Rolipram inhibits airway microvascular leakage induced by platelet-activating factor,histamine and bradykinin in guinea-pigs

Abstract— Rolipram (0·1–1000 μg kg^?1, i.v.) reduced the increase in microvascular permeability induced by platelet-activating factor (PAF; 50 ng kg^?1, i.v.) at different sites of the guinea-pig airways. Rolipram (1–100μg kg^?1, i.v.) inhibited histamine (30μg kg^?1, i.v.)-and bradykinin (0·3 μg kg, i.v.)-induced airway microvascular leakage. These effects of rolipram were obtained at doses which inhibit histamine (7–20 μg kg^?1 min^?1)-induced bronchoconstriction (IC50 = 3 ± 1 μg kg, i.v.) without depressing arterial blood pressure in the guinea-pig. Aminophylline (50 mg kg^?1) did not change the effect of PAF. The anti-exudative effect of rolipram is of potential therapeutic value in asthma.     

Neurogenic airway microvascular leakage induced by toluene inhalation in rats

Toluene is a representative airborne occupational and domestic pollutant that causes eye and respiratory tract irritation. We investigated whether a single inhalation of toluene elicits microvascular leakage in the rat airway. We also evaluated the effects of CP-99,994, a tachykinin NK(1) receptor antagonist, and ketotifen, a histamine H1 receptor antagonist with mast cell-stabilizing properties, on the airway response. The content of Evans blue dye that extravasated into the tissues was measured as an index of plasma leakage. Toluene (18-450 ppm, 10 min) concentration-dependently induced dye leakage into the trachea and main bronchi of anesthetized and mechanically ventilated rats. Toluene at concentrations of ≥ 50 and ≥ 30 ppm caused significant responses in the trachea and main bronchi, respectively, which both peaked after exposure to 135 ppm toluene for 10 min. This response was abolished by CP-99,994 (5 mg/kg i.v.), but not by ketotifen (1mg/kg i.v.). Nebulized phosphoramidon (1 mM, 1 min), a neutral endopeptidase 24.11 inhibitor, significantly enhanced the response induced by toluene (135 ppm, 10 min) compared with nebulized 0.9% saline (1 min). These results show that toluene can rapidly increase airway plasma leakage that is predominantly mediated by tachykinins endogenously released from airway sensory nerves. However, mast cell activation might not be important in this airway response.     

Nociceptin inhibits non-adrenergic non-cholinergic contraction in guinea-pig airway

1. Electrical field stimulation (EFS) of guinea-pig isolated main bronchi induced a non-adrenergic non-cholinergic (NANC) contractile response. Nociceptin (0.01–1 μM) significantly inhibited the contractile response to EFS (P<0.01), but not to capsaicin (P>0.05).
2. The μ-, δ- and κ-opioid receptor antagonists, naloxone (0.3 μM), naltrindole (3 μM) and nor-binaltorphimine (1 μM), respectively, did not significantly affect the inhibitory effect of nociceptin (0.03 μM; P>0.05).
3. The novel nociceptin antagonist, [Phe¹ψ(CH₂-NH)Gly²]nociceptin(1–13)NH₂ (0.03–1 μM); the σ ligands, carbetapentane (30 μM), 3-phenylpiperidine (30–100 μM) and (+)-cyclazocine (10–100 μM) significantly reversed the inhibitory effect of nociceptin (0.03 μM, P<0.05). In contrast, rimcazole, did not significantly reverse the inhibitory effect of nociceptin (0.03 μM) at any concentration tested (P>0.05).
4. EFS of guinea-pig bronchial preparations significantly increased SP-LI release above basal SP-LI (P<0.05). In the presence of nociceptin (1 μM), EFS induced a significant increase in SP-LI release above basal SP-LI release (P<0.05). Nociceptin caused a 59±11% (n=5) inhibition of EFS-induced release of SP-LI.
5. Nociceptin reduces the release of sensory neuropeptides induced by EFS, but not capsaicin, from guinea-pig airways. These experiments provide further evidence for a role for nociceptin in regulating the release of sensory neuropeptides in response to EFS.

