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)

The effect of ozone (3 ppm, 15-120 min) on bronchial reactivity in the guinea-pig was studied. Ozone induced marked (6-250-fold) bronchial hyperreactivity (BHR) to a range of inhaled, but not intravenous bronchoconstrictors. The degree of BHR was related to the duration of prior ozone exposure. The glutathione redox status was shifted to a more oxidized state in lung after 120 min ozone treatment, although no changes were found in the energy status of lung tissue, as judged by the concentrations of adenosine phosphates. Ascorbic acid pretreatment prevented BHR induced by 30 min ozone exposure. Neutral endopeptidase inhibitors elicited BHR to both substance P and histamine, but did not further enhance bronchoconstriction to substance P after ozone exposure for 120 min. Neither mepyramine, fentanyl, indomethacin nor a 5-lipoxygenase inhibitor (BW B70C), given prior to ozone exposure prevented the induction of BHR to histamine. Atropine or bilateral vagotomy reduced BHR after a 120-min, but not 30-min exposure to ozone. We conclude that in the guinea-pig, ozone induces non-specific, route-dependent BHR by oxidative injury, reducing airway NEP activity and enhancing the cholinergic and peptidergic component to bronchoconstriction. Neither cyclooxygenase nor 5-lipoxygenase products appear to play a role in ozone-induced BHR in this animal model.
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PMID:Mechanisms contributing to ozone-induced bronchial hyperreactivity in guinea-pigs. 137 22

We investigated the effects of ozone exposure (3.0 ppm, 2 h) on the responsiveness of guinea pig airway muscle in vitro from animals developing bronchial hyperreactivity. Muscarinic reactivity in vivo was determined by measuring specific airway resistance (sRaw) in response to increasing concentrations of aerosolized acetylcholine (ACh) administered before and 30 min after exposure. Immediately after reactivity testing, multiple tracheal rings from ozone- and air-exposed animals were prepared and the contractile responses to increasing concentrations of substance P, ACh, or KCl were assessed in the presence of 10 microM indomethacin with or without 1 microM phosphoramidon, an inhibitor of neutral endopeptidase. Isometric force generation in vitro was measured on stimulation by cumulative concentrations of the agonists, and force generation (in g/cm2) was calculated after determination of muscle cross-sectional area. The smooth muscle of mucosa-intact airways from guinea pigs with ozone-induced bronchial hyper-reactivity proved to be hyperresponsive in vitro to substance P and ACh but not to KCl. Pretreatment with phosphoramidon abolished the increase in substance P responsiveness but had no effect on muscarinic hyperresponsiveness after ozone exposure. Furthermore, substance P responsiveness was not augmented in ozone-exposed airways in which the mucosa had been removed before testing in vitro. Likewise, muscarinic hyperresponsiveness was not present in ozone-exposed airways without mucosa. Our data indicate that airway smooth muscle responsiveness is increased in guinea pigs with ozone-induced bronchial hyperreactivity and suggest that this hyperresponsiveness may be linked to non-cyclooxygenase mucosa-derived factors.
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PMID:O3-induced mucosa-linked airway muscle hyperresponsiveness in the guinea pig. 169 72

Bradykinin is a potent vasodilator peptide; however, its half-life in vivo is very short because of various plasma and tissue peptidases that hydrolyze bradykinin to inactive fragments. We studied the role of kininase II (angiotensin converting enzyme) and neutral endopeptidase 24.11 (enkephalinase) in the catabolism of bradykinin in vascular tissue by determining the effect of inhibitors of kininase II (captopril) and of endopeptidase 24.11 (phosphoramidon) on the action of bradykinin on rat isolated mesenteric arteries. Because bradykinin may induce prostaglandin formation and release, we also studied the effect of a cyclooxygenase inhibitor, indomethacin, on the action of bradykinin. The mesenteric bed was isolated from rats (250-300 g) with rats under either anesthesia and was perfused with Krebs' solution (4 ml/min) containing phenylephrine (0.5-1.0 microgram/ml) to produce a mean perfusion pressure of 120-130 mm Hg. Bradykinin (2.5-40.0 ng), injected as a bolus, produced a dose-dependent decrease in perfusion pressure. In the presence of indomethacin (1.0 microgram/ml), the amplitude of the vasodilator responses to bradykinin was not significantly affected, although the duration of the responses was increased approximately two to four times. In the presence of captopril (1.0 microgram/ml), bradykinin elicited either a vasodilator or a biphasic effect. The vasodilator effect was greatly potentiated by captopril, whereas the duration of the response was unchanged when compared with control experiments. When present, the pressor responses were also dose related. In the presence of indomethacin plus captopril, bradykinin produced only a fall in perfusion pressure that lasted five to six times longer than without any treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of bradykinin on isolated mesenteric arteries of the rat. 173 87

