Microvascular Leakage In Guinea Pigs Research Articles

Relaxant effect of brain natriuretic peptide in nonsensitized and passively sensitized isolated human bronchi

Brain natriuretic peptide (BNP) relaxes guinea pig tracheal smooth muscle in vitro and is effective in preventing ovalbumin-induced bronchoconstriction and microvascular leakage in guinea pigs in vivo. Nonetheless, published studies on BNP in human airways in vitro are still lacking in the literature. The aim of this study was to investigate the effect of BNP in isolated human bronchi. The relaxant effect of BNP (1 nM to 10 μM) was assessed in nonsensitized and in passively sensitized human bronchial airways pre-contracted with submaximal concentration (EC 70) of carbachol or histamine. At the end of the experiment, papaverine (500 μM) was then added. BNP induced a weak relaxant activity on carbachol-contracted bronchi in nonsensitized (relaxation: 4.23 ± 0.51%) and passively sensitized bronchi (relaxation: 11.31 ± 2.22%). On the other hand, BNP induced a relaxant activity on His-contracted bronchi in nonsensitized (relaxation: 42.52 ± 9.03%) and in passively sensitized (relaxation: 60.57 ± 9.58%). All these findings are a clear documentation of the modest relaxant role of BNP in asthma and, likely, COPD.

Effects of STA2, a Thromboxane A2 Mimetic, in Inducing Airflow Obstruction and Airway Microvascular Leakage in Guinea Pigs

Background: U-46619, a thromboxane A₂ (TXA₂) mimetic, is shown to cause airway microvascular leakage, although the effects is weak when comparing with that to induce bronchoconstriction in guinea pigs. Objective: In order to know the airway effect of TXA₂ more accurately, we have examined the effects of STA₂, a TXA₂ mimetic with higher affinity to TXA₂ (TP) receptors than U-46619, to induce airway microvascular leakage and airflow obstruction. Methods: Anesthetized and ventilated guinea pigs were i.v. given STA₂ (3–30 nmol/kg) or U-46619 (3–100 nmol/kg) 1 min after i.v. Evans blue dye. STA₂- and U-46619-induced increases in lung resistance (R_L) was measured for 6 min. The amount of extravasated Evans blue dye in the lower airways was, then, examined as an index of leakage. In selected animals, specific TP receptor antagonists (10 µg/kg S-1452 or 10 mg/kg ONO-3708) were pretreated i.v. Results: Both STA₂ and U-46619 induced significant increases in leakage and airflow obstruction. However, STA₂ induced a slow and significantly less increase in R_L but caused a significantly greater increase in extravasation of Evans blue dye compared to U-46619. Specific TP receptor antagonists completely abolished both airway effects induced by STA₂ and U-46619. Conclusion: Our present results have supported a possibility that TXA₂ induces microvascular leakage as well as bronchoconstriction in the airways.

Acute effects of prostaglandin D 2 to induce airflow obstruction and airway microvascular leakage in guinea pigs: role of thromboxane A 2 receptors

