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PubMed1999

Mechanisms of capsaicin- and lactic acid-induced bronchoconstriction in the newborn dog.

1. Capsaicin activation of the pulmonary C fibre vanilloid receptor (VR1) evokes the pulmonary chemoreflex and reflex bronchoconstriction. Among potential endogenous ligands of C fibre afferents, lactic acid has been suggested as a promising candidate. We tested the hypotheses that (a) lactic acid behaves as a stimulant of C fibre receptors in the newborn dog to cause reflex bronchoconstriction, and (b) lactic acid causes reflex bronchoconstriction via the same pulmonary C fibre receptor mechanism as capsaicin using the competitive capsaicin/VR1 receptor antagonist capsazepine. 2. Right heart injection of lactic acid caused a significant increase (47 +/- 8.0 %) in lung resistance (RL) that was atropine sensitive (reduced by 75 %; P < 0.05), consistent with reflex activation of muscarinic efferents by stimulation of C fibre afferents. 3. Infusion of the competitive capsaicin antagonist capsazepine caused an 80 % reduction (P < 0.01) in the control bronchoconstrictor response (41 +/- 8.5 % increase in RL) to right heart injections of capsaicin. The effects of capsazepine are consistent with reversible blockade of the VR1 receptor to abolish C fibre-mediated reflex bronchoconstriction. 4. Lactic acid-evoked increases in RL were unaffected by VR1 blockade with capsazepine, consistent with a separate lactic acid-induced reflex mechanism. 5. We conclude that (a) putative stimulation of C fibres with lactic acid causes reflex bronchoconstriction in the newborn dog, (b) capsazepine reversibly antagonizes reflex bronchoconstriction elicited by right heart injection of capsaicin, presumably by attenuating capsaicin-induced activation of the C fibre 'capsaicin' receptor (VR1), and (c) capsazepine resistance of lactic acid-induced bronchoconstriction indicates that lactic acid evokes reflex bronchoconstriction by a separate mechanism, possibly via the acid-sensing ionic channel.

Animals↗

PubMed1991

BAY u3405 an antagonist of thromboxane A2- and prostaglandin D2-induced bronchoconstriction in the guinea-pig.

1. The novel thromboxane (TX) antagonist, BAY u3405, has been evaluated against bronchoconstriction induced by the TXA2 mimetic U-46619, prostaglandin D2 (PGD2), 5-hydroxytryptamine (5-HT), leukotriene D4 (LTD4) and histamine in the guinea-pig in vivo by use of a modification of the model described by Konzett & Rössler. 2. When given intravenously (i.v.) at 30 or 100 micrograms kg-1, U-46619 caused 80% maximal bronchoconstriction in most animals. In contrast, PGD2 caused a smaller 40%-50% maximal bronchoconstriction at the highest dose tested (300 micrograms kg-1, i.v.). 3. BAY u3405, given intravenously, orally (p.o.) or by aerosol antagonized U-46619-induced bronchoconstriction in a dose-related manner. The approximate ID50 values were 600 micrograms kg-1, i.v., 1.7 mg kg-1 p.o. and 0.1% w/v 20 breaths by aerosol. 4. BAY u3405 had similar inhibitory activities against U-46619-induced bronchoconstriction and hypertension suggesting that it had no preferential activity on the airways. 5. When given intravenously BAY u3405 antagonized the bronchoconstrictor effect of intravenous PGD2 with ID50 values between 30-100 micrograms kg-1. 6. The action of BAY u3405 (10 mg kg-1, p.o.) was long lasting, causing significant inhibition of U-46619-induced bronchoconstriction 7 h after dosing. 7. At 1 mg kg-1, i.v., a dose that abolished the response to U-46619 and PGD2, BAY u3405 had no effect on histamine-, 5-HT- or LTD4-induced bronchoconstriction. 8. BAY u3405 potently and selectively antagonized U-46619- or PGD2-induced bronchoconstriction in the Konzett-Rössler model of guinea-pig lung function. It should therefore prove to be a useful tool for defining the role of TXA2- and PGD2 in airway diseases such as asthma.

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

PubMed1994

Sulfur dioxide and sodium metabisulfite induce bronchoconstriction in the isolated perfused and ventilated guinea pig lung via stimulation of capsaicin-sensitive sensory nerves.

