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PubMed1993

Phosphoramidon potentiates the bronchoconstriction induced by inhaled bombesin in guinea pigs.

The effect of the neutral endopeptidase inhibitor, phosphoramidon, on the bronchoconstriction induced by aerosolized bombesin in the guinea pig was investigated. Administered by aerosol for 1 min, bombesin (0.01 or 0.1 mg/ml) induced a dose-dependent increase in pulmonary inflation pressure. Pretreatment of the guinea-pigs with phosphoramidon (0.1 mM), administered by aerosol for 15 min, 15 min prior to challenge, markedly potentiated the increase in pulmonary inflation pressure induced by bombesin (0.01 mg/ml) and substance P (0.1 mg/ml). This result suggests a local hydrolysis of bombesin by airway neutral endopeptidase reducing the activity of this peptide on smooth muscle.

Administration, Inhalation↗
PubMed1994

In vivo evidence for the activation of a septide-sensitive tachykinin receptor in guinea pig bronchoconstriction.

Intravenous administration of the undecapeptide [Sar9]substance P (SP) sulfone (1.5 nmol/kg) and the hexapeptide [Glp6,Pro9]SP(6-11) (septide; 0.4 nmol/kg) produced a comparable (about 30-40% of maximal effect) increase of insufflation pressure (bronchospasm) in anesthetized guinea-pigs. The non peptide NK-1 receptor antagonist, (+/-)CP 96,345 and the peptide NK-1 receptor antagonist, GR 82,334 antagonized dose-dependently the response to both agonists. Both antagonists were more potent against septide than against [Sar9]SP sulfone (9 and 4 fold difference in ED50 for (+/-)CP 96,345 and GR 82,334, respectively). These findings indicate that a 'septide-sensitive' mechanism mediates bronchoconstriction in vivo and it influences the estimate of the potency of NK-1 receptor antagonists.

Animals↗
PubMed1990

The role of tachykinins in air ventilation-induced bronchoconstriction in postmortem guinea pigs.

To investigate the relationship between tachykinins and air ventilation-induced airway constriction after heart ligation, 26 guinea pigs were divided into three groups: Group 1, control (n = 15); Group 2, tachykinin depletion via pretreatment with capsaicin (n = 7); and Group 3, isocapnic ventilation (n = 4). To examine the age effect, the first two groups were further separated into two subgroups: young (n = 12) and mature (n = 10). Animals were anesthetized with pentobarbital, sternotomized and artificially ventilated with room air or with 5% CO2 gas mixture. Before (baseline) and after heart ligation, tidal volume and transpulmonary pressure (Ptp) were recorded during ventilation, and the maximal expiratory flow-volume curve was periodically obtained. Minimal volume (lung volume at Ptp = 0) was determined by neon dilution. Within 30 min after heart ligation in the control group, air ventilation significantly decreased dynamic compliance, vital capacity, peak maximal expiratory flow, maximal expiratory flow at 50% total lung capacity, and forced expiratory volume in 0.2 sec. Tachykinin depletion significantly prevented, whereas isocapnic (5% CO2) ventilation failed to alter, the above changes. Young and mature subgroups showed similar results. Our data indicate that air ventilation after heart ligation induced severe airway constriction and that this bronchoconstriction can be prevented by tachykinin depletion.

Animals↗
PubMed1991

Methacholine-induced bronchoconstriction and phrenic motoneuron activity in dogs.

