Effect of an inhaled neutral endopeptidase inhibitor, phosphoramidon, on baseline airway calibre and bronchial responsiveness to bradykinin in asthma.

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Part of the contractile response of adenosine in the asthmatic airways may be due to the activation of peptidergic pathways with subsequent local release of spasmogenic neuropeptides. At present, little is known about the potential role of lung peptidases in modulating adenosine-induced airway dysfunction in humans in vivo. We have, therefore, investigated the change in bronchial reactivity to adenosine 5'-monophosphate (AMP), after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double-blind, placebo-controlled, randomized study of 12 asthmatic subjects.Subjects attended on six separate occasions, during which concentration response studies with inhaled AMP and methacholine were carried out, initially in the absence of treatment and then after nebulized phosphoramidon sodium salt (10 -5 M) or matched placebo 5 min prior to a bronchoprovocation test with AMP or methacholine. Agonist responsiveness was expressed as the provocative concentration of AMP or methacholine producing a 20% fall in FEV1 from baseline (PC20,AMP or PC20,meth, respectively).When compared to placebo, phosphoramidon failed to potentiate the airway response to AMP. The geometric mean (range) PC20 AMP value of 23.4 (4.4-190.6) mg·mL -1 after placebo was not significantly different from that of 20.7 (4.5-100.9) mg·mL -1 obtained after phosphoramidon.The lack of change in bronchial reactivity to adenosine 5'-monophosphate after phosphoramidon indicates that endogenous airway neutral endopeptidase may not be of physiological importance in modulating the contractile response of adenosine in the airways. Thus, the present data do not support the view that activation of peptidergic pathways with subsequent local release of spasmogenic neuropeptides is important in the airway response to adenosine

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 52%

mentioning

confidence: 99%

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Neutral endopeptidase inhibition with inhaled phosphoramidon: no effect on bronchial responsiveness to adenosine 5'-monophosphate (AMP) in asthma

Polosa

Santonocito²,

Magrì³

et al. 1997

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“…It has also been reported that the inhibition of NEP caused by aerosolized phosphoramidon is accompanied by a significant increase in airway smooth muscle tone in asthmatic subjects; thus, suggesting that tachykinins and NEP may participate in the regulation of resting airway calibre [46]. However, these observations conflict with previous results obtained using a similar experimental approach [38].…”

Section: Effect Of Nep Inhibition On Airway Responses To Tachykinins contrasting

confidence: 57%

Regulation of airway neurogenic inflammation by neutral endopeptidase

Maria¹,

Bellofiore²,

Geppetti³

1998

Airway neurogenic inflammation is caused by tachykinins released from peripheral nerve endings of sensory neurons within the airways, and is characterized by plasma protein extravasation, airway smooth muscle contraction and increased secretion of mucus. Tachykinins are degraded and inactivated by neutral endopeptidase (NEP), a membrane-bound metallopeptidase, which is located mainly at the surface of airway epithelial cells, but is also present in airway smooth muscle cells, submucosal gland cells and fibroblasts. The key role of NEP in limiting and regulating the neurogenic inflammation provoked by different stimuli has been demonstrated in a large series of studies published in recent years. It has also been shown that a variety of factors, which are relevant for airway diseases, including viral infections, allergen exposure, inhalation of cigarette smoke and other respiratory irritants, is able to reduce NEP activity, thus enhancing the effects of tachykinins within the airways. On the basis of these observations, the reduction of neutral endopeptidase activity may be regarded as a factor that switches neurogenic airway responses from their physiological and protective functions to a detrimental role that increases and perpetuates airway inflammation. However, further studies are needed to assess the role of neutral endopeptidase down regulation in the pathogenesis of asthma and other inflammatory airway diseases.

“…The constrictor effect of bradykinin is attenuated by the release of epithelial-derived prostaglandin E2 [29] and by its degradation by two major bronchial peptidases, neutral endopeptidase (NEP) and kininase II [15]. With damage of the epithelium and the resulting loss of these epithelial-bound peptidases, a selective increase in bradykinin airway responsiveness would be expected, because methacholine is not a substrate for these enzymes [30,31]. Moreover, damage to the epithelium might also enhance sensory nerve stimulation to the action of bradykinin, resulting in the release of spasmogenic neuropeptides by way of an axon reflex [15].…”

Section: Discussionmentioning

confidence: 99%

Sputum eosinophilia is more closely associated with airway responsiveness to bradykinin than methacholine in asthma

Polosa¹,

Renaud²,

Cacciola³

et al. 1998

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Hyperresponsiveness of the airways to various spasmogenic stimuli is a characteristic feature of bronchial asthma. However, the association between the different stimuli to which asthmatic airways are hyperresponsive and airways inflammation is not completely understood. We have investigated the relationship between airway inflammation and airway hyperresponsiveness in asthma, as assessed by bronchoprovocation tests to methacholine and bradykinin, two well defined bronchoconstrictor agonists. Sputum induction by hypertonic saline and methacholine and bradykinin challenges were performed in 14 nonsmoking subjects with mild-to-moderate asthma. Airway responsiveness to either agonist did not correlate with sputum neutrophils, lymphocytes, and macrophages. Whilst the absolute number of eosinophilia failed to be significantly related to methacholine responsiveness (r=-0.47; p=0.09), it correlated markedly and significantly with provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (r=0.72; p<0.01). When expressed as % of total cell counts, sputum eosinophils correlated with both types of responsiveness (r=-056; p=0.04 and r=-0.76, p<0.001, respectively). Although the concentration of eosinophil cationic protein (ECP) in the sputum correlated with the absolute numbers of eosinophils (r=0.62; p<0.02), no correlation was found between ECP levels and the airway responsiveness to any of the agonists tested. In subjects with mild-to-moderate asthma, airway responsiveness to bradykinin is more strongly associated with the magnitude of eosinophilic inflammation in the airways than methacholine. This finding underlines the selectivity of diverse agonists in assessing airway hyperresponsiveness and cellular inflammation in asthma.