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1.
The role of platelet-activating factor (PAF) as a mediator of increased conjunctival vascular permeability was investigated in a guinea-pig model of immediate hypersensitivity. Vascular permeability of the conjunctiva was determined by measuring the albumin content in lavage fluid (LF) after topical challenge with either PAF or ovalbumin. PAF produced a dose-dependent increase of the vascular permeability within minutes. Topical pretreatment with levocabastine, a potent histamine H(1)-antagonist demonstrated no effect towards the vascular permeability in response to PAF provocation. Pretreatment with eyedrops containing the specific PAF antagonist BN 52021 (1%) showed a significant inhibition of the vascular permeability (60.2%) and the clinical score (27.5%) after PAF challenge. In sensitized guinea-pigs, levocabastine showed a marked inhibition of both the vascular permeability (80.5%) and the clinical score (70%) after topical challenge with ovalbumin. BN 2021, although to a lesser extent, showed a similar effect towards the vascular permeability (26.8%) and the clinical score (28%) after antigen provocation. When BN 52021 and levocabastine were administered in combination, the vascular permeability was significantly decreased after antigen challenge in comparison with eyes pretreated with levocabastine alone. These results indicate that PAF plays a role in the acute phase of allergic conjunctivitis in the guinea-pig.  相似文献   

2.
Peptidoleukotrienes (LTs), LTC4 and LTD4, cause potent vasoconstriction and myocardial depression in a range of species including man. The recent availability of specific LTD4 antagonists has allowed the evaluation of LT involvement in disease states and the characterisation of LT receptors in the airways. We decided to study the actions of four LT antagonists; ICI 198,615, SK + F 104,353, MK-571 and CGP45715A on LTD4-, LTC4- and U46619-induced effects in the coronary vasculature and on cardiac contractility in the guinea-pig isolated heart. We found a difference in the actions of the antagonists in the GP heart compared with the lung. ICI 198,615 retained its selectivity towards LTD4 whereas SK + F 104,353 antagonised both LTD4 and LTC4. MK-571 and CGP45715A had a non specific action against the LTs. Our results also indicated a direct action of the LTs on cardiac contractility which was not associated with the constriction of the coronary vasculature. These studies indicate that if the leukotrienes are involved in cardiac disease antagonists specific for the peptidoleukotrienes may be of therapeutic benefit in many of the disease states of the heart.  相似文献   

3.
Allergic sheep with antigen-induced early and late responses were used to determine whether airway hyperresponsiveness (AHR) to carbachol is present during the late response and whether blocking the late response with the leukotriene D4 (LTD4) antagonist MK-571 also blocks this AHR. To do this, we first showed that MK-571 blocked the antigen-induced late response, and then, in a separate study, we determined the effect of MK-571 treatment on airway responsiveness 6 h after antigen challenge (at the start of the late response). MK-571 (5 mg, by metered dose inhaler) given 30 min before and 4 h after Ascaris suum challenge had no effect on the acute response to antigen but blocked (P less than 0.05) the late response compared with placebo (n = 7). In the second study (n = 6), the antigen-induced acute increases in mean specific lung resistance (sRL) were also similar in the placebo (249%) and drug trials (247%). By 6 h postchallenge, however, mean sRL in the placebo trial began to increase (54%, P less than 0.05), whereas in the drug trial mean sRL was baseline. Nevertheless, AHR was apparent in both trials as indicated by a mean twofold leftward shift in the dose-response curves to inhaled carbachol (P less than 0.05 vs. prechallenge). Bronchoalveolar lavage at 6 h showed that MK-571 did not prevent the inflammatory cell influx into the lung. These observations suggest that although LTD4 may be a mediator of the late response in sheep, it is not a primary mediator affecting cholinergic AHR during this period.  相似文献   