To evaluate the effect of changes in bronchomotor tone on the firing pattern of single phrenic motoneurons, efferent activity of both the C5 branch phrenic nerve and a single fiber from the contralateral phrenic nerve were studied in dogs anesthetized (chloralose/urethane) and breathing spontaneously (65% O2). Bronchoconstriction was induced by inhalation of methacholine (MCh) aerosol, which increased total lung resistance, decreased dynamic lung compliance and tidal volume. The rate of rise of phrenic activity was significantly increased by the changes in pulmonary mechanics induced by MCh. Single phrenic motoneurons could be separated into early (EOM) and late (LOM) onset types based on the onset time of firing relative to the beginning of whole phrenic nerve activity. The increased phrenic nerve activity was due primarily to the recruitment of LOMs. The recruitment of LOMs consisted of a shift in the time of onset to an earlier portion in inspiration, a longer firing duration, and an increase in the number of spikes per inspiratory cycle. After bilateral cervical vagotomy, all the responses of phrenic nerve to changes in pulmonary mechanics induced by aerosolized MCh were attenuated. These results suggest that phrenic motoneurons activity is modulated by alterations in pulmonary mechanics via a reflex mediated by the vagus nerve and that LOM play an important part in this response.

Action Potentials↗
PubMed1995

Time course of histamine-induced bronchoconstriction and its adrenergic and H2 modulation.

We characterized the complete time course of histamine-induced bronchoconstriction and its modulation via the release of endogenous catecholamines and by its actions on H2-receptors in anesthetized, tracheostomized, paralyzed, and artificially ventilated mongrel dogs. Respiratory resistance (R) and elastance (E) were estimated continuously with a recursive least squares estimator. Three protocols were followed in which multiple histamine bolus injections were given 1 h apart. We found that the time courses of E and R had consistent patterns (transient peak that returned to baseline within 1000 sec) even in cases of low mean arterial pressure (MAP). Indomethacin pre-treatments prevented tachyphylaxis to repeated i.v. challenges. beta-blockade produced a mild increase in baseline and a potentiation of the histamine-induced response in E and these effects were not altered with further alpha-or H2-blockade. Blockade of alpha-receptors increased the time to recovery in both E and MAP presumably by decreasing blood flow. Finally, we suggest that preventing the H2-receptor induced increase in bronchial blood flow may have increased the time to maximal E without affecting the recovery time.

Animals↗
PubMed1995

Age-dependent mechanism in guinea pig bronchoconstriction induced by exsanguination.

Age-related mechanism in exsanguination-induced bronchoconstriction (EIB) was studied in guinea pigs. We used a total of 36 guinea pigs divided into three age categories (immature, adolescent, and mature). Each age category was separated into two groups: control and catalase (CAT). CAT is an antioxidant. Both saline (the control group) and CAT were instilled intratracheally 30 min before exsanguination. The animals were anesthetized, sternotomized and exsanguinated. Maximal expiratory flow (Vmax) was measured both before and 1-30 min after exsanguination. In the control group, exsanguination caused gradual decreases in both total lung capacity (TLC) and Vmax at 50% baseline TLC, and an increase in minimal lung volume, indicating EIB. EIB occurred faster in the immature than in the adolescent and mature guinea pigs, and it was significantly ameliorated by CAT. In 36 additional animals tested before exsanguination, there was no age-related change in either airway neutral endopeptidase (NEP) activity or lung tissue substance P level. Thirty minutes after exsanguination in the control groups, airway NEP activity decreased significantly in all age categories, while lung tissue substance P level increased significantly only in the immature category. CAT prevented most of these NEP and substance P changes. These data suggest that exsanguination increases production of oxygen radicals, which inactivate NEP and enhance breakdown of substance P precursor; the increased tachykinin levels induce EIB. Furthermore, our data indicate that this chain reaction is age-dependent, with a faster and more severe reaction in immature guinea pigs.

Aging↗
PubMed1991

The effect of ONO-3708, a novel TxA2 receptor antagonist, on U-46619-induced contraction of guinea pig and human tracheal strips in vitro and on bronchoconstriction in guinea pigs in vivo.

