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PubMed2006

Deep-breath frequency in bronchoconstricted monkeys (Macaca fascicularis).

Deep-breath frequency has been shown to increase in spontaneously obstructed asthmatic subjects. Furthermore, deep breaths are known to be regulated by lung rapidly adapting receptors, yet the mechanism by which these receptors are stimulated is unclear. This study tested the hypothesis that deep-breath frequency increases during experimentally induced bronchoconstriction, and the magnitude of the increased deep-breath frequency is dependent on the method by which bronchoconstriction is induced. Nine cynomolgus monkeys (Macaca fascicularis) were challenged with methacholine (MCh), Ascaris suum (AS), histamine, or an external mechanical resistance. Baseline (BL) and challenge deep-breath frequency were calculated from the number of deep breaths per trial period. Airway resistance (Raw) and tissue compliance (Cti), as well as tidal volume, respiratory rate, and minute ventilation, were analyzed for BL and challenged conditions. Transfer impedance measurements were fit with the DuBois model to determine the respiratory parameters (Raw and Cti). The flow at the airway opening was measured and analyzed on a breath-by-breath basis to obtain the ventilatory parameters (tidal volume, respiratory rate, and minute ventilation). Deep-breath frequency resulting from AS and histamine challenges [0.370 (SD 0.186) and 0.467 breaths/min (SD 0.216), respectively] was significantly increased compared with BL, MCh, or external resistance challenges [0.61 (SD 0.046), 0.156 (SD 0.173), and 0.117 breaths/min (SD 0.082), respectively]. MCh and external resistance challenges resulted in insignificant changes in deep-breath frequency compared with BL. All four modalities produced similar levels of bronchoconstriction, as assessed through changes in Raw and Cti, and had similar effects on the ventilatory parameters except that non-deep-breath tidal volume was decreased in AS and histamine. We propose that increased deep-breath frequency during AS and histamine challenge is the result of increased vascular permeability, which acts to increase rapidly adapting receptor activity.

Airway Resistance↗

PubMed1998

Food restriction-mediated adrenal influences on antigen-induced bronchoconstriction and airway eosinophil influx in the guinea pig.

The aim of this study was to measure the effects of food restriction on antigen-induced bronchoconstriction and inflammatory cell influx in guinea pigs and to determine the role of plasma cortisol and catecholamine concentrations. Ovalbumin (OA; 0.3 mg/kg, i.v.) was administered to OA-sensitized, anesthetized guinea pigs which had been allowed free access to food or had been food restricted for 18 h prior to OA challenge. In addition to higher plasma levels of epinephrine (30% increase) and cortisol (33% increase), fasted guinea pigs had significantly lower (60% decreased) maximal bronchoconstrictor responses to OA than nonfasted, sensitized litter mates. Additionally, groups of fasted or fed animals were subdivided into two additional treatment groups: (1) saline-pretreated or (2) polyethylene glycol 400 (PEG)-pretreated (1 ml/kg, p.o., 1 h prior to antigen challenge). In saline-treated, fasted animals, bronchoconstrictor responses to antigen were significantly diminished (67% decreased) and epinephrine and cortisol levels were increased (64 and 34%, respectively) compared to the corresponding fed group. In both fasted and fed groups, the PEG-treated guinea pigs had higher plasma epinephrine and cortisol levels than animals which received saline, but no significant differences were detected within the PEG-treated group. Plasma norepinephrine concentrations were lower in all fasted groups. In a separate model in conscious guinea pigs, there were no differences in aerosol OA-induced bronchoconstriction and eosinophil influx between fasted and fed groups. However, compared to the saline pretreatment group, PEG administration reduced the antigen-induced bronchoconstriction and eosinophilia in both fed and fasted guinea pigs. We speculate that the reduced responsiveness to antigen in fasted versus fed animals may result from food-restriction-induced, stress-related release of epinephrine and cortisol from the adrenal glands, thereby suppressing mast cell degranulation or reducing responsiveness to spasmogenic and chemotactic mediators. In addition, the results suggest that oral dosing with 100% PEG may enhance this phenomenon.

Administration, Inhalation↗

PubMed1999

Perception of dyspnea during histamine- and methacholine-induced bronchoconstriction.

