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PubMed1995

Neurokinin receptors subserving bronchoconstriction.

Tachykinin receptor subtypes were initially defined using agonist potency rations for the endogenous ligands substance P (SP), neurokinin (NK) A, and NKB. On this basis it was suggested that there are three tachykinin receptor subtypes. These subtypes were designated NK1, NK2, and NK3, where SP is most potent at NK1 receptors, NKA is most potent at NK2 receptors, and NKB is most potent at NK3 receptors. Recently analogs of the endogenous ligands that show greater selectivity (about 1000-fold) for the different receptor subtype have been developed. In addition selective antagonists, which are either nonpeptides or modified peptides, for the receptor subtypes have been developed. This minireview concentrates on the wealth of new knowledge concerning the tachykinin receptor subtypes subserving bronchoconstriction in several mammalian species, including man, provided by the use of these selective agonists and antagonists.

Animals↗
PubMed2005

Prostaglandin E2 protects lower airways against bronchoconstriction.

Prostaglandin E2 (PGE2), similar to beta-adrenergic receptor agonists, can protect airways from bronchoconstriction and resulting increase in airway resistance induced by a number of agents, including cholinergic receptor agonists and antigen. We examined the impact of sustained alterations in PGE2 pathways on changes in airway resistance. Genetic methods were utilized to alter PGE2 metabolism and signal transduction in the murine lung. PGE2 levels were elevated by generating mice lacking 15-hydroxyprostaglandin (Hpgd-/-), the major catabolic enzyme of PGE2, and by generating a transgenic line in which mouse PGE2 synthase (Ptges) expression is driven by a human lung-specific promoter, hSP-C. Conversely, to determine the impact of loss of PGE2 on airway reactivity, we examined mice lacking this synthase (Ptges-/-) and receptors that mediate the actions of PGE2, particularly the PGE2 EP2 receptor (Ptger2). Diminished capacity to produce and respond to PGE2 did not alter the response of mice to cholinergic stimuli. In contrast, the responsiveness to cholinergic stimulation was dramatically altered in animals with elevated PGE2 levels. The Hpgd-/- and hSP-C-Ptges transgenic lines both showed attenuated airway responsiveness to methacholine as measured by lung resistance. Thus, whereas compromise of the Ptges/PGE2/Ptger2 pathway does not alter airway responsiveness, genetic modulation that elevates PGE2 levels in the lung attenuates airway responsiveness.

Airway Resistance↗
PubMed2006

Exercise-induced bronchoconstriction alters airway nitric oxide exchange in a pattern distinct from spirometry.

Exhaled nitric oxide (NO) is altered in asthmatic subjects with exercise-induced bronchoconstriction (EIB). However, the physiological interpretation of exhaled NO is limited because of its dependence on exhalation flow and the inability to distinguish completely proximal (large airway) from peripheral (small airway and alveolar) contributions. We estimated flow-independent NO exchange parameters that partition exhaled NO into proximal and peripheral contributions at baseline, postexercise challenge, and postbronchodilator administration in steroid-naive mild-intermittent asthmatic subjects with EIB (24-43 yr old, n = 9) and healthy controls (20-31 yr old, n = 9). The mean +/- SD maximum airway wall flux and airway diffusing capacity were elevated and forced expiratory flow, midexpiratory phase (FEF(25-75)), forced expiratory volume in 1 s (FEV(1)), and FEV(1)/forced vital capacity (FVC) were reduced at baseline in subjects with EIB compared with healthy controls, whereas the steady-state alveolar concentration of NO and FVC were not different. Compared with the response of healthy controls, exercise challenge significantly reduced FEV(1) (-23 +/- 15%), FEF(25-75) (-37 +/- 18%), FVC (-12 +/- 12%), FEV(1)/FVC (-13 +/- 8%), and maximum airway wall flux (-35 +/- 11%) relative to baseline in subjects with EIB, whereas bronchodilator administration only increased FEV(1) (+20 +/- 21%), FEF(25-75) (+56 +/- 41%), and FEV(1)/FVC (+13 +/- 9%). We conclude that mild-intermittent steroid-naive asthmatic subjects with EIB have altered airway NO exchange dynamics at baseline and after exercise challenge but that these changes occur by distinct mechanisms and are not correlated with alterations in spirometry.