Background: Although prostaglandin D 2 (PGD 2), a mast cell-derived inflammatory mediator, may trigger allergic airway inflammation, its potency and the mechanism by which it induces airway microvascular leakage, a component of airway inflammation, is not clear. Objective: We wanted to evaluate the relative potency of PGD 2 to cause microvascular leakage as compared to airflow obstruction, because both responses were shown to occur simultaneously in allergic airway diseases such as asthma. The role of thromboxane A 2 receptors (TP receptors) in inducing these airway responses was also examined. Methods: Anesthetized and mechanically ventilated guinea pigs were given i.v. Evans blue dye (EB dye) and, 1 min later, PGD 2 (30, 100, 300 or 1,000 nmol/kg). For comparison, the effect of 150 nmol/kg histamine or 2 nmol/kg leukotriene D 4 (LTD 4) was also examined. Lung resistance (R L) was measured for 6 min (or 25 min for selected animals) and the lungs were removed to calculate the amount of extravasated EB dye into the airways as a marker of leakage. In some of the animals, specific TP receptor antagonists, S-1452 (10 μg/kg) or ONO-3708 (10 mg/kg), or a thromboxane A 2 synthase inhibitor, OKY-046 (30 mg/kg), was pretreated before giving PGD 2. Results: Injection of PGD 2 produced an immediate and dose-dependent increase in R L (peaking within 1 min), which was significant at all doses studied. At 1,000 nmol/kg, PGD 2 induced a later increase in R L, starting at 3 min and reaching a second peak at 8 min. By contrast, only PGD 2 at doses of 300 and 1,000 nmol/kg produced a significant increase in EB dye extravasation. The relative potency of 1,000 nmol/kg PGD 2 to induce leakage as compared to airflow obstruction was comparable to histamine at most of airway levels, but less than LTD 4. Both responses caused by PGD 2 were completely abolished by S-1452 and ONO-3708, but not by OKY-046. Conclusion: PGD 2 may induce airway microvascular leakage by directly stimulating TP receptors without generating TXA 2 in guinea pigs. Microvascular leakage may play a role in the development of allergic airway inflammation caused by PGD 2.

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 μg). Intratracheal tryptase (3–30 μg) had no effect on airway tone as measured by pulmonary insufflation pressure. Tryptase-induced airway microvascular leakage was partially blocked by the tachykinin NK 1 receptor antagonist CP 99994 [(+)-(2 S,3 S)-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 H 1 receptor antagonists or a tachykinin NK 2 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.

575 Differential effects of STA2 and U-46619 in inducing airflow obstruction and airway microvascular leakage in Guinea Pigs

575 Differential effects of STA2 and U-46619 in inducing airflow obstruction and airway microvascular leakage in Guinea Pigs

Adrenomedullin inhibits ovalbumin-induced bronchoconstriction and airway microvascular leakage in guinea-pigs.

Human adrenomedullin is a potent vasodilator with bronchodilation properties. The effects of adrenomedullin on antigen-induced bronchoconstriction and airway microvascular leakage in guinea-pigs was investigated. The portion of the adrenomedullin molecule possessing these pulmonary active profiles was also examined, using two truncated adrenomedullin molecules: adrenomedullin (1-25) and adrenomedullin (22-52). Four weeks after sensitization with ovalbumin (0.1 mg x k(-1)), the guinea-pigs were anaesthetized and mechanically ventilated. Respiratory resistance, dynamic compliance and arterial blood pressure were monitored. Airway microvascular leakage was evaluated by extravasation of 20 mg x kg(-1) Evans blue into airway interstitial tissue. In order to enhance the pulmonary effects of adrenomedullin, the active production of endogenous nitric oxide was inhibited by coadministration of a nitric oxide synthase inhibitor, L-N(G)-nitroarginine methethyl ester (10 mg x kg(-1)). Intravenous pretreatment with adrenomedullin (10, 30 and 100 microg x mL(-1)) dose-dependently inhibited ovalbumin-induced bronchoconstriction and airway microvascular leakage in all airway segments. Inhaled adrenomedullin (100 microg.mL(-1), 1 min) also significantly inhibited pulmonary changes induced by ovalbumin inhalation (3 mg x mL (-1) , 3 min). These pulmonary profiles of adrenomedullin were enhanced by inhibiting the active production of endogenous nitric oxide. In conclusion, adrenomedullin has inhibitory effects on antigen-induced microvascular leakage and bronchoconstriction in guinea-pigs. These beneficial effects strongly related to its unique ring structure and N-terminal segment, making it a potential anti-asthma.

Induction of nitric oxide synthase by lipopolysaccharide inhalation enhances substance P-induced microvascular leakage in guinea-pigs.