BACKGROUND: Perception of dyspnea is poorly related to bronchoconstriction and may be influenced by distinct psychophysiologic stimuli. OBJECTIVE: This study compared the perceived psychophysiologic changes during histamine- and methacholine-induced bronchoconstriction using verbal as well as nonverbal assessment techniques. METHODS: Perception of dyspnea was studied during induced bronchoconstriction in 40 atopic subjects randomly ascribed to either histamine (n = 20) or methacholine (n = 20) bronchial challenge. A 100% increase in specific airway resistance (sR(aw)) indicated airway hyperresponsiveness (AHR). Dyspnea was verbally assessed by the Borg Scale (BS) and the Asthma Symptom Checklist (ASL). A hand dynamometer (HD) served for nonverbal assessment. Both challenge groups did not differ significantly with respect to age, anthropometric data, smoking and lung function before challenge. RESULTS: AHR did not differ between groups but groups differed significantly with respect to the number of symptoms and to symptom intensity reported after challenge. Subjects who underwent the histamine challenge scored significantly higher on both measures derived from the ASL. BS ratings and HD scores correlated significantly but were not significantly related to the degree of AHR. Accurate and poor perceivers could be discriminated by analysis of the relationship between BS and sR(aw). CONCLUSIONS: These findings suggest that perception of induced dyspnea differs between histamine and methacholine when assessed by a symptom report.

Adult↗

PubMed1993

Further evidence for prejunctional GABA-B inhibition of cholinergic and peptidergic bronchoconstriction in guinea pigs: studies with new agonists and antagonists.

We examined the effect of the potent and selective GABA-B agonists, baclofen, 3-aminopropylphosphinic acid (3-APPi) and 3-aminopropyl (methyl) phosphinic acid (SKF 97541), and the GABA-B antagonists, 3-aminopropyl (diethoxymethyl) phosphinic acid (CGP 35348), 2-hydroxysaclofen and 3-aminopropylphosphonic acid (3-APPA) on cholinergic and peptidergic contractile responses in the airways of guinea pigs. Electrical field stimulation of the isolated guinea pig trachea produced cholinergic contractions that were inhibited by baclofen (EC50 = 5 mumol/l), 3-APPi (EC50 = 0.3 mumol/l) and SKF 97541 (EC50 = 0.4 mumol/l). The inhibition by baclofen (30 mumol/l) was reduced by CGP 35348 (IC50 = 65 mumol/l), 2-hydroxysaclofen (IC50 = 273 mumol/l) and 3-APPA (IC50 = 355 mumol/l). The in vivo cholinergic bronchoconstrictor response to vagal nerve stimulation (5 V, 20 Hz, 0.5 ms for 5 s) was attenuated by intravenous baclofen (ED50 = 1.7 mg/kg), 3-APPi (ED50 = 0.9 mg/kg) and SKF 97541 (ED50 = 0.2 mg/kg). The inhibition of vagally induced bronchoconstriction by baclofen was blocked by CGP 35348 (1-10 mg/kg, i.v.) and 2-hydroxysaclofen (10 mg/kg, i.v.). A cholinergic bronchoconstriction induced by CNS stimulation (400 microA, 2 ms, 32 Hz for 5 s) was inhibited by baclofen (ED50 = 5.1 mg/kg, i.v.) and 3-APPi (ED50 = 0.6 mg/kg, i.v.). The effect of baclofen was attenuated by 3-APPA (5 mg/kg, i.v.). A peptidergic bronchoconstriction was evoked by intravenous nicotine (1 mg/kg) in animals treated with ipratropium and phosphoramidon.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Selective inhibition of cough and bronchoconstriction in conscious guinea pigs.

In guinea-pigs citric acid-induced cough and bronchoconstriction were inhibited by beta 2-agonist and xanthine drugs. Lidocaine inhibited only cough. Cromoglycate and ipratropium bromide inhibited only bronchoconstriction. We conclude that cough and bronchoconstriction in guinea-pigs are distinct reflexes and that the inhibitory pharmacology of these airway reflexes may agree in many respects, with that observed in asthmatic subjects.

Animals↗

PubMed1992

Modification of histamine- and methacholine-induced bronchoconstriction by calcium antagonist gallopamil in asthmatics.