Adaptation, Physiological↗
PubMed1990

A theoretical study of the effect of airway smooth muscle orientation on bronchoconstriction.

If airway smooth muscle shortened in vivo to the extent that it does in vitro, then maximal bronchoconstriction would result in complete closure of virtually all airways. The fact that this does not happen indicates the existence of inhibitory mechanisms preventing maximal muscle shortening. There are many factors potentially limiting shortening in vivo. In this study we investigated one of these factors, the orientation of the smooth muscle around the airway wall. The airway was modeled as a cylinder of given wall thickness around which the muscle was wound as a spiral. The longitudinal and circumferential elasticities of the airway were embodied in a 2 x 2 matrix of elastic coefficients. We investigated smooth muscle shortening under three conditions: 1) a longitudinally stiff airway, 2) a circumferentially stiff airway, and 3) a longitudinally and circumferentially compressible airway. In case 1, for a given degree of smooth muscle shortening, airway resistance increased markedly with increasing pitch of the smooth muscle spiral. On the other hand, the muscle tension required to elicit a given change in resistance also increased markedly with pitch. In case 2, the effect with increasing pitch was reversed. In case 3, resistance first increased and then decreased as spiral pitch increased. Similarly, the muscle tension required to elicit a given change in resistance first increased and then decreased with pitch. These results suggest that the orientation of the smooth muscle about the airway may be very important in determining airway responsiveness.

Airway Resistance↗
PubMed1993

Lemakalim attenuates hypocapnia- and dry air-induced bronchoconstriction in canine peripheral airways.

To determine the effect of changes in potassium (K+) flux on airway constriction, we studied effects of lemakalim, a K+ channel opener, and glibenclamide, an ATP-sensitive K+ channel blocker. A wedged bronchoscope technique was used to measure peripheral airway resistance (Rp) in anesthetized dogs. Rp was measured before and after constriction of the airways by hypocapnic challenge, acetylcholine aerosol, or dry air hyperpnea. Lemakalim (5 micrograms/kg i.v.) was administered, and the challenge was repeated. Lemakalim attenuated responses to hypocapnia by 72 +/- 7% (n = 6, P = 0.0007) and to dry air challenge by 37 +/- 8% (n = 6, P = 0.005) but not to acetylcholine. On separate days, sublobar segments were pretreated with aerosolized glibenclamide (2 mg/ml), and responses to hypocapnic challenge were measured before and after lemakalim (5 micrograms/kg i.v.), nifedipine (20 micrograms/kg i.v.), or albuterol (1 microgram/kg i.v.). In the presence of glibenclamide, lemakalim had no significant effect on responses to hypocapnia; however, both nifedipine (n = 6, P = 0.0003) and albuterol (n = 6, P = 0.0001) attenuated responses to hypocapnic challenge. These findings suggest that lemakalim attenuated hypocapnic bronchoconstriction by promoting K+ efflux through ATP-sensitive K+ channels.

Acetylcholine↗
PubMed1993

Effects of acute passive smoking on exercise-induced bronchoconstriction in asthmatic children.

This study was designed to investigate the acute effects of environmental tobacco smoke (ETS) in children with mild asthma during rest and exercise. We studied 13 children [8 males, 5 females; mean age 10 (range 8-13) yr; mean forced expired volume in 1 s (FEV1) 93% (range 82-108%) of predicted] with exercise-induced bronchoconstriction [46 +/- 4% (SE) fall in FEV1 after exercise during cold air breathing]. Children were exposed to ETS (20 ppm carbon monoxide) or ambient air (AA) for 1 h. During the first 54 min of exposure, children were at rest, and during the last 6 min they exercised on a bicycle ergometer (2 W/kg body wt). Spirometry was performed before and during exposure and after exercise. Respiratory symptoms were recorded before and after exposures. In seven children the experiments with AA and ETS were done in duplicate. FEV1 between 5 and 54 min of exposure at rest decreased by 3.2 +/- 0.8% (SE) during AA and by 7.2 +/- 2.3% during ETS exposure compared with preexposure values; the difference between AA and ETS was statistically significant (P = 0.04). The drop in FEV1 was achieved within 5 min and did not change with ongoing exposure. Analysis of individual data revealed that the mean changes during ETS were mainly effected by three children with a significant fall and one child with a significant improvement in FEV1 (P < 0.05). Maximum postexercise fall of FEV1 was 25 +/- 4% after AA and 24 +/- 3% after ETS, which did not differ significantly. Upper and lower respiratory tract symptoms were not significantly different between exposures.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Intratracheal antioxidants attenuate exsanguination-induced bronchoconstriction in guinea pigs.