     

Alteration in airway microvascular leakage induced by sensorineural stimulation in rats exposed to inhaled formaldehyde

Inhaled formaldehyde can rapidly produce microvascular leakage in the airway through stimulation of tachykinin NK1 receptors by tachykinins released from sensory nerves. Tachykinin NK1 receptors are known to be internalized in the cytoplasm after being stimulated, thus leading to transient attenuation of their action. We investigated time changes in airway microvascular leakage during formaldehyde inhalation for 45 min, and whether pre-inhalation of formaldehyde (5 ppm, 30 min) decreases the responses induced by subsequent inhaled formaldehyde (5 ppm, 15 min), intravenous capsaicin (75 μg/kg) and intravenous substance P (10 μg/kg) in rat airway. Evans blue dye content extravasated into the tissues was measured as an index of plasma leakage. Formaldehyde rapidly produced dye leakage in the airway, a response that ended within 15 min after the start of formaldehyde inhalation. Pre-inhalation of formaldehyde markedly decreased the responses induced by formaldehyde and capsaicin, but not substance P. However, dye leakage induced by formaldehyde was significantly enhanced by formaldehyde inhalation 20 h earlier. Our results suggest that tachyphylaxis in neurogenic airway microvascular leakage seen after formaldehyde inhalation may be due to impairment of tachykinin release from sensory nerves or decreases in tachykinins within sensory nerves. However, desensitization of tachykinin NK1 receptors was unlikely to be important in the tachyphylactic response.     

Nociceptin inhibits vanilloid TRPV-1-mediated neurosensitization induced by fenoterol in human isolated bronchi

Chronic exposure to ₂-adrenoceptor agonists, especially fenoterol, has been shown to increase smooth muscle contraction to endothelin-1 in human bronchi partly through tachykinin-mediated pathways. The purpose of this work was to further investigate the role of sensory nerves in fenoterol-induced sensitization of human airways and the effect of nociceptin, a nociceptin/orphanin FQ (NOP) receptor agonist, on the increase in contraction after fenoterol exposure. Human bronchi from 62 patients were sensitized to endothelin-1 by prolonged incubation with fenoterol (0.1 M, 15 h). The sensitizing effect of fenoterol was inhibited by high concentration of capsaicin (10 M, 30 min before fenoterol sensitization), which induces depletion of mediators from sensory nerves, or co-incubation of fenoterol and capsazepine (1 M), a vanilloid TRPV-1 receptor antagonist. Moreover, short pretreatment of bronchi with capsaicin (10 M) or capsazepine (1 M) after sensitization by fenoterol decreased the rise in smooth muscle contraction to endothelin-1. Nociceptin (1 M) also inhibited the increased contraction in fenoterol-sensitized bronchi. Tertiapin (10 M), an inhibitor of the inward-rectifier K⁺ channels, but not naloxone (0.1 M), a DOP/KOP/MOP receptor antagonist, prevented the inhibitory effect of nociceptin. In conclusion, fenoterol induces sensitization of human isolated bronchi to endothelin-1 in part through the stimulation of the vanilloid TRPV-1 receptor on tachykininergic sensory nerves. Nociceptin inhibits airway hyperresponsiveness via NOP receptor activation. This effect involves inward-rectifier K⁺ channels.     

Nociceptin/orphanin FQ inhibits capsaicin-induced guinea-pig airway contraction through an inward-rectifier potassium channel

