Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the presence of the neutral metalloendopeptidase inhibitor, phosphoramidon, substance P (SP) is a highly potent spasmogen for isolated lung parenchymal strips as well as tracheal rings from the guinea pig. We studied the mechanism of action of this peptide, and of the related tachykinin, substance K (SK), on both tissue preparations. The cyclooxygenase inhibitors, indomethacin (1 microM) or aspirin (100 microM), in combination with phosphoramidon (1 microM) effectively block SP-induced contractions in lung parenchymal strips. The lipoxygenase inhibitor, nordihydroguaiaretic acid (10 microM), the H1 antihistamine, pyrilamine (1 microM) and the anticholinergic agent, atropine (1 microM), all had no significant effect on SP-induced contractions. No detectable levels of thromboxane B2, or prostaglandins D2, E2, F2 alpha, or 6-keto-F1 alpha were released into the tissue bathing fluid. These data suggest that the contractile response of guinea pig lung parenchymal strips is mediated by cyclooxygenase metabolites, which are not released in significant concentration from the cells. In the presence of phosphoramidon, SK has a concentration-response curve similar to SP on guinea pig lung parenchymal strips. Its contractile activity is also inhibited by indomethacin but less effectively than SP. In marked contrast, the contractile responses of guinea pig tracheal tissues to the tachykinins were not affected significantly by indomethacin, alone or in combination with phosphoramidon. Additionally, tracheal tissue is 20- to 100-fold more sensitive to SK than SP in the presence or absence, respectively, of the endopeptidase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of substance P contractile activity on isolated guinea pig lung tissues. 244 71

Ferret tracheal segments were infected with human influenza virus A/Taiwan/86 (H1N1) in vitro. After 4 days, the smooth muscle contractile responses to acetylcholine and to substance P were measured. The response to substance P was markedly accentuated, with a threefold increase in force of contraction at a substance P concentration of 10(-5) M, the highest concentration tested. In contrast, the response to acetylcholine was not affected by viral infection. Histological examination of tissues revealed extensive epithelial desquamation. Activity of enkephalinase (neutral metallo-endopeptidase, EC.3.4.24.11), an enzyme that degrades substance P, was decreased by 50% in infected tissues. Inhibiting enkephalinase activity by pretreating with thiorphan (10(-5) M) increased the response to substance P to the same final level in both infected and control tissues. Inhibiting other substance P-degrading enzymes including kininase II (angiotensin-converting enzyme), serine proteases, and aminopeptidases did not affect the response to substance P. Inhibiting cyclooxygenase and lipoxygenase activity using indomethacin and BW 755c did not affect hyperresponsiveness to substance P. Pretreating tissues with antagonists of alpha-adrenoceptors, beta-adrenoceptors, and H1 histamine receptors (phentolamine 10(-5) M, propranolol 5 X 10(-6) M, and pyrilamine 10(-5) M, respectively) had no effect on substance P-induced contraction. These results demonstrate that infection of ferret airway tissues with influenza virus increases the contractile response of airway smooth muscle to substance P. This effect is caused by decreased enkephalinase activity in infected tissues.
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PMID:Influenza infection causes airway hyperresponsiveness by decreasing enkephalinase. 304 36

The contractile response of guinea-pig tracheal preparations with or without epithelium to substance P has been studied in the presence or absence of thiorphan, an endopeptidase 24.11 inhibitor, paying special attention to the kinetics of the response. Without thiorphan, the response to substance P was greater in tracheal preparations without epithelium than in tracheal preparations with epithelium. The concentration-response curve was shifted to the left in the absence of the epithelium. In the presence of 10 microM thiorphan, the maximal contractile response induced by single doses of substance P (0.1 to 10 microM) was lower in tracheal preparations without epithelium. The maximal responses required 10 min in tracheal preparations with epithelium and 2 min in tracheal preparations without epithelium. These epithelium-dependent differences of reactivity remained in the presence of lipoxygenase or cyclooxygenase inhibitors and of selective antagonists of muscarinic, serotoninergic and histaminergic receptors, after the pre-treatment of tissues with capsaicin or compound 48/80 and in the presence of tetrodotoxin. The profile of the cumulative concentration-response curves for substance P was largely dependent on the time between two successive doses. When this time was short (2-4 min), curves established with or without the epithelium were parallel and both reached similar maximal values (2696 +/- 214 mg and 2780 +/- 62 mg, respectively). The curve in tracheal preparations without epithelium was slightly shifted to the left (EC50s: 24 +/- 10 nM and 78 +/- 19 nM). When this time was longer (10 min, ie corresponding to the time required for a full response to a single dose in intact trachea) the potency of substance P was not modified (EC50s: 13 +/- 3 nM and 52 +/- 11 nM), but a lower maximal response was observed with tracheal preparations without epithelium (1440 +/- 182 mg and 2832 +/- 209 mg). Similar results were observed with neurokinin A and neurokinin B. Thus, the removal of the epithelium led to a more rapid contraction and to a decrease of the maximal response to neurokinins, ie a decreased intrinsic activity, a property known to be drug- and tissue-dependent. These data suggest that the intrinsic activity of drugs depends on the cellular environment of the target cells in a tissue and is partly related to the diffusion and metabolism of drugs and to drug-induced hyporeactivity of the target cells.
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PMID:Epithelium modulates the kinetics of the response to substance P and its intrinsic activity in the guinea-pig trachea. 752 61