In this study the relationship between sulfur dioxide-induced sensory nerve activation and acute bronchoconstriction was assessed. We also studied the effects of sodium metabisulfite, an agent that is suggested to increase airway resistance via activation of sensory nerves. Sulfur dioxide (250 ppm) induced a characteristic biphasic bronchoconstriction. Concomitantly sulfur dioxide induced the release of calcitonin gene-related peptide (CGRP) from capsaicin-sensitive sensory nerves into the pulmonary circulation. In lungs of guinea pigs pretreated with a neurotoxic dose of capsaicin, the first phase of bronchoconstriction was reduced and the overflow of CGRP was not detectable. Tetrodotoxin abolished the initial phase of the bronchoconstriction induced by sulfur dioxide, indicating that a local neural reflex depending on sodium channels was operant. Inhibition of the vanilloid receptor with capsazepine slightly, although not significantly, reduced the contractile responses to sulfur dioxide. Sodium metabisulfite, when infused via the pulmonary circulation (3 mM), induced bronchoconstriction which was abolished by capsaicin pretreatment, but not significantly reduced by capsazepine. The results indicate that in the isolated guinea pig lung inhaled sulfur dioxide induces initial bronchoconstriction in part via sensory nerve activation, while other mechanisms are involved in the late effect. Sensory nerve activation appears to be the only mechanism for bronchoconstriction induced by infused sodium metabisulfite. A role for sensory nerve-mediated bronchoconstriction by sulfur dioxide or sodium metabisulfite via activation of the vanilloid receptor could not be conclusively demonstrated by this study using capsazepine.

Animals↗

PubMed1990

The time course of bronchoconstriction in asthmatics during and after isocapnic hyperventilation.

We studied the effect of changing the duration of isocapnic hyperventilation on the time course of bronchoconstriction in five subjects with asthma. Each subject performed hyperventilation challenges of 4, 8, and 16 min. No significant bronchoconstriction occurred until the hyperventilation was stopped, regardless of its duration. We found increased bronchoconstriction as the duration of hyperventilation increased. The declines in FEV1 (mean +/- SD) from baseline were 13 +/- 10%, 22 +/- 7%, and 29 +/- 12% for 4, 8, and 16 min of hyperventilation, respectively (1 versus 3, p less than 0.01). Mean times after hyperventilation until maximal bronchoconstriction were 12 +/- 4 min, 9 +/- 6 min, and 6 +/- 4 min. We also found slight bronchodilation during the first 4 min of hyperventilation. After 2 and 4 min of hyperventilation, the FEV1 was 103 +/- 5% and 103 +/- 3% of baseline, respectively (both p less than 0.05, compared to baseline). We conclude that increasing the duration of hyperventilation delays the onset of bronchoconstriction but causes greater bronchoconstriction once the hyperventilation is stopped. These results suggest that either hyperventilation itself inhibits bronchoconstriction or that the mechanisms that induce bronchoconstriction in response to hyperventilation operate after, rather than during, hyperventilation.

Adolescent↗

PubMed1990

Allergen-induced biphasic bronchoconstriction in rats.

The development of an allergic bronchoconstriction model in rats is described. In actively sensitized Donryu strain rats, there was a remarkable biphasic increase in airway resistance within 10 min after antigen challenge on day 9 to day 21. The increase in airway resistance, correlated with the IgE titer and the dose of antigen, was inhibited by disodium cromoglycate (DSCG) or by aminophylline. This bronchoconstriction was remarkably blocked by methysergide (25 and 100 micrograms/kg) while pyrilamine inhibited it partially at the same dose. Serotonin (greater than 30 micrograms/kg) but not histamine (less than 1,000 micrograms/kg) induced a bronchoconstriction. FPL-55712 (1,10 mg/kg) inhibited it significantly. The content of thromboxane B2 (TxB2) in plasma increased during the bronchoconstriction while the content of peptide-leukotrienes (p-LTs) in plasma did not increase significantly. OKY-046 inhibited not only allergic bronchoconstriction but also the increase in TxB2 levels in plasma. The late phase of the bronchoconstriction was more susceptible to OKY-046. In conclusion, this model seems to be useful for the screening of antiasthma drugs because of a relationship with the dose of antigen, IgE titer and the susceptibility to an antiallergic drug or a bronchodilator. It is demonstrated that the major part of this allergic bronchoconstriction depends on serotonin, and it is also suggested that thromboxane A2 may play an important role in the late phase of the bronchoconstriction.

Airway Resistance↗

PubMed1990

[The influence of exercise-induced bronchoconstriction on participation in organized sport].