Nociceptin/orphanin FQ (N/OFQ), an endogenous opioid-like orphan receptor (NOP receptor, previously termed ORL1 receptor) agonist, has been found to inhibit capsaicin-induced bronchoconstriction in isolated guinea-pig lungs and in vivo. The underlying mechanisms are not clear. In the present studies, we tested the effect of N/OFQ on VR1 channel function in isolated guinea-pig nodose ganglia cells. Capsaicin increased intracellular Ca(2+) concentration in these cells through activation of vanilloid receptors. Capsaicin-induced Ca(2+) responses were attenuated by pretreatment of nodose neurons with N/OFQ (1 microM). N/OFQ inhibitory effect on the Ca(2+) response in nodose ganglia cells was antagonized by tertiapin (0.5 microM), an inhibitor of inward-rectifier K(+) channels, but not by verapamil, a voltage gated Ca(2+) channel blocker, indicating that an inward-rectifier K(+) channel is involved in N/OFQ inhibitory effect. In isolated guinea-pig bronchus, N/OFQ (1 microM) inhibited capsaicin-induced airway contraction. Tertiapin (0.5 microM) abolished the N/OFQ inhibition of capsaicin-induced bronchial contraction. Capsaicin (10 microg) increased pulmonary inflation pressure in the isolated perfused guinea-pig lungs. This response was significantly attenuated by pretreatment with N/OFQ (1 microM). Tertiapin also abolished the N/OFQ inhibitory effect on capsaicin-induced bronchoconstriction in perfused lungs. Capsaicin increased the release of substance P and neurokinin A from isolated lungs. N/OFQ (1 microM) blocked the capsaicin-induced tachykinin release. These results indicate that N/OFQ-induced hyperpolarization of tachykinin containing airway sensory nerves, through an inward-rectifier K(+) channel activation, accounts for the inhibition of capsaicin-evoked broncoconstriction.     

速激肽受体拮抗剂对白三烯C_4诱导豚鼠气道收缩和微血管渗漏的作用

本实验探讨了内源性速激肽是否参与白三烯Ｃ４（ＬＴＣ４）的气道效应．ＬＴＣ４（０．５μｇｋｇ－１，ｉｖ）可增高豚鼠肺内压（ＩＰＰ）和气道内依文思蓝渗出。速激肽ＮＫ－１受体拮抗剂ＣＰ－９６３４５｛（２Ｓ，３Ｓ）－顺式－２－（二苯甲基）－Ｎ－［（２－甲氧苯）－甲基］－１－杂氮双环［２．２．２］辛烷－３－胺｝１ｍｇｋｇ－１，ｉｖ，可减弱ＬＴＣ４诱导的依文思蓝渗出；ＮＫ－２受体拮抗剂ＳＲ－４８９６８｛（Ｓ）－Ｎ－甲基－Ｎ－［４－（４－乙酰氨基－４－苯基哌啶）－２－（３，４－二氯苯基）丁基］苯甲酰胺｝，１ｍｇｋｇ－１，ｉｖ，可抑制ＩＰＰ的增高．白三烯拮抗剂ＯＮＯ－１０７８（０．０３ｍｇｋｇ－１，ｉｖ）可阻断这两种反应．结果说明内源性速激肽增强ＬＴＣ４的气道作用，其中ＮＫ－１受体介导微血管渗漏，ＮＫ－２受体介导支气管收缩．     

Modulation of neurally mediated airway microvascular leakage in guinea-pig airways by beta 2-adrenoceptor agonists.

The effect of two beta 2-adrenoceptor agonists, salbutamol (100 micrograms/kg i.v.) and broxaterol (100 micrograms/kg i.v.), on airway microvascular leakage induced by vagal stimulation was studied in anaesthetised guinea pigs. Airway microvascular leakage was measured by Evans blue extravasation. Broxaterol, but not salbutamol, inhibited Evans blue dye extravasation at all airway levels, an effect prevented by pretreatment with propranolol (1 mg/kg). Neither of the beta 2-agonists had any effect on substance P-induced Evans blue dye extravasation. Broxaterol inhibits the prejunctional release of tachykinins from airway sensory nerves by stimulation of beta-receptors. The mechanism by which beta-adrenoceptor agonists prevent airway microvascular leakage deserves further study.     