The effect of (9, 11), (11, 12)-didedoxa-9 alpha, 11-alpha-dimethylmethano-11,12-methano-13,14-dihydro-13-aza-14-oxo -15-cyclo-pentyl-16, 17, 18, 19, 20-pentanor-15-epi-TxA2 (ONO-3708) on 9,11-methanoepoxy-prostaglandin H2 (U-46619)-induced contraction of airway smooth muscle in the guinea pigs and human in vitro and bronchoconstriction in guinea pigs in vivo was investigated. In in vitro experiments, ONO-3708 inhibited the U-46619-induced contraction of isolated guinea pig and human tracheal smooth muscle in a dose related fashion (guinea pig; pA2=7.78, human; pA2 = 7.43). The contractions of guinea pig tracheal muscle caused by histamine and leukotriene D4 (LTD4) were not inhibited by ONO-3708. In in vivo experiments, intravenous injection of ONO-3708 at doses between 1 and 20 mg/kg inhibited the U-46619-induced increase of airway insufflation pressure as measured by Konzett-Rössler method. In addition, ONO-3708 inhibited the U-46619-induced increase in airway reactivity to acetylcholine. These data suggest that ONO-3708 has possible therapeutic utility for asthma in which TxA2 participates.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Effect of the oral leukotriene antagonist, ICI 204,219, on antigen-induced bronchoconstriction in subjects with asthma.

We studied the effect of a single oral dose of ICI 204,219 on subject response to bronchoprovocation and quantitative skin testing with standardized allergen (cat dander). Cat-allergic male subjects with asthma entered the double-blind, randomized, placebo-controlled, crossover study. Each subject received a 40 mg dose of ICI 204,219 or placebo on study days separated by at least 10 days. After dosing, each subject underwent bronchoprovocation with cat allergen until a provocative dose of allergen caused a 20% decrease in FEV1 or a maximum dose of 30,000 AU/ml was reached. Fifteen subjects entered and 13 completed the study. No significant shift in the dose-response curve of the quantitative skin test occurred in any subject. A mean tenfold increase in the interpolated provocative concentration causing a 20% decrease in FEV1 was observed between ICI 204,219 (6996 +/- 3204 AU/ml) and placebo (460 +/- 98 AU/ml). Eight of 12 subjects required more antigen to provoke a bronchoprovocation response after dosing with ICI 204,219 than that required with placebo (range, threefold to 30-fold), three demonstrated no difference (less than twofold), and one subject required less antigen after ICI 204,219 (sevenfold less). Area under the curve measurements were significantly different (p less than 0.05) between ICI 204,219 and placebo for the fixed time from the end point of the allergen bronchoprovocation to 5 hours after provocation. In conclusion, this trial demonstrates that a single oral dose of ICI 204,219 antagonizes the bronchoconstriction induced by inhaled cat allergen.

Administration, Oral↗
PubMed1993

Tachykinin control of ferret airways: mucus secretion, bronchoconstriction and receptor mapping.

The effects of synthetic tachykinin receptor agonists on mucus secretion by ferret trachea was determined in vitro in Ussing chambers using 35SO4 as a mucus marker and the synthetic peptides [Sar9,Met(O2)11]substance P (SarSP), [beta Ala8]neurokinin A-(4-10) and [MePhe7] neurokinin B which are selective for NK1, NK2 and NK3 tachykinin-receptors respectively. The bronchomotor effects of the same agonists were also studied in vitro and tachykinin receptors were localized by autoradiographic mapping. SarSP was the only synthetic agonist able to elicit a concentration-dependent increase in mucus secretion and was much more potent than SP. The EC50 for SarSP was 1.7 x 10(-6) M. Moreover, the maximal increase in release of 35SO4 produced by SarSP 10(-5) M was 95% of the increase produced by methacholine 10(-4) M indicating that this concentration of SarSP induced a near maximal secretory response. There was no significant difference in the secretory action of SP administered from the luminal or the submucosal side of the tissue. Only the NK2 agonist was able to produce a concentration-dependent contractility of bronchial ring preparations and its effect was relatively weak (EC50 6.4 x 10(-6) M). Capsaicin (10(-5) M) produced only a slight increase in tracheal mucus secretion (28 +/- 5%; n = 6) and was completely ineffective in inducing bronchoconstriction. Binding sites for [125I]-Bolton Hunter SP were more evident than sites for [125I]-NKA on submucosal glands and epithelium. In contrast, only binding sites to NKA could be observed over the smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effects of peptidase inhibitors on bradykinin-induced bronchoconstriction in the rat.