4.
Cysteinyl leukotrienes are potent inflammatory molecules playing a major role in asthma. The involvement of these mediators in hypersensitivity in mice is not well known. This study aimed at elucidating their implication by using MK-571, a cysLT(1)receptor antagonist. Mice were sensitized with a suspension of ovalbumin (8 microg) adsorbed to alum (2 mg) and were challenged with an aerosolized ovalbumin solution (0.5%). Inflammatory cell infiltration in the bronchoalveolar lavage (mostly eosinophils) following antigen challenge was inhibited by dexamethasone (0.1, 1 and 5 mg kg(-1)s.c.) and MK-571 (1, 10, 100 mg kg(-1)i.v.) in a dose-dependent manner. Maximal inhibition was 95% with 5 mg kg(-1)dexamethasone and 90% with 100 mg kg(-1)MK-571. When injected together they showed an additive inhibitory effect on eosinophil infiltration. Bronchial hyperreactivity, measured by the increased pulmonary insufflation pressure to carbachol injections, was also inhibited dose-dependently by MK-571. The EC(50)values for carbachol were of 22.39+/-1.12 microg kg(-1)in sensitized and challenged animals that did not receive MK-571 and increased to 43.65+/-1.10, 50.12+/-1.15 and 83.18+/-1.16 microg kg(-1)in animals treated with 1, 10 and 100 mg kg(-1)MK-571 respectively. Lung microvascular leakage (as measured by Evans blue extravasation) induced by antigen bronchoprovocation was reduced by 22% after treatment with 10 mg kg(-1)MK-571. All these inhibitory effects of MK-571 suggest a role for leukotriene D(4)in this animal model of allergic asthma.  相似文献   

5.
The effects of 4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone (NZ-107) on immediate type hypersensitivity reactions in rats and guinea-pigs were studied. 1. When NZ-107, at a dose of 50 mg/kg (i.p.) or 100 mg/kg (orally), was administered to rats, 48-h homologous passive cutaneous anaphylaxis (PCA) reaction and histamine-, leukotriene C4 (LTC4)- and leukotriene D4 (LTD4)-induced skin reactions were suppressed by the agent. 2. NZ-107 (10(-6) g/ml) inhibited both LTC4- and LTD4-induced contractions of isolated rat stomach smooth muscle. 3. NZ-107 inhibited antigen-induced histamine release from rat peritoneal mast cells by 26% at a concentration of 10(-4) g/ml. 4. NZ-107, at doses of 25 and 50 mg/kg (orally), significantly inhibited guinea-pig 3-h heterologous PCA reaction. 5. NZ-107 inhibited antigen-induced histamine release from guinea-pig lung tissue by 17% and 48% at concentrations of 5 x 10(-5) and 10(-4) g/ml, respectively. 6. NZ-107, at doses of 25 and 50 mg/kg (i.p.), inhibited antigen-induced bronchoconstriction and eosinophil accumulation in the bronchoalveolar lavage fluid (BALF) of guinea-pigs. These results suggest that NZ-107 has anti-allergic action including inhibition of eosinophil accumulation in an antigen-challenged airway lesion in rats and guinea-pigs. The anti-allergic action of this agent is thought to be due to its action as a histamine and LT antagonist and its consequent inhibition of antigen-induced histamine release.  相似文献   