We studied the comparative modification of histamine- and methacholine-induced bronchoconstriction by a calcium antagonist, gallopamil, in 8 subjects with bronchial asthma. Dose-response curves to aerosolized methacholine or histamine were performed, without and following pretreatment with inhaled gallopamil (10 mg), on 6 different experiment days to determine the cumulative provocative dose (PD50) of each agonist in breath units which caused a 50% decrease in specific airway conductance (SGaw). Baseline values of SGaw were similar on different experiment days and gallopamil had no significant effect on SGaw. PD50 values for histamine on control and placebo days were 6.8 +/- 2.8 and 5.2 +/- 2.8 breath units (mean +/- SE), respectively. Pretreatment with gallopamil increased histamine PD50 to 19.8 +/- 7.5 breath units, which was significantly greater than on control and placebo days (p < 0.01). PD50 values for methacholine on control and placebo days were 9.5 +/- 5.6 and 8.8 +/- 5.8 breath units, respectively. Gallopamil pretreatment had no significant effect on methacholine-induced bronchoconstriction; methacholine PD50 increased to 13.4 +/- 5.5 breath units (p = NS). The mean dose ratio (ratio of PD50 for the agonist in the presence and absence of gallopamil) for histamine was 6.9, which was 3.7-fold higher than the dose ratio of 1.9 methacholine in the same subjects. These data suggest that gallopamil causes greater inhibition of histamine- versus methacholine-induced bronchoconstriction. This suggests that calcium influx in airway smooth muscle through voltage-dependent channels primarily occurs in response to histamine and not to methacholine.

Adult↗

PubMed1996

Histamine in wine. Bronchoconstriction after a double-blind placebo-controlled red wine provocation test.

A 38-year-old woman with a history of seasonal rhinoconjunctivitis reported repeated attacks of wheezing after drinking various alcoholic beverages. Two consecutive histamine provocations using two identical samples of red wine containing 200 micrograms histamine/l and 3,700 micrograms/l, respectively, were performed in a double-blind placebo-controlled fashion to assess a possible histamine-induced bronchoconstriction. Lung function, plasma histamine, skin temperature, pulse rate and symptoms were assessed. In 3 male controls, four consecutive wine tests were performed in a randomised double-blind placebo-controlled fashion. Drinking wine with 3,700 micrograms histamine/l caused coughing and wheezing with a decrease in lung function. Plasma histamine showed an increase at 10 and 20 min and decreased at 30 min both after histamine-rich as well as histamine-poor wine, reaching the peak increase after histamine-rich wine. Controls did not react and plasma histamine levels did not increase. Bronchoconstriction after wine or food rich in histamine seems to be caused by diminished histamine degradation on the basis of reduced activity of diamine oxidase. Histamine in wine may induce bronchoconstriction in patients suffering from histamine intolerance.

Adult↗

PubMed1994

Effect of inhaled amiloride on water-induced bronchoconstriction in asthmatic children.

To determine whether the inhaled diuretic, amiloride, can modify bronchoconstriction induced by ultrasonically nebulized distilled water (UNDW) in asthmatic children, a double-blind, randomized, placebo-controlled study was done. The UNDW inhalation challenge was performed in 12 asthmatic children (nine boys and three girls; mean age +/- SEM, 11.2 +/- 0.75 yr), who had at least a 20% fall in FEV1 after UNDW inhalation. On separate days, these subjects underwent UNDW inhalation challenge after inhalation of amiloride (0.3 mg/m2 body surface area) or placebo (0.9% saline). Neither bronchodilation nor bronchoconstriction after amiloride inhalation was observed. The mean value and SEM of the UNDW PD20 after placebo inhalation was 4.55 +/- 0.80 ml. After inhalation of amiloride, PD20 increased to 7.93 +/- 0.75 ml (p < 0.01). We concluded that inhaled amiloride exerted a protective effect against UNDW-induced bronchoconstriction in asthmatic children.

Administration, Inhalation↗

PubMed1995

A comparison of the effects of inhaled furosemide and ethacrynic acid on sodium-metabisulfite-induced bronchoconstriction in subjects with asthma.

