub>2<\/jats:sub>\n                      receptors). On the other hand, the Ala-(1-5) effects on cardiomyocytes and mouse aortic rings were abolished only by MrgD genetic deletion, but not by Mas or AT2 receptor knockout.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our data demonstrate that Ala-(1-5) is a newly identified peptide within the renin-angiotensin system, with strong blood pressure\u2013lowering effects that vary in mechanisms of action among different tissues. Ala-(1-5) has distinct characteristics that differentiate it from the conventional renin-angiotensin system pathways responsible for reducing blood pressure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.326174","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T10:00:12Z","timestamp":1762941612000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Identification and Characterization of Alamandine-(1-5), a New Component of the Renin-Angiotensin System"],"prefix":"10.1161","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8738-5852","authenticated-orcid":true,"given":"Robson A.S.","family":"Santos","sequence":"first","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa Tainan Silva","family":"Dias","sequence":"additional","affiliation":[{"name":"Department of Pharmacology (M.T.S.D., L.S.A.C.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9806-4376","authenticated-orcid":true,"given":"Amanda de S\u00e1 Martins","family":"Bessa","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1204-2596","authenticated-orcid":true,"given":"Carolina Fonseca","family":"Barros","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matheus F.","family":"Itaborahy","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1418-9591","authenticated-orcid":true,"given":"Filipe Alex","family":"da Silva","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2210-0902","authenticated-orcid":true,"given":"Sthefanie Chaves de Almeida","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4011-637X","authenticated-orcid":true,"given":"Lucas","family":"Rodrigues-Ribeiro","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8186-8476","authenticated-orcid":true,"given":"Kamylle Silva","family":"Ferraz","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9862-4262","authenticated-orcid":true,"given":"Ana Paula","family":"Davel","sequence":"additional","affiliation":[{"name":"Institute of Biology, University of Campinas (Unicamp), Brazil (A.P.D., N.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nat\u00e1lia","family":"N\u00f3brega","sequence":"additional","affiliation":[{"name":"Institute of Biology, University of Campinas (Unicamp), Brazil (A.P.D., N.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno Durante da","family":"Silva","sequence":"additional","affiliation":[{"name":"Heart Institute, University of S\u00e3o Paulo (INCOR-USP), Brazil (B.D.S., L.E.S., A.A.S., M.C.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1496-878X","authenticated-orcid":true,"given":"S\u00e9rgio","family":"Scalzo","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1183-7610","authenticated-orcid":true,"given":"Pedro Alves","family":"Soares","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (P.A.S., A.C.S.-E.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9800-4979","authenticated-orcid":true,"given":"Jo\u00e3o Batista Rodrigues","family":"Dutra","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences, Federal University of Goi\u00e1s (UFG), Brazil (J.B.R.D., C.H.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3987-5738","authenticated-orcid":true,"given":"Ivana","family":"Lula","sequence":"additional","affiliation":[{"name":"Department of Chemistry (I.L.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isadora Zhong Liang Ferreira","family":"Feng","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uri Flegler","family":"Vieira-Machado","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4789-1691","authenticated-orcid":true,"given":"Ana Caroline Ventris","family":"de Godoy","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8334-1219","authenticated-orcid":true,"given":"Adelson H\u00e9ric Alves","family":"Monteiro","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8942-6822","authenticated-orcid":true,"given":"Marcos","family":"Eliezeck","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9029-609X","authenticated-orcid":true,"given":"Bruno","family":"Sanches","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3632-9145","authenticated-orcid":true,"given":"Andr\u00e9","family":"Monteiro","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0875-5591","authenticated-orcid":true,"given":"Gabriela","family":"Magalh\u00e3es","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00edcia Pedreira","family":"Soares","sequence":"additional","affiliation":[{"name":"INCT-Nanobiofar, Department of Physiology and Biophysics (R.A.S.S., A.S.M.B., C.F.B., M.F.I., F.A.S., S.C.A.G., L.R.-R., K.S.F., S.S., I.Z.L.F.F., U.F.V.-M., A.C.V.G., A.H.A.M., M.E., B.S., A.M., G.M., N.P.S., D.A.A.P., J.R.R., M.L.D.-P., D.M.-S., M.A.P.F., A.S.H., T.V.-B., S.G., M.F.L., M.J.C.-S.), Federal University of Minas Gerais (UFMG), Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4111-7008","authenticated-orcid":true,"given":"Danilo Augusto 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