Airway Responsiveness In Guinea Pigs Research Articles

Effect of endotoxin inhalation on airway responsiveness in guinea pigs

Effect of endotoxin inhalation on airway responsiveness in guinea pigs

Heterogeneous effect of leucotriene CysLT1receptor antagonists on antigen-induced motor and inflammatory responses in guinea-pig airways

1. The effect of montelukast or MEN91507, selective leucotriene CysLT1 receptor antagonists, on antigen-induced airway inflammation and bronchoconstriction were compared in anaesthetized guinea-pigs. 2. In sensitized animals, ovalbumin (0.3 mg kg(-1), i.v.)-induced microvascular leakage in trachea, intrapulmonary airways, total lung (parenchyma and intrapulmonary airways) and urinary bladder was reduced by MEN91507 (0.01-1 micromol kg(-1), i.v.), whereas montelukast (0.01-1 micromol kg(-1), i.v.) antagonized the effect of the antigen only in the lung and urinary bladder. 3. Ovalbumin (1 mg kg(-1), i.v.)-induced bronchoconstriction was dose dependently antagonized by MEN91507 (10-30 micromol kg(-1), i.v.), whereas the effect of montelukast (0.1-30 micromol kg(-1), i.v.) was marginal (15-30% inhibition). Neither MEN91507 nor montelukast (30 micromol kg(-1), i.v.) affected the bronchoconstrictor response induced by acetylcholine (0.3 micromol kg(-1), i.v.) in sensitized animals. 4. It is concluded that montelukast and MEN91507 display a differential activity against the effect of endogenous leucotrienes, despite the fact that both compounds show a similar antagonist profile against exogenous leucotrienes acting through CysLT1 receptors.

Hydrogen sulfide causes vanilloid receptor 1‐mediated neurogenic inflammation in the airways

Hydrogen sulfide (H(2)S) is described as a mediator of diverse biological effects, and is known to produce irritation and injury in the lung following inhalation. Recently, H(2)S has been found to cause contraction in the rat urinary bladder via a neurogenic mechanism. Here, we studied whether sodium hydrogen sulfide (NaHS), used as donor of H(2)S, produces responses mediated by sensory nerve activation in the guinea-pig airways. NaHS evoked an increase in neuropeptide release in the airways that was significantly attenuated by capsaicin desensitization and by the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine. In addition, NaHS caused an atropine-resistant contraction of isolated airways, which was completely prevented by capsaicin desensitization. Furthermore, NaHS-induced contraction was reduced by TRPV1 antagonism (ruthenium red, capsazepine and SB366791), and was abolished by pretreatment with the combination of tachykinin NK(1) (SR140333) and NK(2) (SR48968) receptor antagonists. In anesthetized guinea-pigs, intratracheal instillation of NaHS increased the total lung resistance and airway plasma protein extravasation. These two effects were reduced by TRPV1 antagonism (capsazepine) and tachykinin receptors (SR140333 and SR48968) blockade. Our results provide the first pharmacological evidence that H(2)S provokes tachykinin-mediated neurogenic inflammatory responses in guinea-pig airways, and that this effect is mediated by stimulation of TRPV1 receptors on sensory nerves endings. This novel mechanism may contribute to the irritative action of H(2)S in the respiratory system.

Exposure to diesel exhaust exacerbates allergen-induced airway responses in guinea pigs.

Diesel exhaust (DE) is a major air pollutant in urban areas. To clarify the effects of DE on the exacerbation of asthma, guinea pigs were exposed 12 h daily to 3 mg/m(3) DE or air for 8 wk with or without sensitization to ovalbumin (OVA). In the DE-exposed sensitized animals, both immediate (IAR) and late (LAR) airway responses were enhanced after the inhalation challenge by OVA, compared with the DE-unexposed sensitized animals. Mucus was greatly accumulated in the airways of DE-exposed sensitized animals during IAR. The number of eosinophils and level of sialic acid concentration in bronchial lavage fluids were also significantly higher in the DE-exposed sensitized animals than in the DE-unexposed control animals. During LAR, intercellular spaces of the bronchial epithelium became enlarged in the DE-exposed sensitized animals, showing infiltration by numerous eosinophils. Albumin concentration was significantly higher in the bronchial lavage fluids from the DE-exposed sensitized animals than in those from the DE-unexposed control animals. These results suggest that exposure to DE enhances mucus hypersecretion and eosinophilic inflammation during IAR. DE exposure also increases airway permeability and airway inflammation during LAR. Thus, DE exposure exacerbates allergen-induced airway responses in guinea pigs.