Inducible nitric oxide (NO) synthase (iNOS)-mediated hyperproduction of NO in airways has been reported in asthmatic patients. However, the role of NO in the pathogenesis of asthma has not yet been fully elucidated. The aim of this study was to examine whether the iNOS-derived NO affects airway microvascular leakage, one of the characteristic features of asthmatic airway inflammation. Guinea-pigs were exposed to lipopolysaccharide (LPS) (1 mg x mL(-1)) by inhalation in order to induce iNOS in the airways, and the histochemical staining of reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-diaphorase activity was determined 5 h after the inhalation to confirm the iNOS induction. Airway microvascular leakage to subthreshold doses of substance P (0.3 microg x kg(-1), i.v.) was also examined in the absence and presence of an iNOS inhibitor (aminoguanidine) in LPS- or saline-exposed (control) animals using Evans blue dye and Monastral blue dye. In the LPS-exposed animals, increased NADPH-diaphorase activity was observed in the airway microvasculature compared with the control animals. Substance P caused significant airway microvascular leakage assessed by Evans blue dye in all airway levels in the LPS-exposed animals but not in the control group. This was also confirmed by Monastral blue dye extravasation. Aminoguanidine abolished this LPS-induced enhancement of plasma leakage to substance P without changing the systemic blood pressure. These results may suggest that inducible nitric oxide synthase-derived nitric oxide is capable of potentiating neurogenic plasma leakage in airways.

The effects of NK1 receptor antagonists (FK224 and FK888) on agonist- and antigen-induced nasal microvascular leakage in guinea pigs.

To study the inhibitory effects of two NK1 receptor antagonists on substance P (SP) and antigen-induced increase of nasal vascular permeability in ovalbumen (OA)-sensitized guinea pigs. Male Dunkin-Hartley guinea pigs. SP (100 mumol/l), FK224 (1-10 mumol/kg) and FK888 (0.2-2 mumol/kg). The in vivo model of nasal microvascular leakage was used for nasal allergic challenge in ovalbumin (OA)-sensitized guinea pigs, or nasal stimulation with substance P (SP) in non-sensitized animals. Nasal microvascular leakage was measured by the accumulation of Evans Blue dye after intravenous injection. Following nasal stimulation with SP 100 microM, the concentration of dye in the nasal lavage fluid rapidly increased. NK1 receptor antagonists FK224 (10 mumol/kg i.v.) and FK888 (2 mumol/kg i.v.) inhibited SP-induced microvascular leakage. In OA-sensitized guinea pigs, exudation of dye into nasal lavage fluid was observed soon after topical antigenic stimulation and continued for over 60 min. Both NK1 receptor antagonists inhibited the immediate phase of the antigen-induced microvascular leakage. We conclude that the immediate change of vascular permeability during the nasal allergic response is mediated by activation of the NK1 receptor in the guinea-pig.

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 (RL) 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 RL 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.

Effects of selective phosphodiesterase inhibitors on platelet-activating factor- and antigen-induced airway hyperreactivity, eosinophil accumulation, and microvascular leakage in guinea pigs.