Approximately 70-80% of all asthma sufferers develop acute airway obstruction with exercise, while at least 7% of children in the general population develop exercise-induced bronchoconstriction. The purpose of this study was: (i) to determine whether children in the Cape Peninsula who suffer from asthma and/or exercise-induced bronchoconstriction are as inactive and uninvolved in sport as asthmatic children in the USA; and (ii) whether this uninvolvement is a direct result of their susceptibility to exercise-induced bronchoconstriction. An in-depth study was done on the intensity, frequency and level of participation in sport by children with asthma and/or exercise-induced bronchoconstriction compared with a control group of healthy children without a history of asthma or exercise-induced bronchoconstriction. Children with asthma and/or exercise-induced bronchoconstriction generally maintained a similar level of sport participation as healthy children, and only children with serious asthma or exercise-induced bronchoconstriction experienced limitations with regard to physical activity. It was found that, in contrast to children in the USA, non-participation in sport could not be explained by asthma and/or exercise-induced bronchoconstriction.

Adolescent↗

PubMed1987

The mechanism of aerosol-induced bronchoconstriction.

To gain insight into the mechanism of aerosol induced bronchoconstriction the differences between ultrasonically-nebulized aqueous-induced bronchoconstriction and cough are contrasted. Both normal subjects and asthmatics cough in response to inhalation of aerosol low in chloride ions (Cl-). This is putatively a result of stimulation of rapidly-adapting receptors (RARs). Normals do not develop bronchoconstriction as a result of inhalation of aqueous aerosols. Asthmatics however do but only when the tonicity is increased above or below normal; (Cl-) is not important. Inhaled lignocaine inhibits cough but not bronchoconstriction whilst sodium cromoglycate (SCG) inhibits bronchoconstriction but not cough. As SCG may inhibit vagal C-fibre receptors it is possible that different vagal afferent receptors are involved in cough and bronchoconstriction. Small but significant bronchodilatation in normals attenuates aerosol-induced cough which can be explained by central modulation of medullary cough neurones by slowly-adapting receptors (SARs). As the same occurs with reflex bronchoconstriction, a complex organisation of vagal afferents can be suggested, where different receptors are responsible for cough and bronchoconstriction and SAR activity modulates the medullary neurones which initiate the two reflexes.

Aerosols↗

PubMed2003

Mast-cell stabilising agents to prevent exercise-induced bronchoconstriction.