Chronic smoking enhances tachykinin synthesis and airway responsiveness in guinea pigs.

This study tests the hypothesis that the bronchial hyperreactivity induced by chronic cigarette smoke (CS) exposure involves the increased expression and release of tachykinins and calcitonin gene-related peptide (CGRP) from afferent nerve fibers innervating the airways. In guinea pigs chronically exposed to CS (20 min twice daily for 14-17 d), peak response in total lung resistance to capsaicin (1.68 microg/kg, intravenously) was significantly greater than that evoked by the same dose of capsaicin in control (air-exposed) animals. This augmented response in CS-exposed animals was abolished after treatment with CP-99994 and SR-48968, the neurokinin (NK)-1 and NK-2 receptor antagonists, suggesting the involvement of tachykinins in chronic CS-induced airway hyperresponsiveness (AHR). Further, substance P (SP)-like immunoreactivity (LI) and CGRP-LI in the airway tissue were significantly greater in the CS animals than in the control animals. Finally, beta-preprotachykinin (PPT, a splice variant from the PPT A gene encoding tachykinins including SP and NKA) messenger RNA levels as measured by in situ hybridization histochemistry displayed a significant increase in jugular ganglion neurons but not in dorsal root or nodose ganglion neurons. These data suggest that chronic CS-induced AHR is related to an increase in SP synthesis and release in jugular ganglion neurons innervating the lungs and airways.

Role of neutrophil elastase in ozone-induced airway responses in guinea-pigs.

Ozone-induced airway hyperresponsiveness occurs concurrently with neutrophilic inflammation and epithelial injury in various species including humans. The mechanism of neutrophil-induced airway hyperresponsiveness, however, has not yet been fully clarified. Neutrophil elastase (NE) is a multipotent protease released from activated neutrophils, which may play a role in ozone-induced airway hyperresponsiveness. In order to address this issue, the effects of ONO-5046, a specific NE inhibitor, were investigated in ozone-exposed guinea-pigs. Awake animals were exposed to ozone at 3 parts per million for 2 h, airway responsiveness to acetylcholine (ACh) measured and examination of bronchoalveolar lavage fluid (BALF) performed. Ozone exposure increased airway responsiveness to both inhaled and intravenous ACh, the concentration of NE in BALF and the number of neutrophils and airway epithelial cells in BALF. Although pretreatment with ONO-5046 (200 mg x kg(-1), i.p.) had no effect on these changes immediately after the exposure, it significantly inhibited airway hyperresponsiveness to inhaled ACh, whilst decreasing the number of neutrophils and epithelial cells in BALF 3-5 h after the exposure. In contrast, ONO-5046 showed no significant effect on airway hyperresponsiveness to intravenous ACh at any time. These results suggest that neutrophil elastase contributes to ozone-induced airway hyperresponsiveness developing during the hours after exposure, presumably by means of inducing epithelial injury.

Detection of Endothelin Receptors in Rat and Guinea-pig Airway Nerves by Immunohistochemistry

We investigated the existence of endothelin (ET) receptor subtypes in airway neurones from the rat and guinea-pig and determined the ability of these receptors to modulate contractile function. Rat tracheal neuron cultures as well as rat and guinea-pig whole mount preparations were labelled with antibodies to the cholinergic nerve marker choline acetyltransferase (ChAT), the neuron specific marker protein gene product 9.5 (PGP 9.5) and to ETAand ETBreceptors. Following incubation with fluorescent secondary antibodies, fluorescence was detected using confocal microscopy with dual emission protocols. Specific fluorescence was detected both in whole mount preparations and neuron cultures, in association with the primary antibodies. Specific fluorescence associated with either ETAand ETBreceptors was colocalized with that for PGP 9.5. Despite the presence of ETAand ETBreceptors on airway nerves, ET-1 failed to significantly alter cholinergic, excitatory or inhibitory non-adrenergic–non-cholinergic nerve-mediated responses in guinea-pig airways. This is in sharp contrast to ET-1-induced potentiation of responses to cholinergic nerve-evoked contraction in rat trachea. Thus, although ETAand ETBreceptors exist in airway cholinergic neurons in whole mount preparations and in primary neuron cultures from rat and guinea-pig trachea, the influence of these receptors on contractile function appears to be species-dependent.