Objectives of this study were to determine if aerosolized bradykinin causes bronchoconstriction in anesthetized, mechanically ventilated rats, and if pretreatment with enalaprilat, an inhibitor of angiotensin-converting enzyme (ACE), or phosphoramidon, an inhibitor of endopeptidase 24.11 (EP 24.11), alters the response. We found that aerosolized bradykinin elicited a reproducible bronchoconstrictor response that was significantly amplified by pretreatment with aerosolized enalaprilat or phosphoramidon. Neither inhibitor alone affected airway tone or caused nonspecific airway hyperreactivity. These findings indicate that both ACE and EP 24.11 contribute to bradykinin degradation in rat airways.

Aerosols↗
PubMed1995

Bronchoconstriction and airway hyperresponsiveness after ovalbumin inhalation in sensitized mice.

To investigate the mechanisms underlying airway hyperresponsiveness a murine model was developed with several important characteristics of human allergic asthma. Mice were intraperitoneally sensitized with ovalbumin and after 4 weeks challenge via an ovalbumin aerosol. After aerosol, lung function was evaluated with a non-invasive forced oscillation technique. The amount of mucosal exudation into the airway lumen and the presence of mast cell degranulation was determined. Tracheal responsiveness was measured at several time points after challenge. At these time points also bronchoalveolar lavage and histology were performed. Sensitization induced high antigen-specific IgE levels in serum. Inhalation of ovalbumin in sensitized mice induced an immediate but no late bronchoconstrictive response. During this immediate phase, respiratory resistance was increased (54%). Within the first hour after ovalbumin inhalation increased mucosal exudation and mast cell degranulation were observed. At 12 and 24 h after ovalbumin challenge, mice showed tracheal hyperresponsiveness (29% and 34%, respectively). However, no apparent inflammation was found in the lungs or bronchoalveolar lavage. From these results it can be concluded that hyperresponsiveness can develop via mechanisms independent of an inflammatory infiltrate. Since mast cell degranulation occurred after ovalbumin exposure, we hypothesize that mast cells are involved in the induction of airway hyperresponsiveness in this model.

Animals↗
PubMed1995

Eicosanoid release in allergen-induced bronchoconstriction in dogs. Its relationship to airways hyperreactivity and pulmonary inflammation.

In vitro studies have demonstrated the release of histamine, PGD2, TXB2, PGE2, PGF2 alpha, 6-keto-PGF1 alpha and the peptidoleukotrienes from sensitized lung. We have assessed the release of these mediators following antigen challenge in vivo. Antigen challenge of allergic dogs resulted in an acute bronchoconstriction and an increase in bronchial reactivity to histamine and an increase in neutrophil and eosinophil numbers recovered by bronchoalveolar lavage (BAL), 2 and 24 h later. The acute response was associated with histamine and PGD2 release but there was no increase in the levels of other eicosanoids in recovered BAL. Bronchial hyperreactivity and pulmonary inflammation, 2 and 24 h post-challenge was not associated with a concommitant (antigen specific) increase in BAL fluid eicosanoid levels. We conclude that although PGD2 is released during the acute response to antigen the subsequent changes (hyperreactivity and inflammation) are not characterised by a maintained elevation in eicosanoid levels detectable by BAL.

Airway Resistance↗
PubMed1989

The protective effects of intravenous theophylline and enprofylline against histamine- and adenosine 5'-monophosphate-provoked bronchoconstriction: implications for the mechanisms of action of xanthine derivatives in asthma.

