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This Article Full Text Full Text (PDF) All Versions of this Article: 93/5/665    most recent expphysiol.2007.040311v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Elased, K. M. Articles by Morris, M. PubMed PubMed Citation Articles by Elased, K. M. Articles by Morris, M. Related Collections Themed Issue papers Autonomic Neuroscience

¹ Wright State University, Boonshoft School of Medicine, 3640 Colonel Glenn Highway, Dayton, OH 45435, USA ²State University of Campinas, Faculty of Dentistry of Piracicaba, Piracicaba, SP, Brazil

Angiotensin (Ang)-converting enzyme 2 (ACE2) metabolizes Ang II to the vasodilatory peptide Ang(1–7), while neprilysin (NEP) generates Ang(1–7) from Ang I. Experiments used novel Surface Enhanced Laser Desorption Ionization-Time of Flight (SELDI-TOF) mass spectroscopic (MS) assays to study Ang processing. Mass spectroscopy was used to measure proteolytic conversion of Ang peptide substrates to their specific peptide products. We compared ACE/ACE2 activity in plasma, brain and kidney from C57BL/6 and NEP^–/– mice. Plasma or tissue extracts were incubated with Ang I or Ang II (1296 or 1045, m/z, respectively), and generated peptides were monitored with MS. Angiotensin-converting enzyme 2 activity was detected in kidney and brain, but not in plasma. Brain ACE2 activity was highest in hypothalamus. Angiotensin-converting enzyme 2 activity was inhibited by the specific ACE2 inhibitor, DX600 (10 µM, 99% inhibition), but not by the ACE inhibitor, captopril (10 µM). Both MS and colorimetric assays showed high ACE activity in plasma and kidney with low levels in brain. To extend these findings, ACE measurements were made in ACE overexpressing mice. Angiotensin-converting enzyme four-copy mice showed higher ACE activity in kidney and plasma with low levels in hypothalamus. In hypothalamus from NEP^–/– mice, generation of Ang(1–7) from Ang I was decreased, suggesting a role for NEP in Ang metabolism. With Ang II as substrate, there was no difference between NEP^–/– and wild-type control mice, indicating that other enzymes may contribute to generation of Ang(1–7). The data suggest a predominant role of hypothalamic ACE2 in the processing of Ang II, in contrast to ACE, which is most active in plasma.

(Received 6 December 2007; accepted after revision 7 February 2008; first published online 8 February 2008)
Corresponding author: M. Morris: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH 45435, USA. Email: mariana.morris{at}wright.edu

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