Neutral Endopeptidase Modulates Substance P-Induced Activation of Human Neutrophils

Abstract

Neutral endopeptidase (NEP; EC 3.4.24.11) is well recognized as a regulatory peptidase for substance P (SP)-induced responses in various tissues. To determine whether NEP regulates SP-induced activation of human neutrophils, we examined the effect of the NEP inhibitor phosphoramidon on SP-induced superoxide generation and chemotaxis in human blood neutrophils. SP (10^––6––10^––4M) induced superoxide generation and chemotaxis in the neutrophils dose dependently. The NEP inhibitor enhanced the SP-induced responses. Thus, phosphoramidon (10^––6M) shifted the dose-response curves of SP-induced superoxide generation and chemotaxis of the neutrophils to the left by 0.5–0.6 log. Phosphoramidon prevented the hydrolysis of SP by the neutrophils, the NEP activity of the neutrophils being assessed as 125 ± 13 pmol of SP/min/10⁶ cells. The N-terminal peptide SP_1–9 (up to 3 × 10^––⁴M), which was a major degrading product by NEP of the neutrophils, did not activate the neutrophils. We conclude that NEP modulates SP-induced activation of human neutrophils.

Time‐dependent blockade of neurogenic plasma extravasation in dura mater by 5‐HT1B/D agonists and endopeptidase 24.11

“…The present paper is the first to our knowledge to show that admininstered endopeptidase 24.11 can block the development of neurogenic plasma protein extravasation. The ability of endopeptidase 24.11 to block neurogenic plasma protein extravasation was anticipated based on previous reports showing that peptidase inhibitors potentiate NI in other models (Sekizawa et al, 1987a,b;Iwamoto et al, 1990), and that the tachykinins mediate the plasma protein extravasation response in dura mater. In previous reports, inhibitors of neutral endopeptidase selectively potentiated substance P-induced effects on airway submucosal gland secretion (Borson et al, 1987), vascular permeability in skin (Iwamoto et al, 1989), smooth muscle contraction (Sekizawa et al, 1987a,b), and potentiated NI in the rat trachea induced by capsaicin or electrical stimulation (Umeno et al, 1989).…”