BACKGROUND: Exercise-induced bronchoconstriction (or asthma) following strenuous physical exertion is common and can cause sub-optimal performance, symptoms such as cough, dyspnea, wheeze, chest tightness, and can lead people to avoid physical activity. Management focuses on prevention with pre-exercise treatment using various pharmacologic agents. Mast cell stabilizing agents are effective in attenuating exercise-induced bronchoconstriction but their effectiveness compared to bronchodilator agents is unclear. OBJECTIVES: To quantitatively compare the effects of inhaling a single dose of either mast cell stabiliser - nedocromil sodium or sodium cromoglycate - to a single dose of short acting beta-agonists or anti-cholinergic agents - atropine or ipratropium bromide - prior to a strenuous exercise challenge in participants with asthma who are at least 6 years of age and suffer from reproducible exercise-induced bronchoconstriction. The review also compares the effects between a short acting beta-agonist alone to a combination of a short acting beta-agonist + mast cell stabiliser. SEARCH STRATEGY: We searched the Cochrane Airways Group ASTHMA and WHEEZ* trials register, Cochrane CENTRAL, Current Contents, review articles, textbooks and reference lists of articles. We also contacted the drug manufacturer and primary authors for additional citations. SELECTION CRITERIA: Randomised trials comparing a single prophylactic dose of a mast cell stabiliser to a short acting beta-agonist, anti-cholinergic agent, or a short acting beta-agonist alone to a combination of short acting beta-agonist plus a mast cell stabiliser to prevent exercise-induced bronchoconstriction in asthmatics over six years old. The exercise challenge had to conform to acceptable standards and pulmonary function (PFT) reported as percent decrease from baseline of FEV1 or peak flow. Complete protection (maximum % fall PFT <15% post-exercise) and clinical protection (50% improvement over placebo effect) measures were included. DATA COLLECTION AND ANALYSIS: Trial inclusion and quality assessments were conducted independently by two reviewers using standardised forms. A second reviewer confirmed data extraction and calculations. Attempts were made to contact study authors. The pooled estimate involving continuous pulmonary function measures are reported as a weighted mean difference (WMD), dichotomous data as an odds ratio (OR), both with 95% confidence intervals (95%CI) using a random effects model. Heterogeneity tests for pooled results were performed. MAIN RESULTS: Twenty-four trials (518 participants) conducted in 13 countries between 1976 and 1998 were included. All drugs were effective at attenuating the exercise-induced bronchoconstriction response but to varying degrees even within the same individual. Compared to anti-cholinergic agents, mast cell stabilisers were somewhat more effective at attenuating bronchoconstriction. On average the maximum fall on MCS was reduced to 7.1% compared to 13.8% on AC ( WMD = 6.7%; 95% CI: 3.3 to 10.0), provided more individuals with complete protection (73% vs 56%; OR = 2.2; 95% CI: 1.3 to 3.7) and clinical protection (73% vs 52%; OR = 2.7; 95% CI: 1.1 to 6.4). There were no subgroup differences based on age, severity, or study quality, and no adverse effects were reported for either agent group. When compared to short acting beta-agonists mast cell stabilisers were not as effective at preventing deterioration. On average the maximum fall on MCS was 11.2% compared to 4.3% on beta agonists ( WMD = 6.8%; 95% CI: 4.5 to 9.2). MCS provided fewer individuals with complete protection (66% vs 85%; OR = 0.3; 95% CI: 0.2 to 0.5) or clinical protection (55% vs 77%; OR = 0.4; 95% CI: 0.2 to 0.8). There were no significant subgroup differences based on age, severity, drug, delivery, or study quality. A non-significant difference in side effects was demonstrated with 11% of short acting beta-agonist patients experiencing side effects compared to 3% of those receiving mast cell stabilisers (OR = 0.2; 95% CI: 0.0 to 8.2). Combining masta-agonist patients experiencing side effects compared to 3% of those receiving mast cell stabilisers (OR = 0.2; 95% CI: 0.0 to 8.2). Combining mast cell stabilisers with a short acting beta-agonist did not produce significant advantages to pulmonary function over short acting beta-agonists alone. On average the maximum fall on SABA only was reduced to 5.3% compared to 3.5% on the combination ( WMD = 1.8%; 95% CI: -1.1 to 4.6). Beta-agonists alone provided fewer individuals with complete protection (68% vs 80%; OR = 0.5; 95% CI: 0.2 to 1.4) or clinical protection (70% vs 86%; OR=0.4; 95% CI: 0.1 to 1.2) but the difference did not reach significance (p=0.17). There were no subgroup differences. REVIEWER'S CONCLUSIONS: In a population of stable asthmatics short acting beta-agonists, mast cell stabilisers, or anticholinergics will provide a significant protective effect against exercise-induced bronchoconstriction with few adverse effects. On average, SABAs resulted in more effective attenuation than mast cell stabilisers, while mast cell stabilisers were more effective than anti-cholinergic agents. Combining SABA and mast cell stabilisers may be appropriate in selected cases. The variability in the individual degree of response to these drugs in multi arm trials suggests clinicians and patients work together to identify the most effective prophylactic therapy.

Adrenergic beta-Agonists↗

PubMed1996

Role of tachykinins in enhancement of bradykinin-induced bronchoconstriction by captopril.

In anesthetized, mechanically ventilated guinea pigs, infusion of captopril (1 mg/kg/h), an angiotensin converting enzyme inhibitor, significantly enhanced bronchoconstriction induced by intravenous injection of bradykinin (BK; 0.1-30 nmol/kg). Pretreatment of guinea pigs with capsaicin (100 mu g/kg) slightly suppressed the bronchoconstriction by BK alone and almost all of the enhancement of BK-induced bronchoconstriction by captopril was suppressed. Intravenous injection of substance P (SP; 0.1-100 nmol/kg), neurokinin A (NKA; 0.1-30 nmol/kg) and neurokinin B (NKB; 0.1-30 nmol/kg) also induced dose-dependent bronchoconstriction but captopril treatment enhanced only the bronchoconstriction induced by SP. BK degradation in bronchoalveolar lavage fluid (BALF) in vitro was significantly suppressed by captopril (p < 0.05). Captopril infusion to guinea pigs significantly increased the levels of BK, SP, and NKA in BALF after BK injection (p < 0.05). FK224, an NK1 and NK2 receptor antagonist and SR 48968, an NK2 receptor antagonist, significantly suppressed the bronchoconstriction induced by BK alone (p < 0.01 and p < 0.05, respectively) as well as the enhancement by captopril (p < 0.01). It can be concluded that the enhancement of BK-induced bronchoconstriction by captopril was attributable to inhibition of the degradation of BK itself and thereby enhanced release of NKA and partly of SP from sensory nerves by BK.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1991

Effect of the selective PAF antagonist SM-10661 on an asthmatic model. 1. Effect on passive anaphylactic bronchoconstriction in guinea pigs.