There is currently interest in the potential use of selective inhibitors of cyclic nucleotide phosphodiesterases (PDE) in the treatment of asthma. In this study we examined the effects of three selective PDE inhibitors, milrinone (PDE III), rolipram (PDE IV) and zaprinast (PDE V), on the broncoconstriction produced by antigen and histamine, the airway hyperreactivity and microvascular leakage after aerosol exposure to platelet-activating factor (PAF) and antigen, and the antigen-induced eosinophil infiltration in guinea-pig lung. Inhaled rolipram (0.01-10 mg ml-1) inhibited dose dependently the bronchospasm produced by aerosol antigen (5 mg ml-1) an anaesthetised, ventilated guinea-pigs. Rolipram (10 mg ml-1) produced maximal inhibition of antigen-induced bronchoconstriction but only partial inhibition of the response to aerosol histamine (1 mg ml-1). Milrinone and zaprinast (each 10 mg ml-1) showed weak, or no, inhibitory effects against bronchoconstriction produced by aerosol antigen or histamine. Pretreatment with rolipram (10 mg kg-1, i.p.) prevented airway hyperreactivity to histamine which develops 24 h after exposure of conscious guinea-pigs to aerosol PAF (500 micrograms ml-1) or antigen (5 mg ml-1). The pulmonary eosinophil infiltration obtained with 24 h of antigen-exposure was inhibited by rolipram. In contrast, milrinone and zaprinast (each 10 mg kg-1, i.p.) failed to reduce either the airway hyperreactivity of the eosinophil accumulation in these animals. Rolipram (1-10 mg ml-1) reduced the extravasation of Evans blue after aerosol PAF (500 micrograms ml-1) at all airway levels while a lower dose (0.1 mg ml-1) was only effective at intrapulmonary airways. Rolipram (0.01-1 mg ml-1) markedly reduced airway extravasation produced by inhaled antigen (5 mg ml-1). Zaprinast (1-10 mg ml-1) was also effective against airway microvascular leakage produced by aerosol PAF or antigen while milrinone (10 mg ml-1) had no antiexudative effect. These data support previous suggestions that pharmacological inhibition of PDE IV results in anti-spasmogenic and anti-inflammatory effects in the airways and may be useful in the treatment of asthma.

Effect of Y-24180, a Platelet-Activating Factor-Receptor Antagonist, on the Antigen-Induced Airway Microvascular Leakage in Guinea Pigs

The inhibitory effect of Y-24180 ((±)-4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethylJ-6,9-dimethyl-6H-thieno[3,2-f)[1,2,4]triazolo[4,3-a][1,4]diazepine) on platelet-activating factor (PAF)-or antigen-induced airway microvascular leakage was studied in guinea pigs by oral administration. The tissue content of extravasated Evans blue dye was used as an index of plasma exudation in the trachea, main bronchi, central intrapulmonary airways and peripheral intrapulmonary airways. In all of these tissues, Y-24180 potently inhibited the leakage induced by PAF. The ED50 value of Y-24180 determined in each of the tissues was approximately 0.02 mg/kg, demonstrating that the inhibitory potency of Y-24180 is 4-6 times that of WEB 2086, another PAF antagonist. Even at a dose of 10 mg/kg, however, Y-24180 showed no inhibitory effect on the leakage induced by leukotriene (LT) D4, histamine or bradykinin. In the antigen-induced model of guinea pigs sensitized with aerosolized ovalbumin, Y-24180 (0.1–10 mg/kg) and WEB 2086 (1–100 mg/kg) potently inhibited the microvascular leakage in all of the examined airway tissues except for the trachea. At 1–100 mg/kg, however, both ONO-1078, an LT-receptor antagonist, and OKY-046, a thromboxane A2 synthetase inhibitor, prevented partially but not significantly the antigen-induced leakage. These results provide evidence that endogenous PAF partially mediates the antigen-induced airway microvascular leakage in guinea pigs.

Histamine N-methyltransferase inhibitor potentiates histamine- and antigen-induced airway microvascular leakage in guinea pigs

Background: Histamine N-methyltransferase (HMT) modulates histamine- and antigen-induced bronchoconstriction. However, it is unclear whether vascular permeability evoked by an allergic reaction can be exaggerated by inhibition of HMT activity. Methods: We studied the effects of intravenously injected SKF 91488, a specific HMT inhibitor, on increases in plasma extravasation induced by intravenously injected histamine in unsensitized guinea pigs and by intravenously injected ovalbumin antigen in guinea pigs sensitized to ovalbumin in vivo with Evans blue dye as a marker. Results: Pretreatment with SKF 91488 shifted, in a dose-dependent fashion, the dose-response curves of the leakage of dye to histamine to lower concentrations in the trachea, main bronchi, and nasal mucosa. Likewise, pretreatment with SKF 91488 (20 mg/kg intravenously) significantly increased the leakage of dye induced by ovalbumin antigen (200 μg/kg intravenously) in three parts of the airway ( p < 0.05). In contrast to SKF 91488, intravenously injected aminoguanidine, a specific inhibitor of diamine oxidase (16 mg/kg intravenously), did not alter the leakage of dye induced by histamine (from 0.001 μg/kg to 10 μg/kg intravenously) ( p > 0.20). HMT activities were observed in the nasal mucosa, as well as in the trachea and main bronchi, as shown in a previous study. Conclusion: These findings suggest that HMT modulates the effects of exogenous histamine and endogenously released histamine induced by antigen challenge on plasma extravasation in the airway in guinea pigs in vivo. (J A LLERGY C LIN I MMUNOL 1995;96:910-6.)