Bronchopulmonary inflammation and airway smooth muscle hyperresponsiveness induced by nitrogen dioxide in guinea pigs

We investigated whether acute exposure to nitrogen dioxide (NO 2) causes major inflammatory responses (inflammatory cell recruitment, oedema and smooth muscle hyperresponsiveness) in guinea pig airways. Anaesthetised guinea pigs were exposed to 18 ppm NO 2 or air for 4 h through a tracheal cannula. Bronchoalveolar lavage was performed and airway microvascular permeability and in vitro bronchial smooth muscle responsiveness were measured. Exposure to NO 2 induced a significant increase in eosinophils and neutrophils in bronchoalveolar lavage fluid, microvascular leakage in the trachea and main bronchi (but not in peripheral airways), and a significant in vitro hyperresponsiveness to acetylcholine, electrical field stimulation, and neurokinin A, but not to histamine. Thus, this study shows that in vivo exposure to high concentrations of NO 2 induces major inflammatory responses in guinea pig airways that mimic acute bronchitis induced by exposure to irritant gases in man.

Effect of a novel PACAP-27 analogue on muscarinic airway responsiveness in guinea-pigs in vivo.

A recent study showed that the novel pituitary adenylate cyclase-activating peptide (PACAP)-27 analogue [Arg15,20,21,Leu17]-PACAP-27-Gly-Lys-Arg-NH2 causes sustained airway smooth muscle relaxation in vitro. This study examined whether this analogue also has bronchoprotective effects, by inhibiting muscarinic airway responsiveness in vivo. Total lung resistance was measured in anaesthetized, tracheostomized and ventilated guinea-pigs. Increasing doses of acetylcholine were given i.v. once before and thereafter repeatedly each hour after intratracheal instillation of either the PACAP-27 analogue or the clinical beta2-agonist bronchodilator salbutamol. Mean arterial blood pressure (MAP) was monitored to detect cardiovascular side-effects. Both the PACAP-27 analogue and salbutamol significantly attenuated the airway responsiveness to acetylcholine. The total inhibitory effect of the PACAP-27 analogue (350 nmol) corresponded to that of salbutamol (35 nmol). The inhibitory effect of salbutamol (35 nmol) peaked during the second hour and disappeared prior to 5 h after administration. In contrast, the corresponding effect of the analogue (350 nmol) gradually increased and peaked during the fifth hour after administration, whereas it did not fade during the observation period. Both the PACAP-27 analogue (350 nmol) and salbutamol (35 nmol) produced a transient decrease in MAP within 6 min after administration. In conclusion, the novel pituitary adenylate cyclase-activating peptide-27 analogue has bronchoprotective properties, by decreasing muscarinic airway responsiveness in guinea pigs in vivo. The time course of its effect is compatible with a more sustained duration of action compared with salbutamol.

Inhibitory effect of NPC-17731 on BK-induced and antigen-induced airway reactions in guinea-pigs.

Bradykinin (BK) has been suggested to act as a mediator in the airways in inflammatory conditions, such as asthma through the activation of B2-receptors. NPC-17731 (D-Arg0[Hyp3, D-HypE(trans-propyl)7, Oic8]BK) has potent antagonistic activity against B2-receptors without agonistic activity. We have evaluated the inhibitory effect of NPC-17731 against BK in guinea-pig airways. In addition, we have investigated the effects of NPC-17731 on antigen-induced airway responses. Bronchoconstriction was assessed as an increase in lung resistance (RL) and a decrease in dynamic compliance (Cdyn). Airway plasma leakage was assessed by extravasation of intravenously injected Evans blue dye. To estimate the effect of drugs on antigen-induced reactions, guinea-pigs were actively sensitized by exposure to aerosol ovalbumin (OA) twice and challenged by OA inhalation. Acute bronchoconstriction was measured for 15 min. Airway vascular leakage was measured at 10 min after the challenge. Assessment of airway hyperresponsiveness against acetylcholine and bronchoalveolar lavage were conducted at 18-24 h after the antigen-challenge. NPC-17731 (0.3-30 microg/kg, i.v.) inhibited intravenously applied BK-induced bronchoconstriction in a dose-dependent manner. The 50% inhibitory doses (ID50) were 1.3 microg/kg for RL and 2.8 microg/kg for Cdyn. NPC-17731 (1-10 microg/kg, i.v.) inhibited BK-induced microvascular leakage in a dose-dependent manner (ID50 = 4.2 microg/kg). In addition, 10 microg/kg of NPC-17731 abolished the inhaled BK-induced bronchoconstriction. In the sensitized animals, 100 microg/kg NPC-17731 significantly reduced the airway microvascular leakage and the decrease in Cdyn induced by ovalbumin exposure (P < 0.05), but did not influence the increase in RL. NPC-17731 (100 microg/kg) inhibited the antigen-induced airway hyperresponsiveness and the increase in eosinophils in BAL fluids. These results indicate that NPC-17731 is a potent BK antagonist in vivo and that BK may partially contribute to the antigen-induced airway responses in guinea-pigs.