The i.v. administration of substance P (SP, 0.25-16 micrograms/kg) or of the selective metabolic stable NK-1 agonist, [Glp6,Pro9]SP-(6-11) (septide, 0.03-0.25 microgram) to atropine-treated guinea pigs or to isolated perfused lungs triggered a dose-dependent bronchoconstriction, which was enhanced in animals actively sensitized to ovalbumin. In vivo, bronchial hyper-responsiveness was restricted to SP and to septide, inasmuch as neurokinin A (0.06-1 microgram/kg)- or capsaicin (0.5-32 micrograms/kg)-induced bronchoconstriction were not modified. In contrast, isolated lungs from sensitized guinea pigs exhibited an increased bronchoconstriction also in response to capsaicin (0.01-10 micrograms), which was inhibited by atropine in the medium. Pretreatment of actively sensitized guinea pigs either with indomethacin plus mepyramine, the lipoxygenase inhibitor BW A4C or with the platelet-activating factor antagonist SR 27417, did not modify bronchial hyper-reactivity to SP. Captopril (5 mg/kg i.v.), but not thiorphan (0.8 mg/kg i.v.), increased the SP-induced bronchoconstriction in actively sensitized animals, whereas both inhibitors were equally effective in nonsensitized guinea pigs. Thiorphan, however, did not modify the in vivo response to septide. Our results demonstrate that guinea pigs sensitized to ovalbumin exhibit bronchial hyperreactivity to SP, but not to neurokinin A, as compared to nonsensitized animals, suggesting a decrease in the neutral endopeptidase activity in the airways brought by the immunization. However, the results obtained by using septide indicate that other mechanisms may be involved in the bronchial hyper-reactivity to SP.
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PMID:Effect of active sensitization on the bronchopulmonary responses to tachykinins in the guinea pig. Modulation by peptidase inhibitors. 835 11

The released neutrophil chemotactic activity (NCA) from bronchial epithelial cells (BECs) in response to smoke extract was evaluated by reverse-phase, high-performance liquid chromatography (RP-HPLC) and the involvement of proteolytic activity was assessed for the release of NCA from BECs. Smoke extract stimulated the release of NCA (55.3 +/- 5.2 vs. 17.3 +/- 4.1 cells per high-power field [HPF], p < .001). The released activity determined by RP-HPLC analysis was 15-hydroxyeicosatetraenoic acid and leukotriene B4. Several structurally and functionally different serine protease inhibitors, including alpha-1-protease inhibitor (alpha-1-PI), chloromethyl ketone (CK) derivatives, N-tosyl-L-lysine CK (TLCK), methoxysuccinyl-Ala-Ala-Pro-Val CK (SPCK), N-alpha-tosyl-L-phenylalanine CK (TPCK), and N-alpha-p-tosyl-L-arginine methyl ester hydrochloride (TAME), attenuated the release of NCA (P < .01) in a dose-dependent fashion. Leupeptin, a cysteine protease inhibitor, has only a small effect on the release of NCA (p < .05), and phosphoramidon, a neutral endopeptidase inhibitor, had no effect. The measurement of proteolytic enzyme activity using synthetic substrate S-2288 revealed that smoke extract significantly (p < .05) augmented the serine protease activity in BEC layers. Culture supernatant fluids and cell lysates of BECs in response to smoke extract solubilized 14C-labeled casein. These results suggest that BECs may release lipoxygenase-derived NCA in response to smoke extract and that the release of NCA may involve the activation of proteolytic activity of BECs which was inhibited by serine protease inhibitors.
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PMID:Antiproteases attenuate the release of neutrophil chemotactic activity from bronchial epithelial cells induced by smoke. 883 32