Effects of three alpha 2-adrenoceptor agonists, rilmenidine, UK 14304 and clonidine on bradykinin- and substance P-induced airway microvascular leakage in guinea-pigs.

The effects of three alpha 2-adrenoceptor agonists, clonidine, rilmenidine and UK 14304 on the increase of microvascular permeability induced by bradykinin or substance P in guinea-pigs airways have been studied in vivo. Extravasation of intravenously (i.v.) injected Evans blue dye was used as index of permeability. The effects of the three alpha 2-adrenoceptor agonists on the contraction induced by bradykinin (0.3 micrograms.kg-1, i.v.) and substance P (0.3 micrograms.kg-1, i.v.) were also studied on the isolated guinea-pig trachea. The increase of plasma exudation induced by bradykinin (0.3 micrograms.kg-1, i.v.) was inhibited partially by rilmenidine and UK 14304 (20 micrograms and 100 micrograms, intratracheally) respectively. These two substances had no action on the effects of substance P. The effects of rilmenidine and UK 14304 were abolished by alpha 2-blockers (idazoxan 1mg.kg-1 i.v. and RX 821001 100 micrograms.kg-1, i.v.), but they were not altered by the alpha 1-blocker prazosin (30 micrograms.kg-1, i.v.). Under similar conditions, clonidine or the alpha 1-adrenoceptor agonist methoxamine were without significant effects. In vitro, rilmenidine and UK 14304 inhibited partially the contractile effects of bradykinin but not those of substance P. To conclude, both rilmenidine and UK 14304 inhibit the bradykinin-induced increase of vascular permeability in the airways, and they probably do so on peptidergic nerve endings at the prejunctional level since these substances are without effect on substance P. The absence of activity of clonidine in our study might be due to a difference in spectrum of action on the several types of alpha 2-adrenergic or imidazole receptors.

Platelet-activating factor mediates the ozone-induced increase in airway microvascular leakage in guinea pigs

In the present study, we asked whether platelet-activating factor (PAF) mediates the ozone-induced increase in airway microvascular leakage. To answer this question, we examined the effect of a PAF receptor antagonist on the ozone-induced increase in airway microvascular leakage quantified by the extravasation of Evans blue dye in the guinea pig trachea and main bronchi. Guinea pigs were pretreated with the PAF receptor antagonist, E6123 (( S)-(+)-6-(2-chlorophenyl)-3-cyclopropane-carbonyl-8,11- dimethyl-2,3,4,5-tetrahydro-8 H-pyrido[4′,3′:4,5]thieno[3,2- f][1,2,4]triazolo[4,3- a][1,4]diazepine) (0.01, 0.1 and 1.0 mg/kg i.v.) and then exposed to 3 ppm ozone for 30 min. The PAF receptor antagonist significantly reduced the ozone-induced increase in microvascular leakage in a dose-dependent manner in both the trachea and main bronchi. Our results indicate that PAF mediates the ozone-induced increase in airway microvascular leakage. We therefore suggest that PAF may be involved in ozone-induced airway inflammation.

Effects of cilostazol, a cyclic nucleotide phosphodiesterase III inhibitor, on substance P-induced airflow obstruction and airway microvascular leakage in guinea pigs.