Inhaled furosemide prevents bronchoconstriction induced by a number of challenges in asthma. One approach to determine the mechanism underlying this protection has been to examine the effects of diuretics with different or overlapping pharmacologic effects. We have compared the effects of furosemide on sodium metabisulfite-induced bronchoconstriction with those of equivalent diuretic doses of ethacrynic acid, a loop diuretic that, unlike furosemide, does not interact directly with the membrane Na/K/Cl cotransporter protein or inhibit carbonic anhydrase. Eight subjects with mild asthma were studied on five occasions, receiving nebulized furosemide (20 and 40 mg), ethacrynic acid (25 and 50 mg), or placebo (normal saline) in random order and double-blind 10 min before a cumulative dose challenge with inhaled sodium metabisulfite. After placebo the geometric mean sodium metabisulfite PD20 was 7.9 mumol. Furosemide 20 mg and 40 mg increased the PD20 by a mean 1.1 (95% confidence interval, -0.2-2.4; p > 0.05) and 1.6 (0.4-2.9; p < 0.02) doubling doses to 17.1 and 24.7 mumol, respectively. After inhaled ethacrynic acid 25 mg and 50 mg, the geometric mean PD20 was increased by 0.9 (-0.4-2.2; p > 0.05) and 1.5 (0.2-2.8; p < 0.05) doubling doses to 14.5 and 22.4 mumol, respectively. Thus, equivalent diuretic doses of furosemide and ethacrynic acid have a similar inhibitory effect on sodium metabisulfite-induced bronchoconstriction in asthma. This suggests that interaction with the Na/K/Cl cotransporter protein, or carbonic anhydrase inhibition, is not relevant to the effects of furosemide in asthma.

Administration, Inhalation↗

PubMed1995

5-Hydroxytryptamine facilitates cholinergic bronchoconstriction in human and guinea pig airways.

5-hydroxytryptamine (5-HT) may not play a major role in controlling human airway smooth muscle tone, as it has little direct effect on airway caliber. However, its role as a neuromodulator has not been determined. We have identified a facilitatory effect of 5-HT on cholinergic neurotransmission and characterized the 5-HT receptors involved in human and guinea pig trachea. In guinea pig trachea, 5-HT facilitated electric field stimulation-induced cholinergic bronchoconstriction in a concentration-dependent manner (EC50 = 2.6 microM). The 5-HT3/4 and 5-HT3 antagonists, ICS 205-930 and ondansetron, inhibited the effect of 5-HT competitively (pA2 values of 7.3 and 7.1, respectively); methiothepin (5-HT1/2C antagonist), ketanserin (5-HT2A antagonist), and GR 113808A (5-HT4 antagonist) had no effect. The rank order of potency of 5-HT agonists was 5-HT > 2-methyl-5-HT (5-HT3 selective) > 5-methoxytryptamine (5-HT4 selective) > alpha-methyl-5-HT (5-HT2 selective). 5-carboxamidotryptamine (5-HT1A/B/D) and sumatriptan (5-HT1D selective) were essentially inactive. 5-Hydroxytryptamine had no effect on contractile responses to exogenous acetylcholine, suggesting that 5-HT facilitates cholinergic bronchoconstriction via prejunctional receptors. In human bronchi, 5-HT also facilitated cholinergic bronchoconstriction, which was inhibited by ICS 205-930. The effects of the 5-HT3 antagonists and selective agonists in human and guinea pig airways suggests that these facilitatory effects are mediated by 5-HT3 receptors.

Adult↗

PubMed1995

Effect of an NK1 receptor antagonist (CP-99,994) on hypertonic saline-induced bronchoconstriction and cough in male asthmatic subjects.

To investigate the role of NK1 receptors in the pathogenesis of bronchoconstriction and cough in asthma, we performed a randomized, double-blind, crossover study on the effects of a selective non-peptide tachykinin NK1 receptor antagonist (CP-99,994) on baseline measures of lung function and on hypertonic saline-induced bronchoconstriction and cough in 14 male subjects with mild asthma. CP-99,994 (250 micrograms/2 hours) and placebo were administered intravenously in 2-h infusions during consecutive visits 5 to 7 d apart. Specific airway resistance (SRaw) was measured and spirometry was performed at baseline and at 35 and 60 min. Next, hypertonic saline challenge was performed by delivering 10 breaths of saline of increasing concentration (0.9 to 7% in 1% increments at 5-min intervals) via an ultrasonic nebulizer until SRaw increased from baseline by 200% or 20 units, whichever was greater. Throughout the challenge cough was counted from a taped record made from two microphones placed close to the subject's larynx. We found that CP-99,994 did not significantly affect SRaw or spirometric measures of lung function during the first hour of infusion. Although CP-99,994 infusion markedly attenuated the bronchoconstrictor response to the saline challenge in two subjects, it did not significantly decrease the area under curves obtained for SRaw and cough during saline challenge for the group as a whole (p = 0.9 for SRaw;p = 0.8 for cough). We conclude that administration of 250 micrograms/kg of CP-99,994 over 2 h does not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in subjects with mild asthma and does not have acute bronchodilator activity in these subjects.