Relationship between IgG1 levels and airway responses in guinea pigs actively and passively sensitized to hexahydrophthalic anhydride.

Organic acid anhydrides (OAAs) are industrial chemicals that may cause induction of specific IgE and airway symptoms in exposed workers. They are a good model for studies of relationships between chemical structure and the sensitizing potential of reactive low-molecular-weight compounds. Hexahydrophthalic anhydride (HHPA) is such a compound. This study aimed to evaluate the relationship between specific IgG1 levels and airway responses in a model to predict the sensitizing potential of OAAs. Guinea pigs were either actively or passively sensitized to HHPA. For active sensitization, guinea pigs were injected i.d. with 0.1 ml of olive oil (vehicle) or 0.05, 0.5, or 5% HHPA in olive oil. Passive sensitization was performed by i.p. injection of different volumes of antisera (0.75-6 ml, either unheated to keep IgE or heated to destroy IgE) taken from HHPA-sensitized guinea pigs. Specific antibody levels were evaluated with ELISA and passive cutaneous anaphylaxis. Animals were challenged 16-18 days after active sensitization, or 2 days after passive sensitization, by intratracheal instillation with HHPA conjugated to guinea pig serum albumin (HHPA-GPSA; 0.05% in saline), and the immediate effects on lung resistance (RL), and plasma extravasation, measured as Evans blue dye extravasation, for up to 6 min were recorded. Active sensitization caused production of specific IgG1. Provocation with HHPA-GPSA caused an increase of both RL and Evans blue dye extravasation, which was dependent upon the active sensitization dose. Challenge with HHPA-GPSA in passively sensitized guinea pigs also produced an increase in both RL and Evans blue dye extravasation which was related to the IgG1 level. In the guinea pig model of HHPA-induced airway allergy, the airway responses are closely related to the serum levels of specific IgG1. Thus, the IgG1 levels induced by the immunization may reflect the sensitizing potential of HHPA.

Apafant (a PAF receptor antagonist) suppresses the early and late airway responses in guinea pigs: a comparison with antiasthmatic drugs

We studied the effects of apafant (WEB 2086 BS), a specific and potent platelet activating factor (PAF) receptor antagonist, on the early and late airway responses in conscious and actively sensitized guinea pigs. An increase in airway resistance (Rs) was seen 1 min after the inhaled antigen challenge (early airway response), followed by another increase in Rs which peaked between 4 and 8 h after the provocation (late airway response). Oral administration of apafant as well as theophylline inhibited both early and late airway responses. Ozagrel, an inhibitor of thromboxane A 2 synthetase, salbutamol, a β 2-adrenoceptor agonist, and dexamethasone significantly inhibited either the early or the late airway response only. Disodium cromoglycate inhibited neither the early nor the late airway response. The results showed that apafant inhibited both the early and late airway responses in sensitized guinea pigs and its effect was comparable or superior to that of anti-asthmatic drugs used clinically.

Inhaled bordetella pertussis vaccine decreases airway responsiveness in guinea pigs

Bordetella pertussis (BP) has been used as adjuvant for experimental animal immunization, but its effects on airway responsiveness are uncertain. Three groups of guinea pigs were used: animals with a single exposure to inhaled BP vaccine (strain 134, total dose 1.24 × 10 12germs), animals submitted to a sensitization procedure through inhalation of ovalbumin plus BP and healthy control animals. Four weeks after inhalation of BP or after the beginning of sensitization, dose- or concentration-response curves to histamine were constructed in vivo and in vitro (tracheal and parenchymal preparations). We found that BP alone produced lower responses to histamine than control guinea pigs in vivo (insufflation pressure, p = 0.0003) and in tracheal tissues (p = 0.04), but not in parenchymal preparations. Sensitization did not modify the responsiveness compared with their respective controls. These results suggest that some BP component(s), probably pertussis toxin, causes a long lasting airway hyporesponsiveness in guinea pigs.