Tepoxalin inhibits inflammation and microvascular dysfunction induced by abdominal irradiation in rats

BACKGROUND: Inflammatory cells contribute to the acute and sub-acute sequelae of radiation therapy. Tepoxalin, an inhibitor of cyclooxygenase and 5-lipoxygenase that suppresses NF-kappaB activation, has potent anti-inflammatory activity. AIMS: To assess the effects of tepoxalin on radiation-induced inflammatory damage, and determine its mechanisms of action. METHODS: Leucocyte rolling, adhesion and emigration, and albumin leakage were determined by intra-vital microscopy in rat mesenteric venules. NF-kappaB activation was measured by electrophoretic mobility shift assays, and endothelial intercellular adhesion molecule-1 expression by the radiolabelled antibody technique. Groups of irradiated rats were treated with tepoxalin, N-acetyl-L-cysteine, zileuton (lipoxygenase inhibitor), or vehicle. RESULTS: Irradiated animals had a marked increase in the number of rolling, adherent and emigrated leucocytes in mesenteric venules, and in microvascular permeability. Tepoxalin prevented leucocyte adhesion and the increase in permeability after radiation. Tepoxalin did not inhibit radiation-induced NF-kappaB activation or intercellular adhesion molecule-1 up-regulation, while N-acetyl-L-cysteine, which attenuated NF-kappaB activation, had no effect on leucocyte recruitment. In contrast, tepoxalin inhibited the increase in leukotriene B4 levels after radiation, and the anti-inflammatory effects of the drug were mimicked by zileuton. CONCLUSIONS: Tepoxalin affords significant protection against radiation-induced inflammation and microvascular dysfunction in splanchnic organs through a mechanism dependent on leukotriene synthesis inhibition.     

Effects and interactions of sensory neuropeptides on airway microvascular leakage in guinea-pigs.

1. We have studied the effect of the sensory neuropeptides substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and calcitonin gene-related peptide (CGRP) on microvascular permeability in guinea-pig airways in vivo and investigated whether CGRP would potentiate the effect of SP. We used the extravasation of intravenously-injected Evans blue dye as an index of permeability. 2. The tachykinins SP, NKA and NKB (0.025-5.0 nmol kg-1, i.v.) significantly (P less than 0.05) increased extravasation of dye in a dose-related manner and with a similar pattern of distribution; they were most potent in the trachea and main bronchi, less potent in the larynx and intrapulmonary airways, and had little significant effect in the bladder. 3. SP was significantly more potent in causing extravasation of dye than NKA or NKB with ED50 values (nmol kg-1) in the range 0.04-0.1, depending on the airway level, compared with values in the range 0.3-0.7 for the neurokinins. 4. CGRP (0.0025-2.5 nmol kg-1, i.v.) had no significant effect on microvascular permeability and did not potentiate SP-induced extravasation of dye. 5. Each neuropeptide decreased mean arterial blood pressure, indicating vasodilatation, in a dose-related manner. Co-injection of CGRP and SP produced additive decreases in arterial pressure. 6. We conclude that, in guinea-pig airways, tachykinins increase microvascular permeability via tachykinin receptors of the NK-1 sub-type (indicated by an order of potency of SP greater than NKA = NKB) on endothelial cells. The response appears to be related to mechanisms in addition to vasodilatation. The relevance of the responses to the tachykinins in asthma is discussed.     

Formoterol and salbutamol inhibit bradykinin- and histamine-induced airway microvascular leakage in guinea-pig.

1. The effects of the beta 2-adrenoceptor agonists, salbutamol and formoterol, on the increase of microvascular permeability induced by histamine or bradykinin in guinea-pig airways have been studied in vivo. Extravasation of intravenously injected Evans blue dye was used as an index of permeability. The effects of salbutamol and formoterol on the increase in pulmonary airway resistance induced by histamine or bradykinin have also been studied. 2. The increase in pulmonary airway resistance induced by histamine or bradykinin was totally inhibited by salbutamol and formoterol. The ED50 of the two mediators were 0.59 +/- 0.21 (n = 5) and 0.20 +/- 0.14 (n = 5) micrograms kg-1 respectively for salbutamol, and 0.13 +/- 0.12 (n = 6) and 0.02 +/- 0.01 (n = 6) micrograms kg-1 respectively for formoterol. 3. Salbutamol (10 and 30 micrograms kg-1) and formoterol (1 and 10 micrograms kg-1) inhibited the increase of microvascular permeability induced by histamine (30 micrograms kg-1) in the guinea-pig airways. The inhibitory effect was predominant in the trachea and the main bronchi, with a maximum inhibition of 20 to 50%. The two drugs had little or no inhibitory effect on the other structures studied, viz. nasal mucosa, larynx, proximal and distal intrapulmonary airways. 4. Salbutamol and formoterol (1 and 10 micrograms kg-1) abolished the increase in microvascular permeability induced by bradykinin (0.3 micrograms kg-1). This inhibitory effect of two beta-adrenoceptor stimulants was predominant in the trachea and the nasal mucosa where it was observed with 1 microgram kg-1 of the beta-adrenoceptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tryptase-induced airway microvascular leakage in guinea pigs: involvement of tachykinins and leukotrienes.