6.
Mast cell histamine (HA) and cysteinyl leukotrienes (CysLT) account for most of the early phase bronchospasm in asthma. However, activation of the smooth muscle CysLT1-receptor plays a major role in asthmatic bronchospasms. CysLT-receptor antagonists or CysLT-synthesis inhibitors are efficacious in asthma but do not completely abolish asthmatic bronchospasms. A recent clinical study showed that combined antagonists loratadine (H1) and zafirlukast (CysLT1) were more effective against allergic bronchospasms than either drug alone. We examined the combined efficacy of H1- and CysLT1-receptor antagonists in allergic human bronchus. The H1- and CysLT1-receptor antagonists chlorpheniramine (CTM; 1 microM) and MK-571 (0.03 microM), were tested alone and in combination, against anti-human IgE antibody (Ab)-induced contractions of passively sensitized isolated human bronchus. Ab-induced allergic contractions were reduced 15% and 36% by CTM (1 microM) and MK-571 (0.03 microM), respectively. Combined CTM (1 microM) and MK-571 (0.03 microM) significantly inhibited the Ab response by 87%. Mechanistic investigations in isolated human bronchus and cultured human cord blood mast cells suggest that H1- and CysLT-receptor interactions likely occur at the airway smooth muscle level. CTM and MK-571 synergistically inhibited human allergic bronchospasm in the present in vitro model. The mechanism underlying this synergistic activity requires further investigation.  相似文献   

7.
The responses of equine trachealis and lung parenchymal strips to a range of contractile agonists were studied. Equine trachealis responded to methacholine greater than histamine greater than serotonin as shown by the maximal responses but failed to respond to either leukotrienes (LT), prostaglandin F2 alpha, or U-44069. Equine parenchymal strips showed considerable tonal activity and responded to LTD4 congruent to LTC4 greater than U-44069 = LTE4 greater than methacholine congruent to histamine congruent to serotonin greater than prostaglandin F2 alpha as determined through pD2 values. Neither the concentration response curve to LTD4 nor the intrinsic tonal activity of the preparations was modified by pretreatment with either atropine or indomethacin, although the maximal response to LTD4 was reversed by addition of the LTD4 receptor antagonist, MK-571. Thus arachidonic acid metabolites, including LTs, must be considered potential mediators of equine small airway disease, a potential model of human bronchial asthma.  相似文献   

8.
Chemically stable analogs of peptide leukotrienes (LT) have been developed in our laboratories by replacement of the natural triene backbone with a C7H15 substituted aromatic moiety (1). These analogs are potent agonists of airway smooth muscle. Substitution in the peptide region resulted in U19052, an LT receptor antagonist. U19052 antagonized LT-induced contractions of guinea-pig tracheal spirals in a concentration-related manner. The pA2 values versus LTD4 and LTE4 were 6.0 and 5.7, respectively, with slopes which were not significantly different from unity. LTC4-induced contractions were antagonized by U19052 with a pKB of 5.6 obtained either in the absence or presence of L-serine borate. In contrast, carbachol and histamine concentration-response curves were not altered by U19052. LTD4 or LTE4 contractions of isolated guinea-pig ileum were antagonized by U19052 with pKB values of 7.2. The results indicate that potent selective LT antagonists can be developed from stable analogs of leukotrienes. U19052, an example of this series, appears to be as effective in antagonizing LTC4- as well as LD4- and LTE4-induced contractions in guinea-pig tracheal spirals.  相似文献   

9.
The conjunctiva is a mucous membrane that covers the sclera and lines the inside of the eyelids. Throughout the conjunctiva are goblet cells that secrete mucins to protect the eye. Chronic inflammatory diseases such as allergic conjunctivitis and early dry eye lead to increased goblet cell mucin secretion into tears and ocular surface disease. The purpose of this study was to determine the actions of the inflammatory mediators, the leukotrienes and the proresolution resolvins, on secretion from cultured rat and human conjunctival goblet cells. We found that both cysteinyl leukotriene (CysLT) receptors, CysLT(1) and CysLT(2,) were present in rat conjunctiva and in rat and human cultured conjunctival goblet cells. All leukotrienes LTB(4), LTC(4), LTD(4), and LTE(4), as well as PGD(2), stimulated goblet cell secretion in rat goblet cells. LTD(4) and LTE(4) increased the intracellular Ca(2+) concentration ([Ca(2+)](i)), and LTD(4) activated ERK1/2. The CysLT(1) receptor antagonist MK571 significantly decreased LTD(4)-stimulated rat goblet cell secretion and the increase in [Ca(2+)](i). Resolvins D1 (RvD1) and E1 (RvE1) completely reduced LTD(4)-stimulated goblet cell secretion in cultured rat goblet cells. LTD(4)-induced secretion from human goblet cells was blocked by RvD1. RvD1 and RvE1 prevented LTD(4)- and LTE(4)-stimulated increases in [Ca(2+)](i), as well as LTD(4) activation of ERK1/2. We conclude that cysteinyl leukotrienes stimulate conjunctival goblet cell mucous secretion with LTD(4) using the CysLT(1) receptor. Stimulated secretion is terminated by preventing the increase in [Ca(2+)](i) and activation of ERK1/2 by RvD1 and RvE1.  相似文献   

