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)

Bradykinin (BK) induces bronchoconstriction in asthmatic but not in normal individuals. Studies in vivo in the human suggest that BK causes cholinergic nerve activation, release of prostanoids, and local axon reflexes with release of tachykinins in the airways. To determine the mechanisms of BK-induced airway narrowing, we investigated the effects of epithelium removal, inhibition of the enzymes neutral endopeptidase (NEP) and cyclooxygenase, and blockade of neural conductance with tetrodotoxin (TTX) on BK-induced responses of human isolated peripheral airways. Responses to BK were recorded from airways with spontaneous intrinsic tone and from airways precontracted with methacholine. Furthermore, we measured the BK-induced release of the prostanoids PGE2, PGI2, and TXA2 from airways with and without epithelium in the absence and presence of indomethacin by radioimmunoassay. Finally, we examined the effect of the bradykinin beta 2 receptor antagonist Hoe 140 and the thromboxane prostanoid (TP) receptor blocking drug GR32191 on BK-induced responses. BK contracted intact and epithelium-denuded airways with spontaneous intrinsic tone, whereas precontracted airways either relaxed or contracted to BK. Removal of the epithelium increased the sensitivity to BK sevenfold without changing the direction of the response. The NEP inhibitor phosphoramidon tended to increase the sensitivity to BK (NS) and did not change the direction of the response. Both contractile and relaxation responses to BK and the release of the prostanoids PGE2, PGI2, and TXA2 by the airway tissues were largely inhibited by indomethacin, whereas TTX had no effect. PGE2, PGI2, and TXA2 were released by both intact and epithelium-denuded airways.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin-induced contraction of human peripheral airways mediated by both bradykinin beta 2 and thromboxane prostanoid receptors. 773 35

We have investigated the contractile effect of bradykinin (BK) in guinea pig lung in vitro. BK induces a dose-related contraction of lung parenchymal strips which is increased significantly in the presence of 10(-5) M captopril (an angiotensin converting enzyme inhibitor) or 10(-5) M DL-thiorphan (a neutral endopeptidase inhibitor). The kininase I inhibitor, DL-2-mercaptomethyl-3-guanidino-ethylthiopropionic acid (MGTPA), has no effect on the BK-induced contraction. BK is more potent in contracting parenchymal lung strips than other contractile agents (histamine, carbachol and substance P), however the BK-induced maximal contraction is lower than those obtained with histamine and carbachol. The B1 agonist, des-Arg9-BK, does not contract lung parenchymal strips. The new BK B2 receptor antagonists (Hoe 140, NPC 17731 and NPC 17761), which possess binding affinities in the nanomolar range, inhibit the BK-induced contractile response in a dose-dependent manner. The BK-induced contraction was unaffected by propranolol, atropine, tetrodotoxin, capsaicin pre-treatment, triprolidine, methysergide, Ro 19-3704 and N omega-nitro-L-arginine-methyl-ester (L-NAME), excluding the involvement of nervous pathways, preformed mast cell mediators, platelet-activating factor and nitric oxide. However, indomethacin, a cyclooxygenase inhibitor, AA-861, a 5-lipoxygenase inhibitor, and furegrelate, a thromboxane A2 synthase inhibitor, decreased the contractile response to BK, suggesting that both cyclooxygenase and 5-lipoxygenase products are involved in this contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin-induced contraction of guinea pig lung in vitro. 799 Sep 78

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. It was suggested that anaphylactic release of tachykinin-like substances is likely to be responsible for the observed increases in tracheal contractions. To obtain additional information on the mechanisms responsible for anaphylactic release of tachykinins in guinea pig trachea, we examined the effects of phosphoramidon, an inhibitor of neutral endopeptidase, on contractile response to antigen after preincubation with the selective 5-lipoxygenase inhibitor AA-861. AA-861 (5 microM) significantly reduced ovalbumin-induced contraction, although the effect was not constant. A marked spontaneous increase in contraction was observed. Phosphoramidon (10 microM) produced significant increase of this contraction (27% after 30 min, and 33% after 45 min). The addition of H1-histamine receptor antagonist (diphenhydramine HCl, 10 microM) produced additional inhibition of the initial phase of antigen-induced contraction, while its later phase, apart from a spontaneous increment in magnitude, remained similar. Phosphoramidon (10 microM) increased the contraction by 26% after 30 min, and by 34% after 45 min. Since the effects of histamine and 5-lipoxygenase pathway products were prevented, we hypothesize that cyclooxygenase pathway products are responsible for the phosphoramidon-dependent increase in antigen-induced contraction. In accordance with previously reported ineffectiveness of contractile prostaglandins, we suggest that the relaxant prostaglandins are most important in mediating the release of tachykinins during the immediate hypersensitivity reaction in guinea pig trachea.
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PMID:Phosphoramidon modulates effects of the 5-lipoxygenase inhibition on anaphylactic contraction of the guinea pig trachea. 811 Dec 48

