Inhibition of neutral endopeptidase potentiates neurogenic inflammation in the rat trachea

Abstract

The present study was performed to determine whether neurogenic inflammation in the rat trachea can be exaggerated by inhibiting neutral endopeptidase, an enzyme that degrades tachykinins that are believed to mediate neurogenic inflammation. Neurogenic inflammation was produced by antidromic electrical stimulation of one vagus nerve (2.5 Hz, 1 ms, 5 V for 5 min) in the presence of atropine or by an intravenous injection of capsaicin (100 micrograms/kg). Neutrophils that adhered to the endothelium of venules were visualized and counted in tracheal whole mounts that were stained by a histochemical reaction for myeloperoxidase. Neural inflammation increased the number of adherent neutrophils. Pretreatment with the neutral endopeptidase inhibitor phosphoramidon (1.0 or 2.5 mg/kg iv) increased neutrophil adhesion induced by neural inflammation. As assessed by the amount of extravasation of Monastral blue pigment, neural inflammation also increased vascular permeability, and this change was potentiated by phosphoramidon. These results are consistent with the concept that neuropeptides released from sensory nerves in the tracheal mucosa cause neutrophils to adhere to venules and increase vascular permeability and that these effects are modulated by neutral endopeptidase.

Differential effects of phosphoramidon on neurokinin A‐ and substance P‐induced airflow obstruction and airway microvascular leakage in guinea‐pig

“…Thus, the bronchoconstrictor response to inhaled SP is shifted close to two log units to the left when NEP24.11 is inhibited (Lotvall et al, 1990b), and the bronchoconstrictor response to endogenous tachykinins, released by electrical vagal stimulation, is potentiated in the presence of an NEP24.11-inhibitor (Dusser et al, 1988). It has also been shown that airway microvascular leakage induced by endogenous tachykinins, is potentiated in rats pretreated with inhibitors of NEP24.11 (Umeno et al, 1989). This study was performed to evaluate the importance of NEP24.11 in the regulation of airway narrowing and airway microvascular leakage induced by inhaled NKA, because both substance P and NKA can be released by airway sensory nerves (Saria et al, 1988).…”

“…Recent work has shown that NEP24.11 is important in regu-lating in vivo responses to both exogenous and endogenous tachykinins (Thompson et al, 1988;Shore et al, 1988;Dusser et al, 1988;Umeno et al, 1989;Lotvall et al, 1990b;Martins et al, 1990). Thus, the bronchoconstrictor response to inhaled SP is shifted close to two log units to the left when NEP24.11 is inhibited (Lotvall et al, 1990b), and the bronchoconstrictor response to endogenous tachykinins, released by electrical vagal stimulation, is potentiated in the presence of an NEP24.11-inhibitor (Dusser et al, 1988).…”

Neutral Endopeptidase Terminates Substance P-Induced Inflammation in Allergic Contact Dermatitis

“…NEP is expressed in several tissues including the kidney, small intestine, brain, airway epithelium, vascular endothelium, and skin (8). The administration of NEP inhibitors augments inflammation of the trachea (10,11). NEP expression is markedly down-regulated during intestinal and respiratory infections, which may contribute to the tissue inflammation response in these diseases (12,13).…”

Enzymatic Modulation of Bronchoconstriction, Gland Secretion, Plasma Extravasation and Cough.

“…Neurogenic plasma extravasation in response to electrical nerve stimulation or to capsaicin is potentiated by NEP inhibitors (Umeno et al 1990;Piedimonte et al 1990a, b). Neutrophil adhesion to postcapillary venular endothelium induced by electrical nerve stimulation or by capsaicin is also potentiated by phosphoramidon (Umeno et al 1989). Although substance P caused prolonged neutrophil adhesion, significant chemotaxis occurred only after treatment with phosphoramidon (Umeno et al 1990), suggesting that substance P is weakly chemotactic for neutrophils.…”

“…Substance P has potent inflammatory effects, including increased vascular permeability (Lundberg et al 1983b;McDonald et al 1988), neutrophil adhesion (Umeno et al 1989), vasodilation (Pernow 1985) and exocytosis in some mast cells (Piotrowski and Foreman 1985). In addition, substance P has potent effects on submucosal gland secretion , ion transport (Al-Bazzaz et al 1985), smooth muscle contraction (Lundberg et al 1983a), cholinergic neurotransmission (Tanaka and Grunstein 1984) and cough (Kohrogi et al 1988; Uj iie et al 1993).…”