The receptors involved in the bronchoconstriction evoked in vivo by intravenous administration to the anesthetized guinea pig of serotonin and serotonin-related agonists have been examined in this study. Animals were pretreated with indomethacin and (+/-)-propranolol to inhibit cyclooxygenase and beta adrenergic receptors, respectively, and pulmonary parameters were obtained with a Buxco pulmonary mechanics computer. Dose-dependent increases in pulmonary resistance and decreases in dynamic lung compliance were produced by serotonin, 2-methyl-serotonin, 5-methoxy-tryptamine, alpha-methyl-serotonin, 5-carboxamidotryptamine, and m-trifluoromethylphenylpiperazine (TFMPP). Responses to all agonists except 2-methyl-serotonin, a selective 5-hydroxytryptamine3 (5-HT3) agonist, were antagonized by the 5-HT2 antagonists, LY53857 and ketanserin. Zaclopride, 1 and 10 mg/kg, a selective 5-HT3 antagonist, blocked responses to 2-methyl-serotonin. A maximally effective dose of LY53857 (1 mg/kg) produced larger shifts of the dose-response curves to serotonin, 5-methoxytryptamine and alpha-methyl-serotonin than did a maximally effective dose of ketanserin (1 mg/kg). Thiorphan, 10 mg/kg, an inhibitor of neutral endopeptidase, potentiated 2-methyl-serotonin and, when studied in the presence of LY53857, also potentiated serotonin, 5-methoxytryptamine and TFMPP. After thiorphan and LY53857, responses to serotonin, but not 5-methoxytryptamine or TFMPP, were blocked by zaclopride. Capsaicin pretreatment of the animals resulted in rightward shifts of the dose-response curves to serotonin, 2-methyl-serotonin and TFMPP, but not to 5-methoxytryptamine or alpha-methyl-serotonin. Potentiation by thiorphan and antagonism by zaclopride of responses to serotonin were still evident after capsaicin pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A pharmacologic examination of receptors mediating serotonin-induced bronchoconstriction in the anesthetized guinea pig. 201 90

We have studied the effect of epithelium removal on responses of guinea pig trachea to bradykinin (BK). BK (1 nM - 10 microM) gave a concentration-dependent relaxation when epithelium was present (E+: EC50 = 10 +/- 3 nM). Epithelium removal resulted in a biphasic response to BK with relaxation at low concentrations (E-: EC50 = 3.0 +/- 1.0 nM) and a recontraction to baseline at higher concentrations (EC50 = 2.0 +/- 1 microM). Phosphoramidon (10 microM), an inhibitor of neutral endopeptidase (NEP), which cleaves BK into inactive peptides, potentiated relaxation (EC50 = 1.0 +/- 0.9 nM in E+ and E respectively) and contraction in trachea with intact epithelium (EC50 = 0.08 +/- 0.03 microM). Inhibition of cyclooxygenase by indomethacin (5 microM), inhibited relaxation to BK in E+ tracheal segments, resulting in a slight contraction (EC50 = 1.0 microM), whereas a potent contractile response was observed in E- segments (EC50 1.6 microM, maximal contraction greater than 1 g). In the presence of both indomethacin and phosphormidon BK caused contraction, even in the presence of epithelium (EC50 = 0.2 +/- 0.11 microM), and the response in the absence of epithelium was similar to the response observed in trachea with intact epithelium (EC50 = 0.25 +/- 0.1 microM). The contractile effect of BK on airway smooth muscle may be inhibited by a protective role of epithelium, due to release of relaxant prostanoids and by degradation by epithelial NEP. In asthma, bronchoconstrictor responses to BK may be partly explained by loss of airway epithelium.
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PMID:Modulation of bradykinin responses in airway smooth muscle by epithelial enzymes. 212 64