In the ferret liquid-filled trachea in vivo, intraluminal bradykinin (BK, 3-300 microM) produced concentration-dependent increases in the output of lysozyme from submucosal gland serous cells and albumin movement into the lumen. Baseline outputs of albumin and lysozyme were not altered significantly by intraluminal indomethacin (10 microM) or thiorphan (10 microM). However, intraluminal indomethacin completely blocked the BK-induced increase in albumin output. Intraluminal thiorphan (10 microM) did not significantly potentiate BK-induced albumin output, although mean output was higher. Neither indomethacin nor thiorphan significantly altered BK-induced lysozyme output, although mean output was reduced in the presence of indomethacin. Thus BK increases albumin output and may increase lysozyme output via the action of cyclooxygenase products. Inhibition of neutral endopeptidase activity may enhance the action of BK on albumin output.
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PMID:The effects of indomethacin and thiorphan on bradykinin-induced albumin output and submucosal gland secretion in the ferret trachea in vivo. 835 81

The effect of phosphoramidon on the increase in pulmonary inflation pressure (PIP) induced by endothelin-1 (ET-1) administered by aerosol in ovalbumin (OA)-sensitized and challenged guinea-pigs was investigated after pretreatment or not of the animals with the neutral endopeptidase inhibitor, phosphoramidon, the cyclooxygenase inhibitor, indomethacin or the platelet activating factor (PAF) antagonist, BN 50730. When guinea-pigs were pretreated by phosphoramidon (0.1 mM, aerosol for 15 min), a significant enhancement of PIP was observed after administration of ET-1 (1 or 3 micrograms ml-1, aerosol for 2 min), whereas these doses of the peptide were only slightly active in control animals. In sensitized and unchallenged guinea-pigs, ET-1 (1 or 3 micrograms.ml-1, aerosol for 2 min) induced, as in controls, a moderate increase in PIP. In contrast, aerosol exposure of OA in sensitized guinea-pigs developed an increased PIP following ET-1 (1 and 3 micrograms.ml-1, aerosol for 2 min) administration, that was non significantly affected by pretreatment of the animals with phosphoramidon after the dose of 3 micrograms ml-1 ET-1. Guinea-pigs exposed to phorphoramidon and treated with indomethacin (10 mg kg-1, i.v.) or BN 50730 (25 mg kg-1, per os) significantly reduced the increase in PIP upon administration of ET-1 (3 micrograms.ml-1, aerosol for 2 min). No inhibitory effect of indomethacin was noted when ET-1 (3 micrograms.ml-1, aerosol for 2 min) was administered to sensitized and OA-exposed guinea-pigs, pretreated or not with phosphoramidon. In contrast, BN 50730 significantly reduced the increase in PIP induced by ET-1 observed in sensitized and OA-exposed guinea-pigs. Moreover, this drug was moderately active in reducing the increase in PIP induced by ET-1, when the animals were pretreated by phosphoramidon. These results suggest that a phosphoramidon-sensitive endopeptidase-like enzyme, present in the airway tissue modulates the effect of ET-1. Furthermore, the increase in PIP to ET-1 observed in aerosol-sensitized and antigen-exposed guinea-pigs appears to be mediated by PAF rather than cyclooxygenase metabolites, even though the participation of other mediators in this process is open.
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PMID:Bronchopulmonary responses to endothelin-1 in sensitized and challenged guinea-pigs: role of cyclooxygenase metabolites and platelet-activating factor. 840 92

