Disease relevance of MME

• These data suggest that tachykinins released from C-fibers upon acute or repeated exposures to high or low concentrations of TDI, respectively, play an essential role in the observed bronchial hyperreactivity, and that the inhibition of NEP by TDI cannot completely account for the observed airway hyperreactivity [1].
• Experiments were performed to study the effects of 30 min pre-treatment with the NEP-inhibitor, thiorphan (10 microM), both at physiological and at low pO(2)s. Hypoxia inhibited the bradykinin-induced relaxation in porcine epicardial coronary arteries [2].

High impact information on MME

• These data indicate that inflamed lungs are more sensitive to the contractile effects of SP because it is less efficiently degraded by NEP and are less sensitive to the relaxant effects of VIP because it is more efficiently degraded by a tryptic enzyme [3].
• In contrast to effluent from saline-exposed animals, lung effluent from antigen-exposed lungs contained less intact VIP, increased amounts of a tryptic hydrolysis product, and no products consistent with the degradation of VIP by NEP [3].
• The efficacy of S (a specific inhibitor of neutral endopeptidase [NEP]) and A and T (serine protease inhibitors) thus implicated NEP and at least one serine protease as primary modulators of VIP activity in the guinea pig lung [4].
• After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon [5].
• The mild chemical oxidant N-chlorosuccinimide mimicked the concentration-dependent inhibitory effect of smoke solution on airway NEP activity [5].

Chemical compound and disease context of MME

• The role of tachykinins in toluene diisocyanate (TDI)-induced non-specific bronchial hyperreactivity (NSBH) in guinea pigs was investigated, and it was determined whether or not the activity of airway neutral endopeptidase (NEP) was inhibited in conditions where a bronchial hyperreactivity to acetylcholine (ACh) was observed [1].

Biological context of MME

• METHODS: The effect of candoxatril, a selective inhibitor of neutral endopeptidase (NEP) 24.11, on GLP-1 pharmacokinetics/pharmacodynamics with or without DPP-IV inhibition was examined in anaesthetised pigs [6].
• Pulse-chase and selective biotinylation studies revealed that the majority (85%) of newly made NEP was directly targeted to the apical membrane [7].
• These results suggest that 1) endogenous tachykinin-like substances are released in allergic airway response and that 2) when endogenous NEP is inhibited in the guinea pig airways in vivo, the substances contribute to bronchoconstriction by partly activating the parasympathetic nerve [8].
• From these results we conclude that 1) PGF2 alpha causes the release of tachykinin-like substances, 2) these substances play a role in bronchial contraction in tissues where NEP activity is inhibited, and 3) nerve conduction is not necessary for the release of these substances in the guinea pig bronchus [9].
• Inhalation of an aerosolized NEP preparation, partially purified from guinea pig kidney, reversed the substance P hyperreactivity produced by ozone exposure.(ABSTRACT TRUNCATED AT 250 WORDS)[10]

Anatomical context of MME

• The purified enzymes had more stable activity when incorporated into suspensions of phospholipid derived from rat liver microsomes than when used alone, so this preparation was used for long-term incubation with HEOD and MME [11].
• Tracheal NEP activity was significantly less after exposure to TDI than after exposure to air, whereas activity in the esophagus was the same in both groups [12].
• However, a soluble form of NEP was found to be secreted in approximately equal amounts from both sides of the monolayer when expressed in LLC-PK1 cells [7].
• Daudi cells, some leukaemic cells shown to be CALLA-positive, and Caco-2 cells, could also be assayed, but N2 cavitation was necessary to fragment the cells, and only part of the total endopeptidase-24.11 activity in Daudi cells was recognized by the e.l.i.s.a [13].
• This observation suggests that Neuro2A cells possess a mechanism for targeting NEP to specific domains of the plasma membrane [14].

Associations of MME with chemical compounds

• Therefore, the influence of candoxatril, a selective NEP inhibitor, on plasma levels of endogenous and exogenous glucagon was examined in anesthetized pigs [15].
• We conclude that cigarette smoke causes enhanced airway responsiveness to substance P in vivo by inactivating airway NEP [5].
• We conclude that there is significant degradation of both SP and NKA after tracheal infusion of peptides by NEP-like but not by ACE activity; this effect significantly influences the physiological effects of these peptides [16].
• Cigarette smoke solution inhibited NEP activity from tracheal homogenate in a concentration-dependent fashion, an inhibitory effect that was mostly due to the gas phase of the smoke, but not to nicotine [5].
• Airway plasma extravasation also was studied in the presence of the NEP inhibitor in guinea pigs pretreated with capsaicin or bilateral vagotomy [17].

Analytical, diagnostic and therapeutic context of MME

• HPLC analysis of [3H]Pro2,4-SP and 125I-Histidyl1-NKA perfused through the airways showed major cleavage products consistent with NEP action [16].
• Labelling of the cell surface with an antibody coupled to colloidal gold particles and examination of the cells by electron microscopy revealed a non-uniform distribution of NEP at the surface of the cells, the protein being preferentially associated with the membrane of neurites compared with the cell body [14].
• Furthermore, carbocysteine dose dependently repaired the antigen-induced decrease of NEP activity in the tracheal tissue, but it did not influence the bronchial hyperresponsiveness or bronchoalveolar lavage cell component [18].
• We studied the effects of the neutral endopeptidase (NEP) inhibitor thiorphan (1.7 mg/kg iv) and the angiotensin-converting enzyme (ACE) inhibitor captopril (5.7 mg/kg iv) on airway responses to rapid intravenous infusions of neurokinin A (NKA) and neurokinin B (NKB) in anesthetized, mechanically ventilated guinea pigs [19].
• Thirty minutes after exsanguination in the control groups, airway NEP activity decreased significantly in all age categories, while lung tissue substance P level increased significantly only in the immature category [20].

References