Lu B, Figini M, Emanueli C, Geppetti P, Grady E F, Gerard N P, Ansell J, Payan D G, Gerard C, Bunnett N
Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nat Med. 1997 Aug;3(8):904-7. doi: 10.1038/nm0897-904.
Plasma extravasation from postcapillary venules is one of the earliest steps of inflammation. Substance P (SP) and bradykinin (BK) mediate extravasation and cause hypotension. The cell-surface enzyme neutral endopeptidase (NEP) inactivates both peptides. 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 recombination. 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.
毛细血管后微静脉的血浆外渗是炎症最早出现的步骤之一。P物质（SP）和缓激肽（BK）介导外渗并导致低血压。细胞表面酶中性内肽酶（NEP）可使这两种肽失活。因此，缺乏NEP可能易引发炎症和低血压。我们在通过同源重组缺失NEP基因的小鼠中研究了这些可能性。NEP基因敲除小鼠的毛细血管后微静脉内皮存在广泛的基础血浆外渗，重组NEP以及SP（NK1）和BK（B2）受体拮抗剂可使其逆转。NEP基因敲除动物的平均动脉血压低20%，但重新引入重组NEP和激肽受体拮抗剂对此并无影响。低血压也与一氧化氮（NO）无关，因为用NO合酶抑制剂处理的NEP基因敲除小鼠相对于野生型仍处于低血压状态。因此，NEP通过降解SP和BK在调节基础微血管通透性方面具有重要作用，并且可能通过一种独立于SP、BK和NO的机制调节血压设定点。本文报道的血压数据提示可将NEP拮抗剂用作心血管疾病的候选药物。