The effect of SM-10661, a selective antagonist of platelet-activating factor (PAF), on passive anaphylactic bronchoconstriction was examined in guinea pigs. A challenge of ovalbumin to passively sensitized guinea pigs induced bronchoconstriction, which peaked at 4 min. When SM-10661 was administered intravenously 2 min before ovalbumin challenge, bronchoconstriction was inhibited dose-dependently with an ID50 of 68 mg/kg. In guinea pigs pretreated with 15 micrograms/kg mepyramine which is a suboptimal dose, antigen-induced bronchoconstriction peaked at 4-6 min, but was inhibited by SM-10661 with an ID50 of 21 mg/kg. When guinea pigs were pretreated intravenously with 2.5 mg/kg mepyramine, 1 mg/kg indomethacin and 0.01 mg/kg propranolol, the antigen-induced bronchoconstriction peaked at 6 min. SM-10661 inhibited the response with an ID50 of 45 mg/kg. Histamine- and leukotriene D4-induced bronchoconstrictions were unaffected by up to 100 mg/kg SM-10661. Ovalbumin challenge of minced lungs from passively sensitized guinea pigs triggered the release of leukotrienes and histamine. SM-10661 had no effect on the antigen-induced release of peptide leukotrienes or histamine up to 10(-4) M. These results indicate that SM-10661 may be a useful tool to investigate the role of PAF in antigen-induced anaphylactic bronchoconstriction.

Anaphylaxis↗

PubMed1996

The effect of inhaled K+ channel openers on bronchoconstriction and airway microvascular leakage in anaesthetised guinea pigs.

Since orally administered K+ channel openers may have cardiovascular side effects, it is possible that inhaled administration would be preferred for the treatment of asthma. We have investigated whether inhaled levcromakalim and HOE 234 inhibit histamine-induced bronchoconstriction and airway plasma exudation in anaesthetised guinea pigs. We have also investigated whether inhaled HOE 234 inhibits the bronchoconstriction and plasma exudation induced by vagus nerve stimulation, which is due to the release of tachykinins from sensory nerves. Lung resistance was measured by airway resistance (RL) computed from airway and transpulmonary pressures and plasma exudation by measurement of Evans blue dye extravasation. Inhaled levcromakalim (25 mu g/ml) had a short duration of action, being effective against histamine-induced bronchoconstriction 2 min after pretreatment, but not at 10 min. Inhaled HOE 234 (25 mu g/ml) was similarly effective against histamine-induced bronchoconstriction but had a longer duration of action. Inhaled levcromakalim partially attenuated histamine-induced plasma extravasation in small airways, but not in the trachea or main bronchi, whereas inhaled HOE 234 had no effect. HOE 234 protected against non-adrenergic non-cholinergic nerve-induced bronchoconstriction, but had no effect on neurogenic- or substance P-induced plasma extravasation in the airway. Inhaled K+ channel openers protect against induced bronchoconstriction, but provide little or no protection against plasma exudation, possibly because of an increase in airway blood flow. In addition, inhaled HOE 234 had no effect on neurogenic leakage, suggesting that its vagal inhibitory effect on bronchoconstriction was on airway smooth muscle, rather than on release of neuropeptides from sensory nerves.

Administration, Inhalation↗

PubMed1999

Low frequency-dependent mechanism of the M2 receptor function on vagally mediated bronchoconstriction in rabbits in vivo.