Effect of Repeated Exposure to Cigarette Smoke on Airway Responsiveness in Guinea Pigs

Effect of Repeated Exposure to Cigarette Smoke on Airway Responsiveness in Guinea Pigs

Airway responses following intradermal sensitization to different types of allergens: ovalbumin, trimellitic anhydride and Dermatophagoides farinae.

Sensitization of guinea pigs by intradermal injections of the occupational allergen trimellitic anhydride (TMA) in oily vehicle has been shown to be very reproducible. We studied the effect of intradermal sensitization with ovalbumin (OA) in oily vehicle on immune and airway responses in guinea pigs. We also compared airway responses to trimellitic anhydride or Dermatophagoides farinae (DF; mite) with those to OA in guinea pigs intradermally sensitized to respective allergens. Three to four weeks after sensitization, the animals were challenged with intratracheal instillation of these allergens. Intradermal injections with OA developed dose-dependently specific IgG1 antibodies to OA demonstrated by ELISA. In animals sensitized with different doses of OA in corn oil vehicle, a challenge with OA induced a reversely dose-dependent airflow obstruction and airway plasma exudation. In contrast, animals sensitized with OA in saline vehicle had dose-dependent airway responses to OA. Challenge with OA caused an immediate peak and subsequently persistent airflow obstruction, whereas this response to either TMA guinea pig serum albumin or Df was slowly progressive in animals sensitized to respective allergens. The animals sensitized to TMA or Df may show a different profile of airway responses following the challenge compared to OA. Intradermal sensitization may be a valuable method of sensitization for the development of an animal model of airway allergy to different types of allergens, including chemicals or mites.

Modulation of neurotransmission in guinea-pig airways by galanin and the effect of a new antagonist galantide

Galanin is localised to sensory nerve fibres and cholinergic nerves in airways. Galantide has been shown to be a novel high affinity antagonist to galanin, since it inhibits galanin-mediated inhibition of glucos-induced insulin secretion and the neuronal action of galanin in the brain. We investigated the effects of galanin on cholinergic and non-adrenergic, non-cholinergic (NANC) responses to electrical field stimulation in guinea-pig airways, and examined whether galantide antagonised the effect of galanin on neurotransmission. Galanin (10 −6M) had no effect on cholinergic bronchoconstrictor responses and inhibitory NANC relaxation responses in trachea, but significantly inhibited excitatory NANC bronchoconstrictor responses in bronchi which is due to the release of tachykinins. Galantide (10 −8–10 −6M) had no effect on the galanin-induced inhibition of the excitatory NANC responses. Galanin may be important in the modulation of excitatory NANC responses but not cholinergic and inhibitory NANC responses in guinea-pig airways. This modulatory effect may be via a different type of galanin receptor than is present in other organs.

Role of eicosanoids in hyperpnea-induced airway responses in guinea pigs

Guinea pigs mechanically hyperventilated with dry gas exhibit hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH). Tachykinins released from airway C-fiber neurons are the central mediators of guinea pig HIB but play only a contributory role in HIBVH. Recent studies suggest that eicosanoid mediators can provoke bronchoconstriction and bronchovascular hyperpermeability, are released by dry gas hyperpnea, and can themselves elicit or modulate tachykinin release. We therefore hypothesized that eicosanoids may participate in HIB and/or HIBVH. To test these hypotheses, we analyzed respiratory system resistance changes and Evans blue-labeled albumin extravasation into the airways of 60 tracheostomized and mechanically ventilated guinea pigs. Animals were subjected to 10 min of isocapnic dry gas hyperpnea or to quiet breathing of humidified gas and received as pretreatment either piroxicam, a cyclooxygenase (CO) inhibitor; A-63162, a 5-lipoxygenase (5-LO) inhibitor; BW-755c, a combined CO and 5-LO inhibitor; ICI-198,615, a leukotriene D4 receptor antagonist; or no drug. HIB was substantially (50-80%) reduced by each of the four eicosanoid-modulating drugs. In contrast, HIBVH was reduced only by BW-755c, and this effect occurred only within the extrapulmonary airways (42% reduction). These data indicate that both CO and 5-LO products, including leukotriene D4, participate in the pathogenesis of HIB but that, like tachykinins, they play only a small contributory role in HIBVH. Together with our previous demonstration that sensory neuropeptide release is critical for the occurrence of HIB, we conclude that the roles of eicosanoids and tachykinins in guinea pig HIB are interdependent.