1. The permeability response to acutely applied bradykinin and [des-Arg9]-bradykinin on single cerebral venular capillaries has been investigated using the low molecular mass fluorescent dyes Lucifer Yellow and Sulforhodamine B with the single vessel occlusion technique. 2. When bradykinin was applied repeatedly for up to 2 h, the permeability increase was small and reversible for concentrations that ranged from 5 nM to 50 microM. 3. The logEC50 of the permeability response to bradykinin was -5.3 +/- 0.15 (logM; mean +/- s.e.m.). This was reduced to -6.37 +/- 0.24 with the angiotensin-converting enzyme inhibitor captopril, to -6.33 +/- 0.19 with the neutral endopeptidase inhibitor phosphoramidon and to -7.3 +/- 0.20 with captopril and phosphoramidon combined. 4. The permeability response to bradykinin was blocked by the bradykinin B2 receptor antagonist HOE 140, by inhibition of the Ca2+-independent phospholipase A2, by the scavenging of free radicals, or by inhibition of both cyclo-oxygenase and lipoxygenase in combination. Block of Ca2+ entry channels with SKF 96365 had no effect on the response. 5. Application of [des-Arg9]-bradykinin also increased permeability over the concentration range 5 nM to 50 microM, with a logEC50 of -5.6 +/- 0. 37. This response was not affected by free radical scavenging, but was completely blocked by the histamine H2 receptor blocker cimetidine. 6. These results imply that the acute permeability response to bradykinin is mediated via the release of arachidonic acid, which is acted on by cyclo-oxygenase and lipoxygenase resulting in the formation of free radicals, and that the response to [des-Arg9]-bradykinin is mediated via histamine.
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PMID:Acute effects of bradykinin on cerebral microvascular permeability in the anaesthetized rat. 1101 16

The responses to adenosine were studied on isolated, methacholine-precontracted tracheal strips of guinea pigs in the course of long-term caffeine or solvent treatment. Guinea pigs were fed caffeine for 10 weeks (average serum caffeine concentration: 39.1 +/- 3.9 microM). In epithelium-intact tracheal preparations (EITPs), sensititization to adenosine-induced relaxation (AIR) developed. It attained a maximum in week 1 of caffeine treatment, and then its level diminished and disappeared completely by weeks 4 - 6. In epithelium-denuded tracheal preparations (EDTPs), an increase in the sensitivity to adenosine was observed from week 1 to week 10 (a 4 - 6-fold reduction in EC50). Use of a coaxial bioassay system confirmed the role of epithelium in this process. The enhancement of the AIR of the EITPs was not modified by inhibitors of cyclooxygenase and lipoxygenase. Following depletion of the neuropeptides by acute capsaicin pretreatment, the AIR of the EITPs was strongly enhanced after caffeine treatment for 6 weeks. In chronically caffeine-treated EITPs, the inhibition of neutral endopeptidase led to dramatic reduction of the AIR. On the basis of the results by inhibiting nitric oxide synthase, it can be supposed that nitric oxide released from EITPs of long-lasting caffeine-treated animals operated as a constrictor agent. Our results show that chronic caffeine treatment gives rise to an initial sensitization to adenosine of the EITPs, this being followed by the development of a specific adaptive process in the epithelial cells, which counterbalances the increased tracheal sensitivity to adenosine.
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PMID:Modulation of adenosine-induced responses in the guinea-pig trachea during long-term caffeine treatment: possible role of epithelium. 1802 75

In the present study, we investigated the mediators involved in the potentiation of antigen-induced contractions by indomethacin in tracheas isolated from ovalbumin (OA)-sensitized guinea-pigs. Indomethacin-induced potentiation of OA contraction was mimicked by prostaglandin DP/EP(1) /EP(2) receptor antagonist, AH-6809 but not by phospholipase A(2) enzyme inhibitor mepacrine. The lipoxygenase inhibitor AA-861 did not affect the contraction response to OA but prevented its potentiation by indomethacin, while the leukotriene receptor antagonist cinalukast inhibited both the OA response and its potentiation. However, the antagonists of platelet-activating factor (PAF) (BN-52021), adenosine (CGS-15943), endothelin ET(A) and ET(B) receptors (BQ-123, BQ-788), and the neutral endopeptidase inhibitor phosphoramidon did not alter the OA-induced contraction and its potentiation by indomethacin. Furthermore, capsaicin and neuropeptide receptor NK1, NK2, and NK3 antagonists (L-732128, MEN-10376, and SB-218795, respectively) also did not affect the OA-induced contractions and its potentiation. On the other hand, the 'transient receptor potential vanilloid 1' (TRPV1) antagonist capsazepine inhibited the potentiation response, while it did not alter the OA contraction itself. In conclusion, the potentiation of OA-induced contraction by indomethacin is more likely due to the increase in lipoxygenase products by the shift of arachidonic acid towards lipoxygenase pathway. Because some of the lipoxygenase products are potent vanilloid agonists, the stimulation of TRPV1 receptors besides leukotriene receptors seems to participate in the potentiation of contraction response in sensitized guinea-pig tracheas. PAF, adenosine, endothelins, and the neuropeptides present in the afferent neurons do not contribute to the potentiation of OA-induced contraction by indomethacin.
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PMID:The investigation into indomethacin-induced potentiation of the contractile response to antigen in ovalbumin-sensitized guinea-pig tracheas. 2121 40