Evidence for an angiotensin-(1–7) neuropeptidase expressed in the brain medulla and CSF of sheep

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Angiotensin-(1–7) [Ang-(1–7)] is an alternative product of the brain renin-angiotensin system that exhibits central actions to lower blood pressure and improve baroreflex sensitivity. We previously identified a peptidase that metabolizes Ang-(1–7) to the inactive metabolite product Ang-(1–4) in CSF of adult sheep. This study purified the peptidase 1445-fold from sheep brain medulla and characterized this activity. The peptidase was sensitive to the chelating agents o-phenanthroline and EDTA, as well as the mercury compound p-chloromercuribenzoic acid (PCMB). Selective inhibitors to angiotensin-converting enzyme, neprilysin, neurolysin, and thimet oligopeptidase did not attenuate activity; however, the metallopeptidase agent JMV-390 was a potent inhibitor of Ang-(1–7) hydrolysis (Ki = 0.8 nM). Kinetic studies using 125I-labeled Ang-(1–7), Ang II, and Ang I revealed comparable apparent Km values (2.6, 2.8, and 4.3 μM, respectively), but a higher apparent Vmax for Ang-(1–7) (72 vs. 30 and 6 nmol/min/mg, respectively; p < 0.01). HPLC analysis of the activity confirmed the processing of unlabeled Ang-(1–7) to Ang-(1–4) by the peptidase, but revealed < 5% hydrolysis of Ang II or Ang I, and no hydrolysis of neurotensin, bradykinin or apelin-13. The unique characteristics of the purified neuropeptidase may portend a novel pathway to influence actions of Ang-(1–7) within the brain.

Angiotensin-(1–7) actions are mediated by the AT7/Mas receptor and include reduced blood pressure, decreased oxidative stress, enhanced baroreflex sensitivity, and increased nitric oxide (NO). Ang-(1–7) is directly formed from Ang I by neprilysin (NEP). We identify a new pathway for Ang-(1–7) metabolism in the brain distinct from angiotensin-converting enzyme-dependent hydrolysis. The Ang-(1–7) endopeptidase (A7-EP) degrades the peptide to Ang-(1–4) and may influence central Ang-(1–7) tone.

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