The present study was undertaken to characterize the direct chronotropic effect of bradykinin in isolated spontaneously beating atria of the guinea pig. Bradykinin caused concentration-dependent increases in the beating rate of atria. In contrast, the active metabolite of bradykinin and the typical bradykinin B1 receptor agonist, Des-Arg9-bradykinin, had no effect on the beating rate of atria. Inhibition of converting enzyme or neutral endopeptidase by captopril or SQ-28603, respectively, did not affect beating rate but potentiated bradykinin-induced increase in beating rate. The potent bradykinin B2 receptor antagonist, HOE 140, antagonized bradykinin-induced chronotropic effect. In contrast, the bradykinin B1 receptor antagonist, Lys-[Leu8]Des-Arg9-bradykinin, had no effect. The increase in beating rate caused by bradykinin was not affected by blockade of beta 1-adrenoceptors, cyclooxygenase, or nitric oxide synthesis using atenolol, indomethacin and N omega-nitro-L-arginine, respectively. Unlike bradykinin, angiotensin I and angiotensin II caused very small or no change in beating rate in the presence or absence of captopril and SQ-28603. These results indicate that bradykinin causes a direct positive chronotropic effect which is mediated by activation of bradykinin B2 receptors independently of prostaglandins and beta 1-adrenoceptors.
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PMID:Bradykinin B2 receptor-mediated chronotropic effect of bradykinin in isolated guinea pig atria. 856 11

To study the mechanisms of wood smoke-induced bronchoconstriction, we measured total lung resistance (RL) and dynamic lung compliance (Cdyn) in anesthetized and mechanically ventilated guinea pigs. Airway exposure to various doses of wood smoke (lauan wood; 5, 10, and 15 breaths) resulted in a dose-dependent increase in RL and decrease in Cdyn. The smoke-induced changes in RL and Cdyn were significantly attenuated by pretreatment with atropine, CP-96,345 [(2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-aza bicyclo(2.2.2.)-octan-3-amine; a tachykinin NK1 receptor antagonist], and SR-48,968 [(S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophen yl)-butyl)benzamide; a tachykinin NK2 receptor antagonist] in combination, atropine alone, and SR-48,968 alone, but were not significantly affected by pretreatment with the inactive enantiomers of CP-96,345 and SR-48,968, CP-96,345 alone, indomethacin (a cyclooxygenase inhibitor), and MK-571 [((3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl((3-dimethyl amino-3-oxo-propyl)thio)methyl)propanoic acid; a leukotriene D4 receptor antagonist]. The activity of airway neutral endopeptidase, a major enzyme for tachykinin degradation, was not significantly influenced by wood smoke during the development of bronchoconstriction. We conclude that: (1) both cholinergic mechanisms and endogenous tachykinins, but not cyclooxygenase products or leukotriene D4, play an important role in the acute bronchoconstriction induced by wood smoke, and (2) the contribution of tachykinins to this airway response is primarily mediated via the activation of tachykinin NK2 receptors, but is not associated with inactivation of the airway neutral endopeptidase.
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PMID:Acetylcholine and tachykinin receptor antagonists attenuate wood smoke-induced bronchoconstriction in guinea pigs. 985 84

A prior airway exposure to wood smoke induces a tachykinin-dependent increase in airway responsiveness to the subsequent smoke inhalation in guinea pigs (Life Sci. 63: 1513, 1998). To further investigate the time course of, and the contribution of other chemical mediators to, this smoke-induced airway hyperresponsiveness (SIAHR), two smoke challenges (each 10 ml) separated by 30 min were delivered into the lungs of anesthetized guinea pigs by a respirator. In the control animals, the SIAHR was evidenced by the bronchoconstrictive response to the second smoke challenge (SM2) which was approximately 5.2-fold greater than that to the first challenge (SM1). This SIAHR was alleviated by shortening the elapsed time between SM1 and SM2 to 10 min or by extending it to 60 min, and was abolished by extending it to 120 min. This SIAHR was reduced by pretreatment with either MK-571 (a leukotriene D4-receptor antagonist) or dimethylthiourea (a hydroxyl radical scavenger), but was not affected by pretreatment with either pyrilamine (a histamine H1-receptor antagonist) or indomethacin (a cyclooxygenase inhibitor). The smoke-induced reduction in the neutral endopeptidase activity (a major enzyme for tachykinin degradation) measured in airway tissues excised 30 min post SM1 was largely prevented by pretreatment with dimethylthiourea. However, this reduction was not seen in airway tissues excised 120 min post SM1. These results suggest that 1) the SIAHR to inhaled wood smoke has a rapid onset time following smoke inhalation and lasts for less than two hours, 2) leukotrienes and hydroxyl radical may play contributory roles in the development of this SIAHR, and 3) hydroxyl radical is the major factor responsible for the smoke-induced inactivation of airway neutral endopeptidase, which may possibly participate in the development of this SIAHR.
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PMID:Wood smoke-induced airway hyperreactivity in guinea pigs: time course, and role of leukotrienes and hydroxyl radical. 1072 44

