THE CONTROL OF MICROVASCULAR PERMEABILITY AND BLOOD-PRESSURE BY NEUTRAL ENDOPEPTIDASE

Plasma extravasation from postcapillary venules is one of the earliest steps of inflammation(1). Substance P (SP) and bradykinin (BK) mediat e extravasation and cause hypotension(2-6). The cell-surface enzyme ne utral endopeptidase (NEP) inactivates both peptides(7,8). Thus, absenc e of NEP may predispose development of inflammation and hypotension. W e examined these possibilities in mice in which the NEP gene was delet ed by homologous recombination(9). There was widespread basal plasma e xtravasation in postcapillary venular endothelia in NEP-/- mice, which was reversed by recombinant NEP and antagonists of SP (NK1) and BK (B 2) receptors. Mean arterial blood pressure was 20% lower in NEP-/- ani mals, 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 i nhibitor remained hypotensive relative to the wild type. Thus, NEP has important roles in regulating basal microvascular permeability by deg rading 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 antagon ists as candidate drugs in cardiovascular disease is suggested by the blood pressure data reported herein.