Adult↗

PubMed1996

Maximal bronchoconstriction in humans. Relationship to deep inhalation and airway sensitivity.

We hypothesized that maximal bronchoconstriction can be predicted from the bronchomoter effect of deep inhalation (DI) and the degree of airway sensitivity to methacholine (MCh). We studied 26 healthy or mildly asthmatic subjects with limited response to MCh (maximal FEV1 decrease, 23 +/- 9 SD%; Group 1) and 26 subjects with moderate to severe asthma with exaggerated response (maximal FEV1 decrease > 40%, Group 2). The effect of DI was quantified as the linear regression coefficient of the percent decrements of maximal (Vm50) versus partial (Vp50) forced expiratory flow at 50% of FVC over the initial steps of challenge (MP slope). Airway sensitivity was inferred from the MCh doses (PDs) causing Vm50 or Vp50 to decrease by 40% or FEV1 by 15%. The absence of limit to bronchonstriction was predicted by either MP slope or any PD with accuracies between 71 and 81%, but with an accuracy of 87% by a discriminant function including MP slope and PD40Vp50. Within Group 1, the maximal FEV1 decrease correlated linearly with MP slope (r2 = 0.41); but it was better predicted by a multiple regression including MP slope and PD40Vp50 (In mg) (r2 = 0.54). We conclude that the magnitude of the bronchodilator effect of DI during induced bronchoconstriction and airway sensitivity predict the level of maximal bronchoconstriction in vivo. We speculate that these parameters reflect some of the mechanisms modulating the response to bronchoconstrictor stimuli such as airway wall structure, airway-to-parenchymal interdependence, and contractile properties of airway smooth muscle.

Adult↗

PubMed1997

Nebulized glutathione induces bronchoconstriction in patients with mild asthma.

To assess the effects on bronchial responsiveness of nebulized glutathione (GSH), one of the most efficient scavengers of oxidant substances in the airways, we studied eight patients with mild asthma (FEV1, 88 +/- 11% predicted [SD]) in a randomized, double-blind, cross-over, placebo-controlled fashion. Bronchial challenge was measured using both FEV1 and total pulmonary resistance (Rrs) by the forced oscillation technique. Patients received nebulized GSH (600 mg with 4 ml of 0.9% sodium chloride) or placebo (identical saline solution) over a period of 25 min, 1 wk apart. Placebo provoked subclinical mild bronchoconstriction (changes from baseline: FEV1, -1%; Rrs, +17%); by contrast, GSH caused major airway narrowing (changes from baseline: FEV1, -19%; Rrs, +61%) and induced cough (four patients) or breathlessness (three patients). Differences between placebo and GSH after challenge were also noticeable in both FEV1 (p = 0.03) and Rrs (p = 0.02). Neither osmolarity (660 mosm.kg-1) nor pH (3.0) of the GSH solution accounted for these effects. Nebulized salbutamol (5.0 mg) given before the GSH challenge blocked GSH-induced bronchoconstriction. Furthermore, GSH-induced FEV1 falls were inversely correlated with metabisulfite bronchoprovocation (provocative dose [PD20], 1.49 +/- 1.83 mumol) but not with methacholine challenge. The detrimental effects of nebulized GSH on the airway bronchial tone in patients with mild asthma strongly suggests bronchoconstriction provoked by sulfite formation.

Adult↗

PubMed1999

Both intravenous and inhaled lidocaine attenuate reflex bronchoconstriction but at different plasma concentrations.