Tryptase, a serine protease synthesized by and stored in mast cells, is implicated as an important mediator in the pathogenesis of airway inflammation. In this study, tryptase was evaluated for its ability to induce microvascular leakage into the airways of guinea pigs. Dose- and time-dependent increases in airway microvascular leakage were produced by intratracheal tryptase (0.3-3 microg). Intratracheal tryptase (3-30 microg) had no effect on airway tone as measured by pulmonary insufflation pressure. Tryptase-induced airway microvascular leakage was partially blocked by the tachykinin NK1 receptor antagonist CP 99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] and an inhibitor of leukotriene formation SCH 37224 (1-(1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-1,8-naphthyridin-2-yl)pyrrolidinium, hydroxide inner salt). Neither CP 99994 nor SCH 37224 inhibited tryptase proteolytic activity in-vitro. Pretreatment of guinea pigs with histamine H1 receptor antagonists or a tachykinin NK2 receptor antagonist had no affect on the airway microvascular leakage induced by tryptase. It is speculated that tryptase may be important in the pathogenesis of airway inflammation, particularly in disorders that involve increased airway microvascular leakage such as asthma.     

速激肽受体拮抗剂对白三烯C4诱导豚鼠气道收缩和微血管渗漏的作用

本实验探讨了内源性速激肽是否参与白三烯C₄(LTC₄)的气道效应. LTC₄(0.5 μg·kg^-1, iv)可增高豚鼠肺内压(IPP)和气道内依文思蓝渗出。速激肽NK-1受体拮抗剂CP-96345｛(2S, 3S)-顺式-2-( 二苯甲基)-N-［(2-甲氧苯)-甲基］-1-杂氮双环［2.2.2］辛烷-3-胺｝ 1 mg·kg^-1，iv，可减弱LTC₄诱导的依文思蓝渗出；NK-2受体拮抗剂SR-48968｛(S)-N-甲基-N-［4-(4-乙酰氨基-4-苯基哌啶)-2-(3,4-二氯苯基)丁基］苯甲酰胺｝，1 mg·kg^-1， iv，可抑制IPP的增高. 白三烯拮抗剂ONO-1078 (0.03 mg·kg^-1, iv)可阻断这两种反应. 结果说明内源性速激肽增强 LTC₄的气道作用，其中NK-1受体介导微血管渗漏，NK-2受体介导支气管收缩.     

Effect of mequitamium iodide (LG 30435) on airway microvascular leakage in the guinea-pig

Intravenous administration of mequitamium iodide (LG 30435) prevented the increase of tracheobronchial vascular permeability induced either by antigen challenge or by exogenous histamine in the guinea-pig, while it was ineffective against PAF, serotonin or capsaicin. These findings indicate that mequitamium iodide selectively interferes with the effect of histamine on airway microvascular leakage, mediated by histamine H₁ receptors, and is more potent than diphenhydramine, mequitazine or astemizole. Histamine receptor antagonism is likely to be a major determinant of the antiallergic activity of the compound, although additional mechanisms may be involved.     

Pharmacological modulation of inhaled sodium metabisulphite-induced airway microvascular leakage and bronchoconstriction in the guinea-pig.