The present study was carried out to investigate whether there is the difference between low and high frequencies of vagal stimulation on the functional appearance of M2 receptors in the rabbit. The animals were anesthetized, artificially ventilated and bilaterally vagotomized. Bilateral vagus nerve stimulation (5 to 30 Hz) for 30 sec caused bronchoconstriction (measured as an increase in R(L) and a decrease in Cdyn) in a frequency-dependent manner. The bronchoconstriction evoked by ACh injection (1 and 3 microg/kg) was dose-dependent. Although administration of methoctramine (50 and 300 microg/kg), a selective M2 receptor antagonist, had no significant effect on ACh-induced bronchoconstriction, methoctramine dose-dependently augmented the R(L) and Cdyn responses to vagal stimulation at 5-15 Hz but did not potentiate bronchoconstrictive responses to the stimulation at 30 Hz. Administration of [D-Pro2, D-Try(7,9)]-SP (0.5 mg/kg, a selective tachykinin receptor antagonist) that had no significant effect on the R(L) and Cdyn responses to vagal stimulation (5-15 Hz) attenuated the bronchoconstrictive response to the stimulation at 30 Hz. Conversely, thiorphan (2 mg/kg, a neutral endopeptidase inhibitor) potentiated the bronchoconstriction evoked by vagal stimulation at 30 Hz only. These results suggest that M2 receptors function as the inhibitory receptors in the bronchoconstrictive response to vagal stimulation at the lower frequencies (5-15 Hz), but that the M2 receptor antagonism is diminished when vagal stimulation at a higher frequency (30 Hz) results in the release of SP from the lungs.

Acetylcholine↗

PubMed2005

Activation of the nociceptin/orphanin FQ receptor reduces bronchoconstriction and microvascular leakage in a rabbit model of gastroesophageal reflux.

1. Nociceptin/orphanin FQ (N/OFQ) is the endogenous peptide ligand for a specific G-protein coupled receptor, the N/OFQ peptide receptor (NOP). The N/OFQ-NOP receptor system has been reported to play an important role in pain, anxiety and appetite regulation. In airways, N/OFQ was found to inhibit the release of tachykinins and the bronchoconstriction and cough provoked by capsaicin. 2. Here we evaluated the effects of NOP receptor activation in bronchoconstriction and airway microvascular leakage induced by intraesophageal (i.oe.) hydrochloric acid (HCl) instillation in rabbits. We also tested the effects of NOP receptor activation in SP-induced plasma extravasation and bronchoconstriction. 3. In anesthetized New Zealand rabbits bronchopulmonary function (total lung resistance (R(L)) and dynamic compliance (C(dyn))) and airway microvascular leakage (extravasation of Evans blue dye) were evaluated. 4. Infusion of i.oe. HCl (1 N) led to a significant increase in bronchoconstriction and plasma extravasation in the main bronchi and trachea of rabbits pretreated with propranolol, atropine and phosphoramidon. 5. Bronchoconstriction and airway microvascular leakage were inhibited by N/OFQ (3-30 microg kg(-1) i.v.) in a dose-dependent manner. The NOP receptor agonist [Arg14,Lys15]N/OFQ mimicked the inhibitory effect of N/OFQ, being 10-fold more potent, UFP-101, a peptide selective NOP receptor antagonist, blocked the inhibitory effects of both agonists. 6. Under the same experimental conditions, N/OFQ and [Arg14,Lys15]N/OFQ did not counteract the bronchoconstriction and airway microvascular leakage induced by substance P. 7. These results suggest that bronchoconstriction and airway plasma extravasation induced by i.oe. HCl instillation are inhibited by activation of prejunctional NOP receptors.

Animals↗

PubMed1995

Sympathoadrenal responses to bronchoconstriction in asthma: an invasive and kinetic study of plasma catecholamines.

1. Bronchoconstriction does not seem to be a stimulus for sympathoadrenal activation, as judged by venous plasma concentrations of noradrenaline, adrenaline or neuropeptide Y-like immunoreactivity. However, venous measurements have methodological drawbacks. In the present study arterial and mixed venous (pulmonary arterial) levels of these variables were determined before and after histamine-induced bronchoconstriction in non-medicated asthmatic subjects. In addition, noradrenaline kinetics in plasma (isotope dilution) and the pulmonary overflows of noradrenaline and neuropeptide Y-like immunoreactivity were determined. 2. Histamine inhalation induced bronchoconstriction; forced expiratory volume in ls decreased by 38.7% +/- 4.1% (SE) and arterial PO2 by 3.0 +/- 0.9 kPa. This acute bronchoconstriction induced significant elevations of arterial and mixed venous plasma noradrenaline from < or = 1.18 nmol/l to > or = 1.40 nmol/l. The clearance of NA from plasma increased marginally. Thus, the arterial plasma NA response was due to increased spillover of noradrenaline to plasma (from 1.80 +/- 0.18 to 2.52 +/- 0.36 mmol min-1/m2 at maximal bronchoconstriction, with a subsequent further increase). There were no elevations of adrenaline or neuropeptide Y-like immunoreactivity in arterial plasma. 3. No sympathetic activation could be demonstrated in the lungs (pulmonary noradrenaline or neuropeptide Y-like immunoreactivity overflow), and no alterations in pulmonary vascular resistance or cardiac output were observed. Neither arterial nor mixed venous plasma concentrations of adrenaline were influenced by bronchoconstriction. 4. Acute bronchoconstriction thus leads to peripheral sympathetic activation (possibly due to the increased work of breathing) which does not involve the lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist.