10.
The biosynthesis of leukotrienes (LT) C4 and B4 is followed by an export of these mediators into the extracellular space. This transport was characterized using plasma membrane vesicles prepared from mastocytoma cells and identified as an ATP-dependent primary active process. The apparent Km-values were 110 nM for LTC4 and 48 microM for ATP. The transport rate was highest for LTC4, whereas LTD4, LTE4, and N-acetyl-LTE4 were transported with relative rates of 31, 12 and 8%, respectively, at a concentration of 10 nM. LTB4 transport was also dependent on ATP. LTC4 transport was inhibited by LTD4 receptor antagonists (IC50 = 1.0 microM for MK-571 and 1.3 microM for LY245769) and by the inhibitor of leukotriene biosynthesis MK-886 (IC50 = 1.8 microM). The ATP-dependent export carrier for leukotrienes in leukotriene-synthesizing cells represents a novel member of the family of ATP-dependent exit pumps.  相似文献   

11.
Both nitric oxide and prostaglandins induce vasodilatation which is an important feature of local inflammation. The purpose of the study described here was to investigate a possible interaction between these two types of mediators in an experimental model of allergic conjunctivitis. A conjunctival allergic reaction was induced with antigen in sensitized guinea pigs. Conjunctival vascular permeability changes were evaluated with the prophylactic use of an inhibitor of nitric oxide synthase (L-NAME) and a cycloxygenase inhibitor (indomethacin). To study a possible interaction between nitric oxide and prostaglandin synthesis in the acute phase of allergic conjunctivitis, the levels of nitrite and PGE2 were determined in lavage fluid. The prophylactic use of L-NAME on the formation of conjunctival edema in response to topical PGD2 administration was studied by measurement of albumin levels in lavage fluid. Both nitric oxide and PGE2 are synthesized in response to antigen provocation and after histamine administration. Nitric oxide and PGE2 are produced simultaneously in the conjunctiva and they showed identical synthesis profiles in response to antigen provocation. Pretreatment with L-NAME inhibited the synthesis of PGE2 whereas exogenous administration of nitric oxide increased the level of PGE2 in lavage fluid. Prophylactic treatment with L-NAME significantly inhibited the PGD2 induced albumin extravasation. Nitric oxide seems to play an important role in the acute phase of allergic conjunctivitis it may stimulate PGE2 production and acts as a secondary mediator in PGD2 and histamine induced conjunctival edema.  相似文献   

