Aminopeptidase A inhibitors as potential central antihypertensive agents

Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental models, such as spontaneously hypertensive rats and transgenic mice expressing both human renin and human angiotensinogen transgenes. We recently reported that, in the murine brain, angiotensin II (AngII) is converted to angiotensin III (AngIII) by aminopeptidase A (APA), whereas AngIII is inactivated by aminopeptidase N (APN). If injected into cerebral ventricles (ICV), AngII and AngIII cause similar pressor responses. Because AngII is metabolized in vivo into AngIII, the exact nature of the active peptide is not precisely determined. Here we report that, in rats, ICV injection of the selective APA inhibitor EC33 [(S)-3-amino-4-mercaptobutyl sulfonic acid] blocked the pressor response of exogenous AngII, suggesting that the conversion of AngII to AngIII is required to increase blood pressure (BP). Furthermore, ICV injection, but not i.v. injection, of EC33 alone caused a dose-dependent decrease in BP by blocking the formation of brain but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol), administered alone via the ICV route, increases BP. This pressor response was blocked by prior treatment with the angiotensin type 1 (AT1) receptor antagonist, losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in BP increase, through interaction with AT1 receptors. These data demonstrate that AngIII is a major effector peptide of the brain RAS, exerting tonic stimulatory control over BP. Thus, APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors as central antihypertensive agents.

Paris, France, 1589-1643 (Time Series Map 7 of 8) (Raster Image)

This layer is a georeferenced raster image from the historic paper map series entitled: Lutece ... plan de la ville de Paris ..., par M.L.C.D.L.M. ; A. Coquart, delineavit et sculp. It was published by Jean & Pierre Cot in 1705. Scale [ca. 1:10,000]. This image is of map 7 entitled: Septiême plan de la ville de Paris son acroissement [sic] et ses embelissemens sous Henry III. et Louis XIII. depuis 1589 jusqu'en 1643: tiré des lettres patentes ou arrest du conseil qui ont ordonné les ouvrages des devis et marchez faits avec les entrepreneurs et levé sur les lieux ou ils ont été construits, et ou la plus grand partie subsistent encore. The map represents Paris, 1589 to 1643. Map in French.The image inside the map neatline is georeferenced to the surface of the earth and fit to the European Datum 1950, Universal Transverse Mercator (UTM) Zone 31N projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as drainage, towns and villages, roads, built-up areas and selected buildings, fortification, ground cover, and more. Relief shown by hachures. Includes index, text, and notes.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.