BACKGROUND: Exercise is a common stimulus of bronchoconstriction in subjects with asthma, who also have bronchoconstriction after inhaling the sulfidopeptide leukotriene D4 (LTD4). The purpose of this study was to investigate the importance of LTD4 as a mediator of exercise-induced bronchoconstriction. METHODS: In a double-blind, randomized, crossover study, 12 subjects with stable asthma were treated intravenously with MK-571 (160 mg), a selective and potent LTD4-receptor antagonist, or placebo, 20 minutes before each of two challenges involving exercise at a level previously demonstrated to cause a fall of at least 20 percent in the forced expiratory volume in one second (FEV1). The two exercise challenges were separated by one week. The results of the challenges were expressed as both the maximal fall in FEV1 after exercise and the time to recovery from bronchoconstriction. RESULTS: Treatment with MK-571 attenuated exercise-induced bronchoconstriction in all the subjects. The mean (+/- SEM) maximal percent decrease in FEV1 after exercise was 25.2 +/- 3.5 percent in the subjects taking placebo and 9.2 +/- 2.5 percent in the subjects taking MK-571 (P less than 0.001). The mean percent inhibition for the entire group was 69.5 percent. The mean time to recovery after exercise was 33.4 +/- 4.0 minutes in the placebo group and 8.4 +/- 2.5 minutes in the MK-571 group (P less than 0.001). CONCLUSIONS: This study demonstrates that pretreatment with a potent and selective LTD4 antagonist markedly attenuates exercise-induced bronchoconstriction, and it suggests that LTD4 is a major mediator of this type of bronchoconstriction.

Asthma, Exercise-Induced↗

PubMed2000

Milrinone attenuates serotonin-induced pulmonary hypertension and bronchoconstriction in dogs.

UNLABELLED: We determined whether milrinone, a phosphodiesterase III inhibitor, attenuates serotonin-induced (5-hydroxytryptamine [5HT]) pulmonary hypertension (PH) and bronchoconstriction. Dogs were anesthetized with pentobarbital (30 mg/kg + 2 mg. kg(-1). h(-1)). Bronchoconstriction and PH were elicited by 5HT (10 microg/kg + 1.0 mg. kg(-1). h(-1)). Pulmonary vascular resistance was used to assess PH. Bronchoconstriction was also assessed by changes in bronchial cross-sectional area obtained from our bronchoscopic method. At 30 min after 5HT infusion started, seven dogs were given milrinone: 0 (saline), 5, 50, 500, and 5000 microg/kg at 10-min intervals. The other 12 dogs were given milrinone 5000 microg/kg 30 min after 5HT infusion, and 5 min later were given propranolol 0.2 mg/kg (n = 6) or saline (n = 6) IV. The 5HT significantly increased percentage of pulmonary vascular resistance to 208% +/- 27% and decreased percentage of bronchial cross-sectional area to 52% +/- 5% of the basal. Milrinone significantly attenuated both PH and bronchoconstriction in a dose-dependent manner. However, -log 50% effective concentration (mean ED(50) in microg/kg) of milrinone for bronchoconstriction: 4.32 +/- 0.13 (47.6) was significantly smaller than that for PH: 3.84 +/- 0.29 (144.9) (P < 0.01). In addition, the spasmolytic effects of milrinone (5000 microg/kg) were not antagonized by propranolol, although this dose significantly increased plasma catecholamines. In conclusion, milrinone attenuates 5HT-induced PH and bronchoconstriction; however, this drug may be more sensitive to phosphodiesterase III in the airway smooth muscle than in pulmonary vascular smooth muscle. In addition, the relaxant effects could not be caused by beta-adrenoceptor activation because beta-blocker did not antagonize. IMPLICATIONS: We studied the effects of milrinone on serotonin-induced pulmonary hypertension and bronchoconstriction in dogs. Milrinone produces pulmonary vasodilation and bronchodilation, whose effects may not be caused by beta-adrenoceptor activation. In addition, this drug may be more sensitive to phosphodiesterase III in the airway smooth muscle than that in pulmonary vascular smooth muscle.