12.
The following communicates the pharmacology of Wy-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methanesulfonamide) a chemically novel and orally potent leukotriene (LT) D4 receptor antagonist. In the isolated guinea-pig trachea pretreated with indomethacin (5 microM) and L-cysteine (10 mM), Wy-48,252 antagonized TD4-induced contraction with a pKB = 7.6. Against LTC4 on tissues pretreated with IND and glutathione (10 mM), Wy-48,252 had a pKB greater than 5. Wy-48,252 (10 microM) did not antagonize pilocarpine-, histamine- or PGF2 alpha-induced tracheal contraction. Further, in the presence of indomethacin and chlorpheniramine (1 microM), Wy-48,252 dose-dependently inhibited the antigen-induced contraction of guinea-pig trachea in a manner consistent with antagonism at the LTD4 receptor and inhibition of LT synthesis. In the Konzett-Rossler model of i.v. LTD4-induced bronchoconstriction in indomethacin treated guinea pigs, intragastric Wy-48,252 (2 hr) had an ID50 of 100 micrograms/kg and a functional half-life of 5 hr. Against i.v. antigen-induced bronchoconstriction in guinea pigs treated with indomethacin and chlorpheniramine, intragastric Wy-48,252 (2 hr) had an ID50 of 0.6 mg/kg and a 5 hr half life. Intragastric Wy-48,252 also selectively blocked the cutaneous wheal reaction to intradermal LTD4 but not histamine. We conclude that Wy-48,252 is distinguished from other selective LTD4 receptor antagonists by its oral potency and should be useful in ascertaining the role of LTD4 mediated processes in asthma, allergy and animal models.  相似文献   

13.
P Sirois  S Roy  P Borgeat 《Prostaglandins》1983,26(1):91-101
The novel metabolites of arachidonic acid, leukotriene (LT) A4, B4, C4, D4 and E4 have potent myotropic activity on guinea-pig lung parenchymal strip in vitro. The receptors responsible for their action were characterized using desensitization experiments and the selective SRS-A antagonist, FPL-55712. During the continuous infusion of LTB4, the tissues became desensitized to LTB4 but were still responsive to histamine, LTA4, LTC4, LTD4 and LTE4. When LTD4 was infused continuously, the lung strips contracted to LTB4 and histamine but were no longer responsive to LTA4, LTC4, LTD4 and LTE4. Furthermore, FPL-55712 (10 ng ml-1 - 10 ug ml-1) produced dose-dependent inhibitions of LTA4, LTC4, LTD4 and LTE4 without inhibiting the contraction to LTB4 and histamine. On the basis of these results, it appears that the guinea-pig lung parenchyma may have one type of receptor for LTB4 and another for LTD4; LTA4, LTC4 and LTE4 probably act on the LTD4 receptor.  相似文献   

14.
Basophils accumulate in response to antigen challenge in cutaneous basophil hypersensitivity (CBH) reactions. Two ocular diseases, vernal conjunctivitis and contact-lens-associated conjunctivitis, are also characterized by this histopathology. We have refined a model previously developed in guinea pig conjunctiva by precisely defining the site of antigen injection and correlating the site with the clinical and histologic changes. Guinea pigs were primed by an intradermal injection of keyhole limpet hemocyanin (KLH) in the flank and challenged (Day 6) by injection of a small bolus of KLH just under the conjunctival epithelium. Twenty-four hours later histologic examination showed a perivascular infiltrate of inflammatory cells containing large numbers of basophils. Eosinophils, neutrophils, macrophages, and mast cells were also seen. Serial sections of the reaction site showed discrete boundaries. At all sites examined in antigen-challenged tissues, there were significantly more basophils than in control-injected conjunctiva. Insertion of a sterile needle or injection of PBS or KLH into normal conjunctiva induced a significant increase in neutrophils and some macrophages. Injection of graded doses of antigen into the conjunctiva of primed animals, resulted in a dose-dependent increase in basophils up to 50 micrograms KLH (optimal dose).  相似文献   