We studied the mechanisms underlying the wood smoke-induced acute airway injury in 120 anaesthetized guinea pigs. Five minutes after airway exposure, various doses of wood smoke produced a dose-dependent increase in Evans blue dye contents at all airway levels measured. Additionally, inhaled wood smoke produced submucosal edema of the trachea and bronchus, and peribronchial edema. These acute airway responses were nearly abolished by pretreatment with CP-96,345 alone [a tachykinin NK(1) receptor antagonist; (2S, 3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyc lo( 2.2.2.)-octan-3-amine] or with a combination of CP-96,345 and dimethylthiourea (a hydroxyl radical scavenger), and were attenuated by pretreatment with dimethylthiourea alone, yet were not affected by pretreatment with SR-48,968 [a tachykinin NK(2) receptor antagonist; (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3, 4-dichlorophenyl)-butyl)benzamide], with a combination of CP-96,344 and SR-48,965 (inactive enantiomers), with MK-886 [a leukotriene biosynthesis inhibitor; L-663, 536(3-(1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl)-2, 2-dimethylpropanoic acid], with indomethacin (a cyclooxygenase inhibitor), or with N(G)-nitro-L-arginine methyl ester (a nitric oxide (NO) synthase inhibitor). The activity of airway neutral endopeptidase (an enzyme for tachykinin degradation) was not influenced by wood smoke at 5-min post-exposure. We conclude that both endogenous tachykinins and hydroxyl radical play an important role in producing smoke-induced acute airway plasma exudation and airway edema in guinea pigs. The contribution of tachykinins to these neurogenic responses is mediated via the activation of tachykinin NK(1) receptors and partly via a hydroxyl radical mechanism, and is not associated with inactivation of neutral endopeptidase.
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PMID:Acute neurogenic airway plasma exudation and edema induced by inhaled wood smoke in guinea pigs: role of tachykinins and hydroxyl radical. 1077 Oct 46

Prostaglandins are known to participate in the antihypertensive actions of angiotensin-converting enzyme (ACE) inhibition and angiotensin type 1 (AT1)-receptor antagonism. Because angiotensin-(1-7) [Ang-(1-7)] is markedly elevated after prolonged ACE-inhibitor treatment, we determined whether the antihypertensive effects of Ang-(1-7) were mediated by release of prostaglandins. Male spontaneously hypertensive rats (SHRs, 10 weeks) were treated for 9 days with either lisinopril (20 mg/kg) or losartan (10 mg/kg) or a combination of both drugs. Rats were implanted with catheters in the carotid artery and jugular vein to record blood pressure and to infuse drug solutions, respectively. Neutralization of circulating Ang-(1-7) by monoclonal antibody resulted in a dose-dependent increase in blood pressure in SHRs treated with either lisinopril or losartan. Administration of CGS 24592 to block Ang-(1-7) formation also resulted in an increase in blood pressure that was comparable to antibody infusion. However, Ang-(1-7) blockade evoked a greater elevation in blood pressure in the lisinopril and lisinopril/losartan-treated rats in comparison to those treated with losartan alone. Acute treatment with the cyclooxygenase (COX) inhibitor indomethacin increased blood pressure to a similar extent to that of CGS 24592, as well as blocked the increase in pressure with the neprilysin inhibitor in the lisinopril/losartan group. In the losartan-treated animals, however, indomethacin increased blood pressure by a larger extent than that of the Ang-(1-7) antibody or CGS 24592, and CGS 24592 did not abolish the subsequent pressor response to indomethacin in these animals. In contrast to the antibody or neprilysin inhibitor, administration of the Ang-(1-7) antagonist D-[Ala7]-Ang-(1-7) increased blood pressure to a similar extent in lisinopril or losartan treatments. Moreover, D-[Ala7]-Ang-(1-7) increased blood pressure to a comparable extent as indomethacin and blocked any further increase with the COX inhibitor in the losartan-treated SHRs. High-resolution emulsion autoradiography revealed 125I-[Sarcosine1, Threonine8]-Ang II (Sarthran) binding in the mesenteric artery and thoracic aorta in the presence of both LOS and the AT2 antagonist PD123319. The non-AT1/non-AT2 Sarthran binding was displaced by Ang-(1-7), DALA, or Ang II. These studies suggest that vasodilatory eicosanoids mediate the antihypertensive effects of endogenous Ang-(1-7) in both LIS and LIS/LOS therapies. Furthermore, in the presence of AT1-receptor blockade, Ang II may interact with a DALA-sensitive site to promote eicosanoid release.
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PMID:Evidence that prostaglandins mediate the antihypertensive actions of angiotensin-(1-7) during chronic blockade of the renin-angiotensin system. 1089 68


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