Neutral endopeptidase and kininase II mediate glucocorticoid inhibition of neurogenic inflammation in the rat trachea.

Abstract

Glucocorticoids inhibit plasma extravasation induced in the rat tracheal mucosa by substance P and other tachykinins released from sensory nerves. This study was performed to determine whether this antiinflammatory effect of glucocorticoids is mediated by the tachykinin-degrading enzymes neutral endopeptidase (NEP) and kininase II (angiotensin converting enzyme, ACE). In addition, we studied the effect of dexamethasone on a nonpeptide inflammatory mediator, platelet-activating factor (PAF), which is not degraded by NEP or ACE. Adult male pathogen-free F344 rats were treated for 2 d with dexamethasone (0.5 mg/kg per d i.p.), or with the vehicle used to dissolve the steroid. The magnitude of plasma extravasation produced by an intravenous injection of substance P (5 Mg/kg) or PAF (10 ,Mg/kg) was then assessed by using Monastral blue pigment as an intravascular tracer. The role of NEP and ACE activities in the changes produced by dexamethasone was investigated by examining the effect of the selective inhibitors of these enzymes, phosphoramidon and captopril. Dexamethasone reduced the substance P-induced extravasation by 57% but did not affect the PAF-induced extravasation. The suppressive effect of dexamethasone on substance P-induced extravasation was completely reversed by simultaneously inhibiting NEP and ACE activities, but the inhibition of these enzymes had no effect on PAF-induced extravasation, regardless of whether the rats were pretreated with dexamethasone or not. These results suggest that NEP and ACE mediate a selective inhibitory effect of glucocorticoids on neurogenic plasma extravasation. (J.

Effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responsiveness to leukotriene D4 in normal and asthmatic subjects

“…It could be argued that therapeutic strategies of asthma could also be directed towards prevention of the release of neuropeptides and the suppression of neurogenic inflammation [21]. This may already be achieved by inhaled steroids [43], which have been observed to reduce the maximal degree of airway narrowing in asthma [40]. In the future, neurogenic inflammation may also be limited by neurokinin receptor antagonists or by recombinant NEP suppletion [21,30].…”

Inhaled corticosteroids: effects on the airway vasculature in bronchial asthma

“…In neurogenic inflammation, the inhibitory effects of corticosteroids are likely to be mediated by neutral endopeptidase and angiotensin-converting enzyme, since dexamethasone's action was completely reversed by inhibiting these tachykinindegrading enzymes [198]. To inhibit airway extravasation of plasma proteins, dexamethasone seems to block mast cell degranulation, and thus the release of leukotrienes B 4 and C 4 in the airways of ovalbumin-sensitised rats in response to antigen challenge [118].…”

Angiotensin converting enzyme binding sites in human heart and lung: comparison with rat tissues

“…The enzyme is widely distributed throughout the body. It has been identified in the luminal aspect of vascular endothelial cells in lung, where it plays an important role in the process of fluid extravasation in the context of the 'neurogenic inflammation' (Piedimonte et al, 1991), and in other areas, where it is implicated in vascular permeability changes (Caldwell et al, 1976). Membranebound ACE is also found in renal proximal tubules (Oshima et al, 1974;Schulz et al, 1988), in the gastrointestinal brush border (Ward et al, 1980), in brain structures (choroid plexuses, circumventricular structures) (Igic et al, 1977;Defendini et al, 1983), and in the testis and epididymis (Srittmaster & Snyder, 1984).…”