The role of oxygen radicals in exsanguination-induced bronchoconstriction (EIB) was investigated using intratracheal instillation of antioxidants. In series 1, 49 guinea pigs (331 +/- 6 g) were employed in the functional study. These animals were divided into seven groups: control, superoxide dismutase (SOD), catalase (CAT), erythrocytes (RBCs), N-[2-(2-oxo-1-imidazolindinyl)-ethyl]-N'-phenylurea (EDU), ruthenium red (RR), and systemic capsaicin pretreatment. SOD, CAT, RBCs, and EDU are antioxidants, whereas RR is a blocker of transmembrane Ca2+ fluxes. All agents except capsaicin were administered by intratracheal instillation 30 min before exsanguination; each animal of the last group received a 5-day subcutaneous capsaicin pretreatment. All animals were anesthetized, sternotomized, and exsanguinated. Before as well as 1-30 min after exsanguination, the maximal expiratory flow maneuver was performed and the minimal volume was obtained. In the control group, exsanguination caused gradual decreases in the maximal expiratory flow at 50% baseline total lung capacity, forced expiratory volume at 0.1 s, and total lung capacity as well as a gradual increase in the minimal volume, indicating that EIB becomes more severe with time. EIB was significantly ameliorated by intratracheal instillation of SOD, CAT, RBCs, EDU, and RR, and it was almost abolished by systemic capsaicin pretreatment. In series 2, however, inactivated CAT did not significantly affect EIB. We determined tracheal neutral endopeptidase (NEP) activity in 23 animals. Thirty minutes after exsanguination, there was a significant decrease in NEP activity in the control but not the CAT group. These results indicate that EIB is modulated by oxygen radicals, which inactivate NEP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Activation of pulmonary rapidly adapting receptors does not induce bronchoconstriction in dogs.

Activation of pulmonary rapidly adapting receptors (RARs) is believed to constrict airways by a vagally mediated reflex. We tested this hypothesis in dogs anesthetized with sufentanil citrate. We ventilated both lungs separately at a positive end-expiratory pressure of 4 cmH2O. We stimulated RARs in one lung under three different conditions: 1) deflation of the lung; 2) decrease in lung compliance; and 3) aerosolization of methacholine. We monitored the airway pressure in the nonstimulated lung as an index for airway muscle tone and could not detect increases in the pressure swing under these conditions. On the other hand, electrical stimulation of the distal end of cervical vagus nerve increased the pressure swing bilaterally (ipsilateral dominant), suggesting that reflex response could be detected in our preparation. Moreover, deflation (or inflation) of either lung increased (or suppressed) diaphragmatic activity. The results indicate intact vagal afferents and central response in our preparation. We conclude that activation of RARs located below the carina does not induce bronchoconstriction by a centrally mediated reflex. If any effect is present, it appears to be small.

Aerosols↗
PubMed1996

Effect of thromboxane A2-receptor antagonist on bradykinin-induced bronchoconstriction in asthma.