1. We have investigated the effects of chlorpheniramine, atropine and capsaicin pretreatment on inhaled sodium metabisulphite (MBS)-induced airway microvascular leakage and bronchoconstriction in anaesthetized guinea-pigs in order to clarify the mechanisms involved in these responses. The effects of frusemide and nedocromil sodium were also examined. 2. Lung resistance (RL) was measured for 6 min after inhalation of MBS (20, 40, 80 and 200 mM; 30 breaths), followed by measurement of extravasation of Evans blue dye into airway tissues, used as an index of airway microvascular leakage. MBS caused an increase in RL and leakage of dye at all airway levels in a dose-dependent manner. 3. Chlorpheniramine (10 mg kg-1, i.v.), atropine (1 mg kg-1, i.v.), their combination or inhaled nedocromil sodium (10 mg ml-1, 7 min) had no effect against the airway microvascular leakage induced by 80 mM MBS (30 breaths). Capsaicin pretreatment (50 mg kg-1, s.c.) caused a significant decrease in the leakage of dye in the main bronchi and inhaled frusemide (10 mg ml-1, 7 min) also in the main bronchi and proximal intrapulmonary airway. 4. Chlorpheniramine, atropine, their combination, capsaicin pretreatment and frusemide, but not nedocromil sodium, inhibited significantly the peak RL induced by 80 mM MBS (30 breaths) by approximately 50%. 5. We conclude that a cholinergic reflex and neuropeptides released from sensory nerve endings may participate in the mechanisms of MBS-induced airway responses. Frusemide but not nedocromil sodium may have an inhibitor effect on these neural mechanisms. The inhibitory effect of nedocromil sodium against lower doses of MBS is not excluded.     

Bradykinin B2 antagonist HOE 140 inhibits late allergic microvascular leakage in guinea pig airways

Because bradykinin has potent inflammatory actions, this molecule may be involved in the late allergic response (LAR). We investigated the role of the molecule in airway microvascular hyperpermeability during the LAR. Three weeks after ovalbumin (OVA) sensitization, animals were pretreated with bradykinin B2 receptor antagonist HOE 140 or vehicle for 30 min before the OVA inhalation challenge. The occurrence of LAR was judged by a two-fold increase in transpulmonary pressure (Ptp) from the baseline values. The microvascular permeability in the trachea was assessed by an index defined as the ratio of the area of vasculature labeled by the Monastral blue dye (area density percent). Significant microvascular hyperpermeability were observed during the LAR. The bradykinin concentrations in the bronchoalveolar lavage-fluid (BAL-f) were increased during the LAR. HOE 140 (0.1-10 mg/kg, s.c.) inhibited the airway microvascular hyperpermeability during the LAR dose-dependently. These findings suggest that bradykinin may play an important role in microvascular hyperpermeability during the LAR.     

A histological method for studying the effects of drugs on mediator-induced airway microvascular leakage in rodents

Methods are described for studying the effects of drugs on increases in tracheobronchial microvascular permeability (leakage) induced by inflammatory mediators. A model in conscious guinea pigs (in which the leakage effects resulted from circulating mediator) and a model in anesthetized rats (in which the leakage effects resulted from application of the mediator to the airway lumen) are described. Inhibitor drugs were given i.v. 2 min before the mediator. In guinea pigs either histamine or leukotriene D₄ (LTD₄) and colloidal carbon (C, the tracer molecule for leakage) were administered together iv.; in rats 5-hydroxytryptamine (5-HT, 100 μg) was injected intratracheally followed by i.v. colloidal carbon. Tracheal and bronchial tissues were removed 15 min later from the killed animals and prepared for histology, and the number of C-labeled microvessels in the mucosal/submucosal region of 7-μm sections was counted. In guinea pigs, leakage produced by LTD₄ or histamine was related to the dose administered and the relative potency of LTD₄: histamine was approximately 123:1, on a molar basis. Leakage caused by histamine, but not by LTD₄, was prevented by mepyramine (1 mg/kg) and LTD₄-induced leakage was prevented by FPL 55712 (1 mg/kg). Terbutaline (1 mg/kg) attenuated leakage to both mediators but never abolished it. In rats, leakage was also seen to 5-HT, which was prevented by methysergide (1 mg/kg) and markedly attenuated by ketanserin (1 mg/kg) or by terbutaline (1 mg/kg). It is suggested that the colloidal carbon tracer technique has application to pharmacological studies designed to examine the effects of drugs on mediator-induced permeability to macromolecules in the tracheobronchial microcirculation.     

