{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:19:59Z","timestamp":1791191999525,"version":"4.1.0"},"reference-count":53,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1999,11,9]]},"abstract":"<jats:p>\n                    Overactivity of the brain renin-angiotensin system (RAS) has been\n implicated in the development and maintenance of hypertension in\n several experimental models, such as spontaneously hypertensive rats\n and transgenic mice expressing both human renin and human\n angiotensinogen transgenes. We recently reported that, in the murine\n brain, angiotensin II (AngII) is converted to angiotensin III (AngIII)\n by aminopeptidase A (APA), whereas AngIII is inactivated by\n aminopeptidase N (APN). If injected into cerebral ventricles (ICV),\n AngII and AngIII cause similar pressor responses. Because AngII is\n metabolized\n                    <jats:italic>in vivo<\/jats:italic>\n                    into AngIII, the exact nature of the\n active peptide is not precisely determined. Here we report that, in\n rats, ICV injection of the selective APA inhibitor EC33\n [(S)-3-amino-4-mercaptobutyl sulfonic acid] blocked the pressor\n response of exogenous AngII, suggesting that the conversion of AngII to\n AngIII is required to increase blood pressure (BP). Furthermore, ICV\n injection, but not i.v. injection, of EC33 alone caused a\n dose-dependent decrease in BP by blocking the formation of brain but\n not systemic AngIII. This is corroborated by the fact that the\n selective APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol),\n administered alone via the ICV route, increases BP. This pressor\n response was blocked by prior treatment with the angiotensin type 1\n (AT\n                    <jats:sub>1<\/jats:sub>\n                    ) receptor antagonist, losartan, showing that blocking\n the action of APN on AngIII metabolism leads to an increase in\n endogenous AngIII levels, resulting in BP increase, through\n interaction with AT\n                    <jats:sub>1<\/jats:sub>\n                    receptors. These data demonstrate that\n AngIII is a major effector peptide of the brain RAS, exerting tonic\n stimulatory control over BP. Thus, APA, the enzyme responsible for the\n formation of brain AngIII, represents a potential central therapeutic\n target that justifies the development of APA inhibitors as central\n antihypertensive agents.\n                  <\/jats:p>","DOI":"10.1073\/pnas.96.23.13415","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:41:48Z","timestamp":1027680108000},"page":"13415-13420","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":179,"title":["Aminopeptidase A inhibitors as potential central antihypertensive agents"],"prefix":"10.1073","volume":"96","author":[{"given":"Annabelle","family":"Reaux","sequence":"first","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche\r M\u00e9dicale, Unit\u00e9 36, Coll\u00e8ge de France, Chaire de\r M\u00e9decine Exp\u00e9rimentale, 3 rue d\u2019Ulm, 75005 Paris, France;\r and Institut National de la Sant\u00e9 et de la\r Recherche M\u00e9dicale, Unit\u00e9 266, D\u00e9partement de\r Pharmacochimie mol\u00e9culaire et structurale, Centre National de la\r Recherche Scientifique, UMR 8600, 4 avenue de l\u2019Observatoire, 75270\r Paris Cedex 06, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Claude","family":"Fournie-Zaluski","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche\r M\u00e9dicale, Unit\u00e9 36, Coll\u00e8ge de France, Chaire de\r M\u00e9decine Exp\u00e9rimentale, 3 rue d\u2019Ulm, 75005 Paris, France;\r and Institut National de la Sant\u00e9 et de la\r Recherche M\u00e9dicale, Unit\u00e9 266, D\u00e9partement de\r Pharmacochimie mol\u00e9culaire et structurale, Centre National de la\r Recherche Scientifique, UMR 8600, 4 avenue de l\u2019Observatoire, 75270\r Paris Cedex 06, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christelle","family":"David","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche\r M\u00e9dicale, Unit\u00e9 36, Coll\u00e8ge de France, Chaire de\r M\u00e9decine Exp\u00e9rimentale, 3 rue d\u2019Ulm, 75005 Paris, France;\r and Institut National de la Sant\u00e9 et de la\r Recherche M\u00e9dicale, Unit\u00e9 266, D\u00e9partement de\r Pharmacochimie mol\u00e9culaire et structurale, Centre National de la\r Recherche Scientifique, UMR 8600, 4 avenue de l\u2019Observatoire, 75270\r Paris Cedex 06, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Zini","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche\r M\u00e9dicale, Unit\u00e9 36, Coll\u00e8ge de France, Chaire de\r M\u00e9decine Exp\u00e9rimentale, 3 rue d\u2019Ulm, 75005 Paris, France;\r and Institut National de la Sant\u00e9 et de la\r Recherche M\u00e9dicale, Unit\u00e9 266, D\u00e9partement de\r Pharmacochimie mol\u00e9culaire et structurale, Centre National de la\r Recherche Scientifique, UMR 8600, 4 avenue de l\u2019Observatoire, 75270\r Paris Cedex 06, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard P.","family":"Roques","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche\r M\u00e9dicale, Unit\u00e9 36, Coll\u00e8ge de France, Chaire de\r M\u00e9decine Exp\u00e9rimentale, 3 rue d\u2019Ulm, 75005 Paris, France;\r and Institut National de la Sant\u00e9 et de la\r Recherche M\u00e9dicale, Unit\u00e9 266, D\u00e9partement de\r Pharmacochimie mol\u00e9culaire et structurale, Centre National de la\r Recherche Scientifique, UMR 8600, 4 avenue de l\u2019Observatoire, 75270\r Paris Cedex 06, 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Sant\u00e9 et de la\r Recherche M\u00e9dicale, Unit\u00e9 266, D\u00e9partement de\r Pharmacochimie mol\u00e9culaire et structurale, Centre National de la\r Recherche Scientifique, UMR 8600, 4 avenue de l\u2019Observatoire, 75270\r Paris Cedex 06, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1999,11,9]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"713","volume-title":"Hypertension: Pathophysiology, Diagnosis, and Management","author":"Oparil S","year":"1995","unstructured":"S Oparil, Y-F Chen, K H Berecek, D A Calhoun, J M Wyss Hypertension: Pathophysiology, Diagnosis, and Management, eds J H Laragh, B M Brenner (Raven, New York), pp. 713\u2013740 (1995)."},{"key":"e_1_3_3_2_2","first-page":"755","volume-title":"Hypertension: Pathophysiology, Diagnosis, and Management","author":"Esler M","year":"1995","unstructured":"M Esler Hypertension: Pathophysiology, Diagnosis, and Management, eds J H Laragh, B M Brenner 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