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

We have studied the effect of epithelium removal on the contractile responses to exogenous tachykinins and to endogenous tachykinins released by capsaicin in guinea pig trachea. We also studied the effects of inhibition of endopeptidase (by phosphoramidon, 10 microM, and thiorphan, 100 microM), and of inhibition of cyclooxygenase (by indomethacin, 5 microM) on these responses. The order of potency of exogenous tachykinins was neurokinin A (NKA) greater than neurokinin B (NKB) greater than substance P (SP). Epithelium removal enhanced the sensitivity and magnitude of the contractile response to SP, and to a lesser extent NKA and NKB. Capsaicin induced only a weak contractile response in guinea pig trachea. Phosphoramidon and thiorphan increased the sensitivity to SP, but had no effect on acetylcholine responses. The leftwardshift due to epithelium removal was reduced, but not abolished, by phosphoramidon and thiorphan. NKA- and NKB-induced contractions were also enhanced significantly by phosphoramidon. The effect of epithelium removal was abolished for NKA, but not for NKB. Phosphoramidon also increased significantly the contraction to capsaicin in the presence of epithelium, without altering the response obtained in the absence of epithelium. Indomethacin potentiated the sensitivity and maximal contractile response to all the tachykinins with the greatest effect on SP responses, and to capsaicin. The combination of indomethacin with phosphoramidon or thiorphan abolished the effect of epithelium removal for all the tachykinins. We conclude that the effects of exogenous and endogenous tachykinins are enhanced by removal of epithelium and by inhibition of metalloendopeptidase and cyclooxygenase, suggesting that tachykinins may be degraded by epithelial enzymes, and may release relaxant prostanoids in airways.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of epithelium on guinea pig airway responses to tachykinins: role of endopeptidase and cyclooxygenase. 246 59

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

Cold air was delivered to anesthetized, artificially ventilated, pathogen-free F344 rats via a tracheal cannula. Inhalation of cold air increased Evans blue dye extravasation in the trachea in a time-dependent (1 to 10 min) manner. Plasma extravasation increased after 3 min exposure to cold air and reached a maximum after 10 min exposure. The neutral endopeptidase inhibitor, phosphoramidon (2.5 mg/kg, intravenously), increased by 84% the plasma extravasation induced by inhalation of cold air for 1 min. The plasma extravasation evoked by 5 min exposure to cold air was abolished by the NK1 tachykinin receptor antagonist, CP-99,994 (4 mg/kg, intravenously); was reduced 30% by the B2 bradykinin receptor antagonist, HOE140 (0.1 mumol/kg, intravenously); and was not affected by H1 (pyrilamine, 10 mg/kg, intraperitoneally) or H2 (cimetidine, 10 mg/kg, intraperitoneally) histamine receptor antagonists or the cyclooxygenase inhibitor indomethacin (5 mg/kg, intravenously). In rats infected with Sendai virus, plasma extravasation evoked by inhalation of cold air was greater than in pathogen-free rats. Pretreatment with CP-99,994 (4 mg/kg, intravenously) inhibited completely the plasma extravasation induced by cold air in virus-infected rats. These findings indicate that cold air increases plasma extravasation in the rat trachea by a neurogenic mechanism that involves the release of tachykinins from sensory nerves. Kinin release may also play a role in this neurogenic inflammatory response.
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PMID:Plasma extravasation in the rat trachea induced by cold air is mediated by tachykinin release from sensory nerves. 769 24


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