Lack of a role for bradykinin in inhaled sodium metabisulphite-induced airway microvascular leakage in guinea pigs

We have investigated the role of bradykinin in airway microvascular leakage and bronchoconstriction induced by inhaled sodium metabisulphite (MBS) in guinea pigs. A selective bradykinin B2 receptor antagonist, HOE 140 (D-Arg[Hyp³, Thi⁵, D-Tic⁷, Oic⁸]-bradykinin), was used because this drug has been shown to abolish the airway responses induced by bradykinin. Lung resistance (R_L) was measured for 6 min after challenge with MBS, followed by measurement of extravasation of Evans Blue dye into airway tissues, used as an index of plasma exudation. Aerosolized MBS (40 and 80 mmol/L, 30 breaths) induced a significant increase in R_L and leakage of dye in the trachea, main bronchi and intrapulmonary airways, whereas 20 mmol/L MBS caused these responses except for the dye leakage in the trachea and main bronchi. HOE 140 (100 nmol/kg iv) had no effect against these airway responses. We conclude that bradykinin-mediated mechanisms do not play a significant role in the acute airway effects induced by inhaled MBS.     

白三烯拮抗剂ONO－1078对辣椒素和P物质诱导豚鼠支气管收缩和微血管渗漏的作用

目的：探讨白三烯特异性拮抗剂４氧８［对（４苯丁氧基）苯甲酰氨基］２（５四唑基）４Ｈ１苯并吡喃半水合物（ＯＮＯ１０７８）对气道辣椒素敏感的感觉神经功能的调节作用．方法：观察豚鼠肺内压（ＩＰＰ）、伊文思蓝渗出量和离体支气管平滑肌收缩反应．结果：辣椒素（Ｃａｐ，００５ｍｇ·ｋｇ－１，ｉｖ）、Ｐ物质（ＳＰ，１μｇ·ｋｇ－１，ｉｖ）和白三烯Ｃ４（ＬＴＣ４，０５μｇ·ｋｇ－１，ｉｖ）增高ＩＰＰ和支气管及肺内气道伊文思蓝渗出量，ＯＮＯ１０７８（００３ｍｇ·ｋｇ－１，ｉｖ）完全阻断ＬＴＣ４的作用，减弱Ｃａｐ的作用，但不影响ＳＰ的作用．ＯＮＯ１０７８（１μｍｏｌ·Ｌ－１）还显著抑制Ｃａｐ收缩支气管平滑肌，对ＳＰ无效．结论：ＯＮＯ１０７８通过抑制感觉神经肽释放而部分抑制Ｃａｐ的作用．     

Nociceptin inhibits cough in the guinea-pig by activation of ORL(1) receptors

We studied the central and peripheral antitussive effect of ORL(1) receptor activation with nociceptin/orphanin FQ in conscious guinea-pigs. In guinea-pig cough studies, nociceptin/orphanin FQ (10, 30, and 90 microg) given directly into the CNS by an intracerebroventricular (i.c.v.) route inhibited cough elicited by capsaicin exposure by approximately 23, 29 and 52%, respectively. The antitussive activity of nociceptin/orphanin FQ (90 microg, i.c.v.) was blocked by the selective ORL(1) antagonist [Phe(1)gamma(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) (180 microg, i.c.v.) and J113397 (10 mg kg(-1), i.p.) but not by the opioid antagonist, naltrexone (3 mg kg(-1), i.p.). Furthermore, intravenous (i.v.) nociceptin/orphanin FQ (1.0 and 3.0 mg kg(-1)) also inhibited cough approximately by 25 and 42%, respectively. These findings indicate that selective ORL(1) agonists display the potential to inhibit cough by both a central and peripheral mechanism, and potentially represent a novel therapeutic approach for the treatment of cough.