We studied the effect of cilostazol, a cyclic nucleotide phosphodiesterase (PDE) III inhibitor, on a substance P (SP)-induced increase in lung resistance and in airway microvascular leakage in guinea pigs in vivo. Four minutes after intravenous (i.v.) administration of cilostazol (1.5 and 5 mg/kg) or vehicle, Evans blue dye (20 mg/kg) was given i.v. One minute later, 30 nmol/kg SP was administered i.v. The SP-induced increase in lung resistance was measured for 6 min. Following the measurement of lung resistance, microvascular leakage at the trachea, main bronchi and intrapulmonary airways was also examined. Cilostazol attenuated the SP-induced increase in lung resistance, with a significant inhibition at the concentration of 5 mg/kg. Five milligrams per kilogram cilostazol also significantly inhibited SP-induced Evans blue dye extravasation at the trachea and main bronchi. These results suggest that cilostazol might reduce airflow obstruction which is seen in diseases such as asthma through attenuation of bronchoconstriction and, possibly, airway edema resulting from airway microvascular leakage in man.

Neurokinin receptor mediated plasma extravasation in guinea pig and rat airways: comparison of 125I-labelled human fibrinogen and 99mTc-labelIed human serum albumin as markers of leakage

In the present study we have characterized NK-1 and NK-2 receptor induced microvascular leakage in guinea pig and rat airways, using 125I-labelled human fibrinogen ([125I]FN) versus 99mTc-labelled human serum albumin ([99mTc]HSA) as markers for plasma protein extravasation. Intravenous administration of the selective NK-1 agonist [Sar9, Met(O2)11]SP (1 nmol kg-1) caused a dose-dependent increase of [125I]FN extravasation in guinea pig trachea, main bronchi, secondary bronchi, and intraparenchymal airways. Extravasation of [125I]FN increased by up to 192 (trachea), 284 (main bronchi), 368 (secondary bronchi), and 271% (intraparenchymal bronchi) over control levels in these regions of the airways. Pretreatment of the animals with CP 99,994 and RP 67,580, two NK-1 nonpeptide antagonists, caused a dose-dependent inhibition of [Sar9, Met(O2)11]SP-induced leakage of [125I]FN. [Sar9, Met(O2)11]SP (1 nmol kg-1) did not induce specific leakage of [99mTc]HSA in the intraparenchymal bronchi. Specific NK-2 receptor induced leakage was detected in the lower airways but only when using [125I]FN as a marker. We have also compared the ability of CP 99,994 and RP 67,580 to inhibit [Sar9, Met(O2)11]SP induced extravasation of [125I]FN in rat airways. CP 99,994 was 40-50 (tracheobronchial region) to 75 (lower airways) times more potent in the guinea pig than the rat airways. In contrast, RP 67,580 had higher affinity for rat airways compared with guinea pig airways. The results of this study highlight the superiority of [125I]FN as a sensitive marker of plasma extravasation over [99mTc]HSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Capsaicin, (±)-CP-96,345 and SR 48968 on the Bradykinin-induced Airways Microvascular Leakage in Guinea-pigs

Summary: The aim of this study was to demonstrate the involvement of neuropeptides in the increase in microvascular permeability induced by bradykinin in guinea-pig airways in vivo and to determine the type of receptor involved. Extravasation of intravenously injected Evans blue dye was used as an index of vascular permeability. Increase in plasma exudation induced by bradykinin (0.3 μg/kg, iv) was reduced or abolished by capsaicin (40 mg/kg, sc, 7 days before experiments), a drug which destroys neurokinins in the NANC nerve endings. (±)-CP-96,345 (3 mg/kg, iv), an antagonist of neurokinin NK 1-receptors, abolished the increase of vascular permeability induced by bradykinin and reduced or abolished the effects of substance P (0.3 μg/kg, iv). The higher dose of (±)-CP-96,345 (10 mg/kg, iv) completely blocked the effects of substance P, but it did not modify those of neurokinin A (100 μg/kg, iv). In contrast, SR 48968 (0.1 and 0.3 mg/kg, iv), an antagonist of neurokinin NK 2-receptors, reduced the increase of vascular permeability induced by neurokinin A without influencing the effects of bradykinin and substance P. These results demonstrate that a stimulation of the non-adrenergic non-cholinergic (NANC) nerves and a subsequent release of neuropeptides, especially of substance P, is involved in the effects of bradykinin.