The contribution of adenosine antagonism to the anti-bronchoconstrictor effect of xanthines was examined in 7 atopic asthmatic subjects. On separate occasions the effect of intravenous infusions of theophylline, enprofylline and saline placebo was observed on bronchoconstriction provoked by increasing inhaled concentrations of histamine and adenosine 5'-monophosphate (AMP). Airway calibre was followed as the maximum expiratory flow at 70% below total lung capacity (Vmax30) and FEV1. Both active drugs produced a similar 6-8% increase in FEV1 and 28-41% increase in Vmax30 at steady state plasma concentrations of theophylline 11 mg/ml and enprofylline 3 mg/ml respectively. During the placebo infusion histamine and AMP caused dose-related reductions in both indices of airway calibre, with AMP being approximately 10 times less potent than histamine in molar terms. Theophylline and enprofylline produced similar protection against histamine induced reductions in FEV1 and Vmax30. Whereas enprofylline afforded a similar degree of protection against the airway effect of AMP and histamine, theophylline produced significantly greater protection against AMP whether airway calibre was assessed as Vmax30 or FEV1. The differential effects of theophylline and enprofylline against AMP, but not histamine or baseline airway calibre suggest that adenosine antagonism has little role to play in the acute bronchodilator actions of xanthines.

Adult↗
PubMed1990

The protective efficacy of inhaled, oral and intravenous nedocromil sodium against adenosine-5'-monophosphate-induced bronchoconstriction in asthmatic volunteers.

We have investigated the pharmacokinetics and pharmacodynamics of nedocromil sodium administered by inhalation (4 mg), by mouth (80 mg) and by intravenous infusion (6 micrograms/kg) against adenosine-5'-monophosphate (AMP) induced bronchoconstriction in 9 mildly asthmatic subjects. Their mean baseline FEV1 was 83.8% of the predicted value, geometric mean (GM) PC20 FEV1 histamine 0.33 mg/ml (range 0.03-4.0), and GM PC50 baseline sGaw AMP 4.37 mg/ml (range 0.158-26.38). Blood collected at intervals for up to 4 h after drug administration was assayed for nedocromil sodium by radioimmunoassay, to derive the maximal drug concentration (Cmax), concentration at time of AMP challenge (Cchall), area under the plasma concentration-time curve (AUC), and the mean residence time (MRT). Airways responsiveness to inhaled AMP was assessed before and after administration of nedocromil sodium by each of the three routes of administration, and the protective efficacy was expressed as the concentration ratio (CR). AMP challenge was carried out 60 min after inhaled nedocromil sodium, 120 min after drug ingestion and 75 min after the start of the intravenous infusion. The GM PC50 sGaw AMP determined after inhaled, oral and intravenous nedocromil sodium was 28.84, 7.24 and 7.94 mg/ml respectively. For the group as a whole, nedocromil sodium by the oral or intravenous routes produced little overall protection against AMP (CR increasing by 0.75 and 0.88 doubling dilutions respectively). However, with inhaled drug, the concentration response curve with AMP was displaced to the right achieving an increased CR of 2.71 doubling dilutions. No relationship could be established between baseline FEV1, and AUC, Cmax or Cchall, or between these indices and the protective efficacy for the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Monophosphate↗
PubMed1993

Importance of secondary TXA2 release in mediating of endothelin-1 induced bronchoconstriction and vasopressin in the guinea-pig.

The i.v. bolus application of 1 nmol/kg endothelin-1 (ET-1) in anaesthetized and ventilated guinea-pigs caused an increase in mean arterial blood pressure (BP) and a bronchoconstriction. Both have been reduced or abolished by COX inhibition (ASA) or substances specifically reducing the thromboxane A2 (TXA2) generation (HOE 944) or receptor binding (BM 13177). The significant increase in TXB2 concentrations in plasma and bronchoalveolar lavage (BAL) after ET-1 challenge (15-fold and 4-fold, respectively) have been reduced or abolished by ASA as well as HOE 944 and not altered by BM 13177.

