Heart Failure Reviews

, Volume 13, Issue 3, pp 299–309 | Cite as

The significance of brain aminopeptidases in the regulation of the actions of angiotensin peptides in the brain



From the outset, the concept of a brain renin-angiotensin system (RAS) has been controversial and this controversy continues to this day. In addition to the unresolved questions as to the means by which, and location(s) where brain Ang II is synthesized, and the uncertainties regarding the functionality of the different subtypes of Ang II receptors in the brain, a new controversy has arisen with respect to the identity of the angiotensin peptide(s) that activate brain AT1 receptors. While it has been known for some time that Ang III can activate Ang II receptors with equivalent or near-equivalent efficacy to Ang II, it has been proposed that in the brain, only Ang III is active. This proposal, which we have named “The Angiotensin III Hypothesis” states that Ang II must be converted to Ang III in order to activate brain AT1 receptors. This review examines several aspects of the controversies regarding the brain RAS with a special focus on brain aminopeptidases, studies that either support or refute The Angiotensin III Hypothesis, and the implications of The Angiotensin III Hypothesis for the activity of the brain RAS. It also addresses the need for further research that can test The Angiotensin III Hypothesis and definitively identify the angiotensin peptide(s) that activate brain AT1 receptor-mediated effects.


Angiotensin II Angiotensin III AT1 receptor Brain renin-angiotensin system 



The authors thank Erick Bourassa for the preparation of figure 2. In preparing this manuscript the authors frequently visited the web site of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) http://www.chem.qmul.ac.uk/iubmb/enzyme/ and the web site of MEROPS peptidase database http://www.merops.sanger.ac.uk/ for background information [111]. Vardan T. Karamyan is supported by the Peptide Radioiodination Service Center of the School of Pharmacy of the University of Mississippi and by NIH Division of Research Resources grant (RR-0212929).


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© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Pharmacology and Research Institute of Pharmaceutical SciencesSchool of Pharmacy, University of MississippiMississippiUSA

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