Bronchoconstriction and airway microvascular leakage in guinea pigs sensitized with trimellitic anhydride.

We have developed a guinea pig model of immediate airway responses following intradermal sensitization with free trimellitic anhydride (TMA). Guinea pigs were given an intradermal injection with either 0.1 ml of 0.3% TMA in corn oil (n = 8) or 0.1 ml of corn oil alone (n = 6). A guinea pig serum albumin conjugate of trimellitic anhydride (TMA-GPSA) was prepared with a substitution ratio of 21:1. All sensitized guinea pigs had raised specific serum IgG1 antibodies (ELISA), and IgE antibodies were detected in six of the eight sensitized guinea pigs by passive cutaneous anaphylaxis. On Days 21 to 28, guinea pigs were anesthetized, tracheostomized, and ventilated. Evans blue dye (20 mg/ml), an albumin marker, was injected intravenously to quantify airway microvascular leakage (MVL). TMA-GPSA (50 microliters; 1%) in saline was instilled into the trachea. Lung resistance (RL) was measured for 6 min. The guinea pigs were killed, and the lungs were removed. Peak RL (cm H2O/ml x s-1) was significantly increased in sensitized guinea pigs from 0.26 +/- 0.01, mean +/- SEM to 21.3 +/- 6.9 (p < 0.05), compared with nonsensitized guinea pigs. There was a significant increase in Evans blue at all levels of the tracheobronchial tree in sensitized guinea pigs compared with the controls (p < 0.005). The site of MVL was localized to the postcapillary venules as assessed by extravasation of intravascular Monastral blue dye. We conclude that intradermal sensitization of guinea pigs to TMA induces a polyclonal immune response, associated with bronchoconstriction and airway microvascular leakage, when challenged specifically with TMA-GPSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Capsaicin pretreatment does not inhibit allergen‐induced airway microvascular leakage in guinea pig

We have studied the effects of tachykinin-depletion on airway microvascular leakage induced by allergen challenge in ovalbumin-sensitised guinea pigs. Tachykinin-depletion was obtained by capsaicin pretreatment 1 week before inhaled allergen challenge. Capsaicin pretreatment did not change airway microvascular permeability induced by allergen challenge. Thus, sensory neuropeptides may not be important in allergen-induced acute airway microvascular leakage in guinea pig in vivo.

Effect of Antiasthma Drugs on Microvascular Leakage in Guinea Pig Airways

We have studied the effect of intravenous epinephrine, albuterol, verapamil, and aminophylline on airway microvascular leakage in guinea pigs. Microvascular leakage was induced by platelet-activating factor (PAF; 50 ng/kg intravenously), which acts directly on venular endothelial cells, and measured by quantifying extravasation of Evans blue (EB) dye. Epinephrine (20 micrograms/kg) inhibited PAF-induced changes in dye leakage in larynx and main bronchi; at 80 and 160 micrograms/kg, significant inhibition was observed in all airways studied. This effect was reversed by phentolamine (2.5 mg/kg) or prazosin (100 micrograms/kg). By contrast, albuterol (20 to 320 micrograms/kg) and aminophylline (12.5 to 50 mg/kg) failed to inhibit dye leakage at any dose studied. Verapamil inhibited PAF-increased leakage in larynx, main bronchi, and intrapulmonary airways at the lowest dose tested (125 micrograms/kg), although inhibition was not dose dependent. These results suggest that the antiedema effect of epinephrine may be due to vasoconstriction rather than to a direct effect on endothelial cell contractility and that neither beta-agonists nor theophylline have an inhibitory effect. The inhibitory effect of epinephrine on airway microvascular leakage may have therapeutic implications for asthma.