15.
To determine whether the release of newly formed mediators such as the peptidoleukotrienes and platelet-activating factor might modulate the food protein induced jejunal smooth muscle contraction observed in sensitized rats, Hooded-Lister rats were sensitized by injection of ovalbumin (10 micrograms i.p.) and controls were sham sensitized with saline. Fourteen days later the contractility of longitudinally (n = 9) and circularly (n = 9) oriented jejunal segments (mucosa intact) were examined in standard tissue baths in response to antigen, leukotrienes, and platelet-activating factor alone and in the presence of a specific leukotriene receptor antagonist (MK-571), a 5-lipoxygenase inhibitor (L651,392), and a platelet-activating factor receptor antagonist (WEB 2086). Although the responses of control and sensitized tissues to stretch and 10(-4) M bethanechol were similar, only sensitized tissues contracted in response to antigen (1 mg/mL). MK-571 (10(-5) M) reduced or significantly inhibited the contractile response of sensitized longitudinally and circularly oriented tissues to 10(-7) M leukotrienes C4, D4, or E4, but neither L651,392 (10(-4) M) nor MK-571 (10(-5) M) significantly reduced the contractile response of sensitized tissues to antigen challenge. WEB 2086 (10(-4) M) significantly (p less than 0.01) reduced the contractile response of sensitized longitudinally and circularly oriented tissues to 10(-7) M platelet-activating factor but did not significantly alter the response to antigen in longitudinally (45% of control, p = 0.14) or circularly (118% of control, ns) oriented jejunal smooth muscle. In this model leukotrienes and platelet-activating factor play an insignificant role in modulating food protein induced jejunal smooth muscle contraction in intestinal anaphylaxis.  相似文献   

16.
Permeability changes in the guinea-pig skin following intradermal (i.d.) injection of tachykinin agonists or antigen were monitored through the extravasation of 99mTc-labelled human serum albumin and blood flow changes through the accumulation of 51Cr-labelled microspheres. A variety of synthetic and natural tachykinins, including substance P and neurokinins A and B, were shown to be potent inducers of permeability changes. Neurokinins A and B, but not substance P, were also shown to be apparent vasoconstrictor agents. Permeability responses in sensitized guinea pigs to i.d. injection of antigen and substance P, but not histamine, were abolished by pretreatment with the tachykinin antagonists [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P and [D-Pro2, D-Trp7,9]-substance P. Interpretation of such results was complicated by the fact that such antagonists may in themselves induce mast cell activation. Depletion of substance P containing neurons by pretreatment of guinea pigs with capsaicin also produced significant inhibition of antigen-induced permeability changes. These results indicate a possible role for tachykinins, such as substance P, in cutaneous anaphylaxis in the guinea pig.  相似文献   

17.
The effects of several calcium antagonists, i.e., nifedipine, verapamil and 8-[N,N-diethylamino]-octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8), were evaluated in situ on agonist-induced increases in permeability of the airway microvasculature in anesthetized guinea pigs. Vascular permeability was measured as tracheal extravascular albumin content by using 125I-bovine serum albumin and the utilization of 51Cr labelled-erythrocytes to correct for blood volume. Intratracheal injections of histamine (1, 10 and 100 micrograms) or leukotriene (LT) D4 (1, 10 and 100 ng) produced dose-dependent increases in extravasated radiolabelled albumin in the trachea. Although histamine produced a greater maximal response than LTD4, the latter provocation was ten times more potent than the former. Nifedipine, a dihydropyridine calcium slow channel blocker, exhibited dose-dependent (30, 100 and 300 micrograms/kg) inhibitory activity against histamine-induced increases in extravascular albumin, while another calcium slow channel blocker, verapamil (100, 300 and 1000 micrograms/kg), exhibited much less activity. TMB-8, a purported intracellular calcium antagonist (1 and 10 mg/kg), was observed to have some inhibitory activity versus histamine. Similar doses of all three calcium antagonists failed to significantly inhibit increases in tracheal microvascular permeability evoked by LTD4. These results suggest that differences in mediator-induced microvascular permeability in the guinea pig trachea are evident depending upon the agonist selected and the pool of calcium utilized.  相似文献   