The role of the thromboxane A2 (TxA2) receptor in bradykinin-induced bronchial responses was investigated in this study by using a selective and potent TxA2-receptor antagonist BAY u 3405. Eleven asthmatic subjects were randomized to receive 50 mg of BAY u 3405 or matched placebo in a crossover and double-blind fashion. Ninety minutes after dosing, serum was taken for drug assay, and subjects underwent provocation with bradykinin or prostaglandin D2 (PGD2) to determine bronchial responsiveness [provocative concentration of agonist required to produce a 20% fall in forced expiratory volume in 1 s from the postdiluent baseline (PC20)]. Pretreatment with BAY u 3405 caused a twofold doubling-dilution reduction in bronchial reactivity to PGD2; the geometric mean PC20 values were 0.132 (0.015-0.871) and 0.034 (0.008-0.095) mg/ml, respectively, for active and placebo days (P = 0.001). There was, however, no significant difference in PC20 values for bradykinin between active and placebo treatment days. We have demonstrated that BAY u 3405 caused a significant inhibition of bronchconstriction induced by inhaled PGD2 but had no influence on bronchial responsiveness to inhaled bradykinin. This study suggests therefore that TxA2 receptors do not play a role in bradykinin-induced bronchoconstriction in asthma.

Adult↗
PubMed1997

Effect of stochastic heterogeneity on lung impedance during acute bronchoconstriction: a model analysis.

In a previous study (J. H. T. Bates, A. M. Lauzon, G. S. Dechman, G. N. Makaym, and T. F. Schuessler. J. Appl. Physiol. 76: 616-626, 1994), we investigated the acute changes in isovolume lung mechanics immediately after a bolus injection of histamine. We found that dynamic resistance and elastance increased progressively in the 80-s period after injection, whereas the estimated tissue hysteresivity reached a stable plateau after approximately 25 s. In the present study, we developed a computer model of the lung to investigate the mechanisms responsible for these observations. The model conforms to Horsfield's morphometry, with the addition of compliant airways and structural damping tissue units. Using this model, we simulated the time course of acute bronchoconstriction after intravenous administration of a bolus of bronchial agonist. Heterogeneity was induced by randomly varying the values of the maximal airway smooth muscle contraction and the tissue response to the agonist. Our results demonstrate that much of the increase in lung impedance observed in our previous study can be produced purely by the effects of airway heterogeneity. However, we were only able to reproduce the plateauing of hysteresivity by assigning a minimum radius to each airway, beyond which it would immediately snap completely shut. We propose that airway closure played an important role in our experimental observations.

Airway Resistance↗
PubMed2000

Eicosanoid and muscarinic receptor blockade abolishes hyperventilation-induced bronchoconstriction.

This study was designed to test the hypothesis that hyperventilation-induced bronchoconstriction (HIB) results from the combined effects of prostanoid and leukotriene metabolism. A bronchoscope was used in anesthetized dogs to record peripheral airway resistance and HIB before and after combined treatment with inhibitors of cyclooxygenase (indomethacin) and 5-lipoxygenase (MK-0591). Bronchoalveolar lavage fluid (BALF) cells and mediators from hyperventilated and control airways were also measured. Pretreatment with MK-0591 and indomethacin significantly attenuated, but did not abolish, HIB. However, addition of atropine nearly eliminated the residual response. Blockade of eicosanoid metabolism markedly reduced the concentrations of eicosanoids recovered in BALF after hyperventilation. Positive correlations between posthyperventilation BALF prostanoid and epithelial cell concentrations are suggestive of mucosal injury-induced mediator production and release. We conclude that HIB is prevented in the presence of eicosanoid and muscarinic-receptor blockade and that both classes of eicosanoids contribute similarly to the development of HIB.

Animals↗
PubMed2002

Nonlinearity of respiratory mechanics during bronchoconstriction in mice with airway inflammation.

Respiratory system resistance (R) and elastance (E) are commonly estimated by fitting the linear equation of motion P = EV + RV + P0 (Eq. 1) to measurements of respiratory pressure (P), lung volume (V), and flow (V). However, the respiratory system is unlikely to behave linearly under many circumstances. We determined the importance of respiratory system nonlinearities in two groups of mechanically ventilated Balb/c mice [controls and mice with allergically inflamed airways (ova/ova)], by assessing the impact of the addition of nonlinear terms (E2V2 and R2V(V)) on the goodness of model fit seen with Eq. 1. Significant improvement in fit (51.85 +/- 4.19%) was only seen in the ova/ova mice during bronchoconstriction when the E2V2 alone was added. An improvement was also observed with addition of the E2V2 term in mice with both low and high lung volumes ventilated at baseline, suggesting a volume-dependent nonlinearity of E. We speculate that airway closure in the constricted ova/ova mice accentuated the volume-dependent nonlinearity by decreasing lung volume and overdistending the remaining lung.