Intravenous lidocaine can attenuate bronchial hyperreactivity. However, lidocaine inhalation might yield the same or better results at higher airway and lower lidocaine plasma concentrations. Therefore, we tested in awake volunteers with bronchial hyperreactivity the effect of lidocaine on histamine-induced bronchoconstriction administered either intravenously or as an aerosol. After approval of the local ethics committee, 15 volunteers were enrolled in this placebo-controlled, double-blinded, randomized study. Volunteers were selected by showing a decrease in FEV1 greater than 20% of baseline (PC20) in response to histamine inhalation. On three different days the challenge was repeated after pretreatment with either intravenous lidocaine, inhaled lidocaine, or placebo. Blood samples for determination of lidocaine plasma concentration were drawn. Comparisons were made using the Friedman and Wilcoxon signed-rank tests. Baseline PC20 was 6.4 +/- 1.1 mg. ml-1. Both inhalation of lidocaine and intravenous administration significantly increased PC20 to 14.8 +/- 3.5 mg. ml-1 and 14.2 +/- 2. 5 mg. ml-1, respectively (p = 0.0007). Peak plasma lidocaine concentrations at the end of challenges were 0.7 +/- 0.1 microg. ml-1 (inhaled) and 2.2 +/- 0.1 microg. ml-1 (i.v.). However, 7 of 15 subjects showed an initial decrease of FEV1 greater than 5% following lidocaine inhalation. While both intravenous as well as inhaled lidocaine attenuate reflex bronchoconstriction significantly, lidocaine plasma concentrations are significantly lower after inhalation. However, the high incidence of initial bronchoconstriction to lidocaine inhalation may limit its use in patients with asthma and thus offers therapeutic advantages for intravenous lidocaine.

Administration, Inhalation↗

PubMed2001

Sputum induction in severe asthma by a standardized protocol: predictors of excessive bronchoconstriction.

Sputum induction is a noninvasive method to evaluate airway inflammation. We investigated whether it can be safely and successfully performed in patients with severe, difficult-to-control asthma, and whether the patients at risk can be identified. Ninety-three severe asthmatics were included, all symptomatic despite inhaled corticosteroids (> or = 1,600 microg/d) and long-acting beta(2)-agonists > 1 yr. Patients with a postbronchodilator FEV(1) < 1 L and < 50% predicted were excluded from participation. Sputum induction was performed according to a strict protocol, using 0.9%, 3.0%, and 4.5% NaCl inhalation. In 74% (CI: 64 to 83%) of patients an adequate sputum sample could be obtained. Twenty-two percent (CI: 14 to 33%) developed excessive bronchoconstriction (decrease in FEV(1) > 15% from baseline) despite the continuing use of long-acting bronchodilators and pretreatment with 400 microg salbutamol. The decrease in FEV(1) was associated with increased use of rescue short-acting beta(2)-agonists in the previous 2 d (r(s) = 0.51, p = 0.002), lower postbronchodilator FEV(1) (r(s) = -0.31, p = 0.004), and lower provocative concentration of histamine causing a 20% reduction in FEV(1) (PC(20)) (r(s) = -0.52, p < 0.001). Recent use of short-acting beta(2)-agonist increased the risk for excessive bronchoconstriction 10.2-fold (CI: 1.2 to 109.8). In conclusion, sputum induction can be safely and successfully performed in patients with severe, difficult-to-control asthma if a standardized protocol is used. However, severe bronchoconstriction may occur despite regular use of long-acting beta(2)-agonist and pretreatment with salbutamol 400 microg. In particular, patients who have used additional short-acting beta(2)-agonists as rescue medication during the days preceding the induction, are at high risk.

Asthma↗

PubMed1990

Bradykinin-induced airway microvascular leakage and bronchoconstriction are mediated via a bradykinin B2 receptor.