Effects of exposure to sulfuric acid‐aerosol on airway responsiveness in guinea pigs: Concentration and time dependency

We investigated the concentration and time dependency of the effects of exposure to sulfuric acid (H2SO4) aerosol on airway responsiveness. Two hundred and sixteen male Hartley guinea pigs were used. The animals were divided into 3 groups (n = 72/group), with 1 group being exposed to filtered air and the other 2 to 1.0 mg/m3 or 3.2 mg/m3 H2SO4 aerosol. In each group, the animals were divided into 4 subgroups (n = 18/subgroup), with exposure terms of 3 d (24 h/d), 7 d, 14 d, and 30 d. Specific airway resistance (SRaw) under room air (SRaw0) and airway responsiveness were determined 1 wk before the beginning of exposure and on the day of termination of the exposure. Specific airway resistance values under room air (SRaw0) prior to and after exposure were compared. There was no significant change in SRaw0 after the exposure to filtered air, 1.0 mg/m3, or 3.2 mg/m3 H2SO4 aerosol. Our results also showed that exposure to filtered air or 1 mg/m3 H2SO4 aerosol did not cause any significant change in airway responsiveness to inhaled histamine aerosol, expressed as the effective concentration of histamine (EC200His) that produced a doubling of SRawNaCl (SRaw after exposure to aerosol of 0.9% NaCl saline). On the contrary, exposure to 3.2 mg/m3 H2SO4 aerosol induced transient airway hyporesponsiveness after a 3-d exposure [EC200His prior to and after exposure: 1.35 +/- 0.28 and 2.23 +/- 0.22 mM (p < .01), respectively] and then transient hyperresponsiveness after a 14-d exposure [EC200His prior to and after exposure: 1.65 +/- 0.21 and 0.95 +/- 0.23 mM (p < .01), respectively]. Overall, the present results revealed that (1) 1.0 mg/m3 or 3.2 mg/m3 H2SO4 aerosol had no significant effect on SRaw0 during a 30-d exposure period, (2) a high concentration (3.2 mg/m3) of H2SO4 aerosol affected airway responsiveness during the 30-d exposure, while a low concentration (1.0 mg/m3) of H2SO4 aerosol did not, and (3) the effect of exposure to 3.2 mg/m3 H2SO4 aerosol on airway responsiveness was transient and stimulatory or inhibitory, depending on the duration of exposure.

Endogenous Sensory Neuropeptide Release Enhances Nonspecific Airway Responsiveness in Guinea Pigs: Reply

"Endogenous Sensory Neuropeptide Release Enhances Nonspecific Airway Responsiveness in Guinea Pigs: Reply." American Review of Respiratory Disease, 147(3), p. 779

Bradykinin-induced airway responses in guinea pig: effects of inhibition of cyclooxygenase and thromboxane synthetase

We studied the effects of indomethacin (10 mg/kg i.v.), a cyclooxygenase inhibitor, and OKY-046 (1, 10 and 30 mg/kg i.v.), a selective thromboxane synthetase inhibitor, on airflow obstruction and airway plasma exudation induced by bradykinin (150 nmol) instilled by the airway route to anesthetized guinea pigs. To do this, we studied changes in lung resistance (R L) and extravasation of Evans Blue dye respectively. Instilled bradykinin produced an immediate and marked increase in R L which peaked at approximately 30 s. We also observed a delayed increase in R L, reaching a second peak at approximately 3 min. Bradykinin produced airway plasma exudation at all airway levels, measured as extravasation of Evans Blue dye. Indomethacin significantly inhibited both the immediate and the delayed increase in R L after bradykinin. OKY-046 had a similar significant and dose-dependent inhibitory effect on these responses. In addition, both drugs inhibited bradykinin-induced Evans blue dye extravasation in intrapulmonary airways. Bradykinin instilled by the airway route significantly decreased systemic blood pressure but this effect was not altered in animals pretreated with either indomethacin or OKY-046. We conclude that the bronchoconstrictor response and airway plasma exudation induced by instilled-bradykinin may be mediated in part via thromboxane A 2 generation.