18.
Verlukast (MK-679) (3-[(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl)[3-(dimethylamino)- 3- oxopropyl)thio)methyl)-thio)propionic acid) is a potent and selective inhibitor of [3H]leukotriene D4 binding in guinea-pig (IC50 = 3.1 +/- 0.5 nM) and human (IC50 = 8.0 +/- 3.0 nM) lung homogenates and dimethyl sulfoxide differentiated U937 cell membrane preparations (IC50 = 10.7 +/- 1.6 nM) but is essentially inactive versus [3H]leukotriene C4 binding in guinea-pig lung homogenates (IC50 values of 19 and 33 microM). Functionally, when tested at 60 nM, it antagonized contractions of guinea-pig trachea (GPT) induced by leukotriene C4, leukotriene D4, and leukotriene E4 (respective-log KB values of 8.6, 8.8, and 8.9) and contractions of human trachea (HT) induced by leukotriene D4 (-log KB value 8.3 +/- 0.2). In contrast, verlukast (20-200 nM) failed to antagonize contractions of GPT induced by leukotriene C4 in the presence of 45 mM L-serine borate. Intravenous (i.v.) and aerosol verlukast antagonized bronchoconstriction (BC) induced in anaesthetized guinea pigs by i.v. leukotriene D4 but did not block BC to arachidonic acid or histamine. Intraduodenal verlukast (0.25 mg/kg) antagonized leukotriene D4 (0.2 micrograms/kg) induced BC in guinea pigs. Oral and aerosol administration blocked leukotriene D4-induced BC in conscious squirrel monkeys. Orally administered compound also blocked ovalbumin-induced BC in conscious sensitized rats treated with methysergide (3 micrograms/kg). The pharmacological profile for verlukast is similar to that of the racemic compound, MK-571. Verlukast is currently in clinical development for the treatment of asthma and related diseases.  相似文献   

19.
The effect of synthetic leukotrienes on tracheal microvascular permeability   总被引:4,自引:0,他引:4  
The effect of synthetic leukotrienes (LT) C4, D4 and E4 on the permeability of the airway microvasculature to plasma albumin was quantitatively evaluated using an in situ guinea pig tracheal model. Vascular permeability was measured as extravascular albumin content by employing 125I-bovine serum albumin and, in order to correct for blood volume, 51Cr-erythrocytes were used. Intratracheal injection of synthetic LTC4, LTD4 and LTE4 (0.1-1000 ng) produced dose-dependent increases in tracheal extravascular albumin content. The leukotrienes were approximately 100-1000 fold more potent than histamine, although histamine did produce a greater maximal increase in extravascular albumin than the leukotrienes. Methacholine did not increase extravascular albumin content. The microvascular permeability effect of LTD4 was antagonized by FPL 55712 but not by mepyramine; conversely, the effect of histamine was antagonized by mepyramine and not by FPL 55712. Additionally, indomethacin did not alter the LTD4-induced increases in tracheal vascular permeability. These results suggest that the effect of LTD4 on tracheal microvascular permeability is directly mediated and is not the indirect result of cholinergic stimulation, histamine release or de novo synthesis of cyclooxygenase products.  相似文献   

20.
Histamine is an important mediator of immediate hypersensitivity for both animals and humans. The action of histamine on target tissues is believed to be mediated by specific cell surface receptors, especially H1 and H2 receptors for hypersensitivity and inflammatory reactions, which involve stimulation of smooth muscle contractility, alterations in vascular permeability, and modifications in the activities of macrophages and lymphocytes. Although the nature of histamine receptors in the brain and peripheral tissues has been studied extensively by many laboratories, the molecular mechanism of histamine receptor-mediated reactions is not fully understood, mainly because histamine receptors are incompletely characterized from the biochemical point of view. In previous studies, we have found that the cultured smooth muscle cell line DDT1MF-2, derived from hamster vas deferens, expresses low-affinity histamine H1 receptors and responds biochemically and functionally to H1-specific stimulation (Mitsuhashi and Payan, J Cell Physiol 134:367, 1988). This cell line provides a model for analyzing the biochemical responses of H1 receptor-mediated reactions in peripheral tissues. In this review, we summarized our recent progress in the study of low-affinity H1 receptors on DDT1MF-2 cells.  相似文献   

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