We have investigated the effects of bradykinin (Bk) antagonists on Bk-induced airway microvascular leakage and bronchoconstriction in mechanically ventilated guinea pigs by simultaneous measuring extravasation of Evans blue dye and airway opening pressure (Pao). Bradykinin (1 microgram/kg intravenously) significantly increased leakage of dye in trachea, main bronchi, and intrapulmonary airways, and increased Pao, indicating airway narrowing. The selective Bk B2 antagonist D-Arg-[Hyp3-Thi5,8-D-Phe7]-Bk (NPC 349; 400 micrograms/kg intravenously) did not alter basal leakage, but when given 2 min before Bk, significantly inhibited the Bk-induced plasma extravasation by 99.8% in the trachea (p less than 0.05), by 75.9% in main bronchi (p less than 0.05), by 83.5% in proximal intrapulmonary airways (p less than 0.05), and by 91.5% in distal intrapulmonary airways (p less than 0.05). NPC 349 also reduced the increase in Pao induced by Bk by 73.5% (p less than 0.05) without affecting the basal Pao. However, NPC 349 had no inhibitory effect on Bk-induced leak or bronchoconstriction when given 30 min before Bk. By contrast, the B1 antagonist des Arg9-Leu8-Bk (500 micrograms/kg intraveneously) had no effect on the Bk-increased plasma extravasation and Pao. We conclude that Bk increases airway plasma leakage and bronchoconstriction via activation of B2 receptors.

Animals↗

PubMed1990

Bronchoconstriction induced by inhaled sodium metabisulfite in the guinea pig. Effect of capsaicin pretreatment and of neutral endopeptidase inhibition.

Sodium metabisulfite (MBS), a commonly used preservative, induces bronchoconstriction in asthmatics, probably through the release of sulfur dioxide (SO2). The mechanisms involved in MBS- and SO2-induced bronchoconstriction are not yet certain. We aerosolized MBS or acid control solution (pH, 2.7) to anesthetized, tracheostomized guinea pigs pretreated intravenously with propranolol (1 mg/kg). MBS was given at increasing doubling concentrations (0.01, 0.02, 0.04, and 0.08 M) every 5 min. Steep concentration-response curves were observed, and most animals responded at 0.02 or 0.04 M. Tachyphylaxis was seen at high concentrations and during a subsequent MBS challenge 15 min later. For pharmacologic studies, we stopped the challenge when lung resistance (RL) had increased by at least 350%; a second challenge was found to be reproducible. MBS response was measured as the concentration needed to increase RL by 350% (PC350). Atropine (1 mg/kg given intravenously) did not affect PC350 or the peak RL response. Inhibition of neutral endopeptidase by inhaled phosphoramidon (7.5 nmol) administered before the repeated challenge did not alter PC350 value to MBS or peak RL responses (phosphoramidon, 201 +/- 49% of first peak; vehicle, 164 +/- 35%). In addition, the increase in RL was not prolonged in the phosphoramidon-treated group. Animals treated subcutaneously with capsaicin (50 mg/kg) 1 wk before the experiment, so as to deplete neuropeptides from airway sensory nerves, had PC350 values similar to those of the control animals. Our data demonstrate that inhaled MBS causes bronchoconstriction in guinea pigs by mechanisms that are due neither to a cholinergic reflex nor to the release of tachykinins from airway sensory nerves.

Aerosols↗

PubMed1991

Tachykinin receptors and noncholinergic bronchoconstriction in the guinea-pig isolated bronchi.

The aim of the study was to assess which type(s) of tachykinin receptor mediate the noncholinergic bronchoconstriction produced by activation (electrical field stimulation) of capsaicin-sensitive primary afferents in epithellum-denuded guinea-pig isolated bronchi. Experiments with natural and synthetic tachykinin agonists indicated the presence of both NK-1 and NK-2 receptors at this level. Experiments with the putative NK-1 (L668, 169) or NK-2 (MEN 10,207, MEN 10,376, L659,877, and R396) selective antagonists against NK-1 and NK-2 selective agonists further supported this conclusion. All the tachykinin antagonists tested reduced the noncholinergic bronchoconstriction to field stimulation with the order of potency MEN 10,207 = MEN 10,376 greater than L659,877 greater than L668,169 congruent to R396. In the presence of peptidase inhibitors, the activity of MEN 10,376 toward the noncholinergic bronchoconstriction was slightly reduced, whereas that of L668,169 was increased. These findings demonstrate that both NK-1 and NK-2 receptors mediate the noncholinergic constriction produced by endogenous tachykinins in guinea-pig bronchi and that the relative contribution of NK-2 receptors is greater than that of NK-1. These findings implicate a major role for neurokinin A rather than for substance P as an endogenous bronchoconstrictor in the guinea-pig isolated bronchi. In the presence of peptidase inhibitors, the relative contribution of NK-1 receptors is increased.

Animals↗