Animals↗

PubMed2001

Efficacy of propofol to prevent bronchoconstriction: effects of preservative.

BACKGROUND: The authors previously showed that propofol attenuates bronchoconstriction. Recently, a newer formulation of propofol with metabisulfite preservative has been introduced. metabisulfite causes airway narrowing in asthmatics. Therefore, we tested whether the preservative metabisulfite abolishes the ability of propofol to attenuate bronchoconstriction. The authors used a sheep model in which anesthetic agents could be directly administered to the airways via the bronchial artery. METHODS: After Internal Review Board approval, seven sheep were anesthetized (pentobarbital 20 mg x kg(-1) x h(-1)) and paralyzed (pancuronium 2 mg), and the lungs were ventilated. After left thoracotomy, the bronchial artery was cannulated and perfused. In random order, propofol with and without metabisulfite, lidocaine (5 mg/ml), or metabisulfite alone (0.125 mg/ml) was infused into the bronchial artery at a rate of 0.06, 0.2, or 0.6 ml/min. After 10 min, airway resistance (Raw) was measured before and after vagal nerve stimulation (30 Hz, 30-ms duration at 30 V for 9 s.) and methacholine challenge (2 microg/ml at 2 ml/min in the bronchial artery). Data were expressed as a percent of maximal response and analyzed by analysis of variance with correction and with significance accepted at P < or = 0.05. RESULTS: Raw at baseline was not significantly different among the four drugs (P = 0.87). Infusion of lidocaine and propofol without metabisulfite into the bronchial artery caused a dose-dependent attenuation of the vagal nerve stimulation-induced bronchoconstriction (P = 0.001). Propofol with metabisulfite had no effect on vagal nerve stimulation-induced bronchoconstriction (P = 0.40). There was a significant difference in the ability of propofol without metabisulfite compared with propofol with metabisulfite to attenuate vagal nerve stimulation-induced (P = 0.0001) and methacholine-induced bronchoconstriction (P = 0.0001). CONCLUSION: Propofol without metabisulfite and lidocaine attenuated vagal nerve stimulation-induced bronchoconstriction in a dose-dependent fashion. Propofol without metabisulfite also decreased direct airway smooth muscle constriction. The preservative used for propofol can have a dramatic effect on its ability to attenuate bronchoconstriction.

Anesthetics, Intravenous↗

PubMed2003

Characterization of adenosine receptor(s) involved in adenosine-induced bronchoconstriction in an allergic mouse model.

We recently reported that adenosine caused bronchoconstriction and enhanced airway inflammation in an allergic mouse model. In this study, we further report the characterization of the subtype of adenosine receptor(s) involved in bronchoconstriction. 5'-(N-ethylcarboxamido)adenosine (NECA), a nonselective adenosine agonist, elicited bronchoconstriction in a dose-dependent manner. Little effects of N(6)-cyclopentyladenosine (A(1)-selective agonist) and 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (A(2A)-selective agonist) compared with NECA were observed in this model. 2-Chloro-N(6)-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-beta-d-ribofuranosyl]adenosine, an A(3)-selective receptor agonist, produced a dose-dependent bronchoconstrictor response, which was blocked by selective A(3) antagonist 2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate (MRS1523). However, MRS1523 only partially inhibited NECA-induced bronchoconstriction. Neither selective A(1) nor A(2A) antagonists affected NECA-induced bronchoconstriction. Enprofylline, a relatively selective A(2B) receptor antagonist, blocked partly NECA-induced bronchoconstriction. Furthermore, a combination of enprofylline and MRS1523 completely abolished NECA-induced bronchoconstrictor response. Using RT-PCR, we found that all four adenosine receptor subtypes are expressed in control lungs. Allergen sensitization and challenge significantly increased transcript levels of the A(2B) and A(3) receptors, whereas the A(1) receptor message decreased. No change in transcript levels of A(2A) receptors was observed after allergen sensitization and challenge. These findings suggest that A(2B) and A(3) adenosine receptors play an important role in adenosine-induced bronchoconstriction in our allergic mouse model. Finally, whether the airway effects of the receptor agonists/antagonists are direct or indirect needs further investigations.

Adenosine↗