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The control of microvascular permeability and blood pressure by neutral endopeptidase

Nature Medicine volume 3, pages 904–907 (1997)Cite this article

Abstract

Plasma extravasation from postcapillary venules is one of the earliest steps of inflammation1. Substance P (SP) and bradykinin (BK) mediate extravasation and cause hypotension2–6. The cell-surface enzyme neutral endopeptidase (NEP) inactivates both peptides7,8. Thus, absence of NEP may predispose development of inflammation and hypotension. We examined these possibilities in mice in which the NEP gene was deleted by homologous recombination9. There was widespread basal plasma extravasation in postcapillary venular endothelia in NEP−/− mice, which was reversed by recombinant NEP and antagonists of SP (NK1) and BK (B2) receptors. Mean arterial blood pressure was 20% lower in NEP−/− animals, but this was unaffected by reintroduction of recombinant NEP and the kinin receptor antagonists. The hypotension was also independent of nitric oxide (NO), because NEP−/− mice treated with a NO synthase inhibitor remained hypotensive relative to the wild type. Thus, NEP has important roles in regulating basal microvascular permeability by degrading SP and BK, and may regulate blood pressure set point through a mechanism that is independent of SP, BK and NO. The use of NEP antagonists as candidate drugs in cardiovascular disease is suggested by the blood pressure data reported herein.

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Author notes

  1. Bao Lu and Michela Figini: These authors contributed equally to this work.

Authors and Affiliations

  1. Ina Sue Perlmutter Laboratory, Children's Hospital, Departments of Pediatrics and Medicine, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Bao Lu, Norma P. Gerard & Craig Gerard

  2. Institute of Pharmacology, University of Ferrara, 44100, Ferrara, Italy

    Michela Figini, Costanza Emanueli & Pierangelo Geppetti

  3. Department of Surgery, University of California, San Francisco, 521 Parnassus Avenue, Room C317, California, 94143, USA

    Eileen F. Grady & Nigel Bunnett

  4. Department of Dermatology, Emory University, 5311 Woodruff Memorial Building, Atlanta, Georgia, 30322, USA

    John Ansell

  5. Department of Medicine, University of California, San Francisco, 521 Parnassus Avenue, Room C317, California, 94143, USA

    Donald G. Payan

  6. Department of Physiology, University of California, San Francisco, 521 Parnassus Avenue, Room C317, California, 94143, USA

    Nigel Bunnett

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  1. Bao Lu
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  8. Donald G. Payan
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  9. Craig Gerard
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  10. Nigel Bunnett
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Lu, B., Figini, M., Emanueli, C. et al. The control of microvascular permeability and blood pressure by neutral endopeptidase. Nat Med 3, 904–907 (1997). https://doi.org/10.1038/nm0897-904

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