Animals↗
PubMed2005

Inhaled lysophosphatidylcholine provokes bronchoconstriction in guinea pigs in vivo.

Lysophosphatidylcholine is increased in the airway of bronchial asthma, but its role is not clear. We investigated the role of lysophosphatidylcholine in asthma in anaesthetized, mechanically ventilated guinea pigs. Pressure at the airway opening was measured as an index of bronchial response. Increasing doses of lysophosphatidylcholine (1--10 mg/ml) were inhaled and then bronchoalveolar lavage was carried out. 100 and 200 microg/ml methacholine were inhaled 10 min after inhalation of 2.5 mg/ml lysophosphatidylcholine, 10 mg/ml dipalmitoyl phosphatidylcholine and 10 mg/ml glycerophosphocholine, all of which per se did not change the pressure at the airway opening. Effect of 1.0 microg/kg salbutamol, or 60 mg/kg diphenhydramine on the lysophosphatidylcholine-induced increase in the pressure at the airway opening was investigated. Inhalation of lysophosphatidylcholine dose-dependently increased the pressure at the airway opening and increased bronchial responsiveness to methacholine. On the other hand, inhalation of dipalmitoyl phosphatidylcholine decreased the pressure at the airway opening and decreased bronchial responsiveness to methacholine. Intravenously administered salbutamol, but not diphenhydramine, prevented the lysophosphatidylcholine-induced increase in the pressure at the airway opening. The percentage of leukocytes in bronchoalveolar lavage fluid did not change significantly at least within 20 min after the lysophosphatidylcholine inhalation. Lysophosphatidylcholine causes bronchoconstriction and enhances bronchial responsiveness without inducing leukocyte infiltration in the airway, suggesting that lysophosphatidylcholine may be a new bronchoconstrictor mediator in bronchial asthma.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2005

Exhaled breath condensate cysteinyl leukotrienes are increased in children with exercise-induced bronchoconstriction.

BACKGROUND: It is recognized that airway inflammation has a central role in the pathogenesis of asthma, but how it relates to exercise-induced bronchoconstriction (EIB) is not completely understood. OBJECTIVE: The aim of our study was to investigate the relationship between EIB and baseline concentrations of cysteinyl leukotrienes (Cys-LTs) and other inflammatory markers in exhaled breath condensate (EBC). METHODS: EBC was collected, and the fraction of exhaled nitric oxide (FE NO ) was measured in a group of 19 asthmatic children, after which they performed a treadmill exercise test. Fourteen healthy children were enrolled as control subjects. RESULTS: The asthmatic children were divided into the EIB group (decrease in FEV 1 , > or =12%) and the non-EIB group. The EBC was analyzed for the presence of Cys-LTs, leukotriene B 4 , and ammonia. Asthmatic patients with EIB (mean FEV 1 decrease, 23% +/- 3%) had higher Cys-LT concentrations than either asthmatic patients without EIB or control subjects (42.2 pg/mL [median] vs 11.7 pg/mL and 5.8 pg/mL; P < .05 and P < .001, respectively). Ammonia concentrations were lower in both the EIB and non-EIB groups than in control subjects (253.2 microM and 334.6 microM vs 798.4 microM; P < .01 and P < .05, respectively). No difference in EBC leukotriene B 4 levels was found among the 3 groups. Both asthmatic groups had higher FE NO levels than control subjects ( P < .001). EBC Cys-LT ( P < .01; r = 0.7) and FE NO ( P < .05; r = 0.5) values both correlated significantly with the postexercise FEV 1 decrease. CONCLUSION: this study shows that EBC Cys-LT values are higher in asthmatic children with EIB and correlate with the decrease in FEV 1 after exercise. These findings suggest that the pathways of both Cys-LT and nitric oxide are involved in the pathogenesis of EIB.

Acetates↗