Administration, Inhalation↗
PubMed2001

The homeostatic rôle of bronchoconstriction.

This article argues in favour of the hypothesis that the homeostatic rôles of bronchoconstriction are to retract the airway tree during expiration, and to assist in the expulsion of mucus from peripheral airways by increasing the velocity of outgoing air. In asthma, this function may be dangerously exaggerated because of the presence of unusually viscous airway secretions and the remodelling of airway walls.

Asthma↗
PubMed2002

Measures of perception of bronchoconstriction and clinical and functional data are not interrelated in asthma.

BACKGROUND: Sensitivity and absolute perceptual magnitude characterize the perception of bronchoconstriction (PB). OBJECTIVES: To define whether clinical and functional characteristics and level of bronchial hyperresponsiveness (BHR) correlate with these two PB indexes during bronchial challenge in asthma. METHODS: PB on both the Borg scale and the visual-analogue scale (VAS) was assessed in 45 consecutive asthmatics during a methacholine-induced decrease in forced expiratory volume in 1 s (FEV(1)) and specifically quantified as Borg and VAS slope, as a measure of sensitivity, whereas scores at a 20% FEV(1) decrease (PB(20)) were assessed as a measure of absolute perceptual magnitude. Clinical score and BHR were also assessed. RESULTS: PB(20) related to slope on both the Borg scale and the VAS (p < 0.0001). PB(20) and slope related neither to clinical score nor to baseline functional data on both scales. The relationship between the level of BHR and PB(20) on either scale was of questionable clinical significance (r(2) = 7%). CONCLUSIONS: Irrespective of the scale employed, our data indicate the need for directly assessing PB rather than deriving it from clinical and functional data and level of BHR.

Adolescent↗
PubMed1997

Sch 37224, an experimental antiallergy compound, inhibits the neuropeptide component of hyperventilation- and nicotine-induced bronchoconstriction in guinea pigs.

Sch 37224 is an experimental antiallergy compound that inhibits hyperventilation-induced bronchoconstriction (HIB) in guinea pigs and cold air bronchospasm in human asthmatics. HIB in guinea pigs may involve the release of tachykinins such as neurokinin A (NKA) and substance P (SP), and the action of Sch 37224 in this model may relate to inhibition of these neuropeptides. We studied the effect of Sch 37224 on the neuropeptide component of HIB that was enhanced in guinea pigs treated with the neutral endopeptidase inhibitors, thiorphan and phosphoramidon. Pulmonary resistance (RL) and dynamic lung compliance (CDyn) were measured in anesthetized, mechanically ventilated guinea pigs. RL and CDyn were measured at baseline (1 ml/100 g tidal volume and 50 breaths/min) and after a 10-min period of hyperventilation (1 ml/100 g, 150 breaths/min). Hyperventilation produced modest changes in RL (+41 +/- 12%) and CDyn (-12 +/- 3%) which were markedly enhanced by treatment with 3 mg/kg of either thiorphan or phosphoramidon (RL + 269 +/- 43% for thiorphan, + 292 +/- 63% for phosphoramidon and CDyn -65 +/- 3% for thiorphan, -51 +/- 13% for phosphoramidon). In the presence of thiorphan or phosphoramidon, the bronchospasm to hyperventilation was significantly reduced (> 70%) with 5 mg/kg, p.o., of Sch 37224. In other studies, the peptidergic (conducted in the presence of ipratropium bromide and phosphoramidon) bronchoconstrictor response to intravenous nicotine (1 mg/kg) was also inhibited by Sch 37224 (0.3-10 mg/kg, p.o.). However, Sch 37224 (5 mg/kg, p.o.) had no effect on the bronchoconstrictor response to intravenous NKA. These results indicate that Sch 37224 inhibits the neuropeptide component of HIB and nicotine in guinea pigs and this effect appears to be mediated by the inhibition of the release of tachykinins from airway C fibers.

Animals↗
PubMed1992

Sulfur dioxide-induced bronchoconstriction in the isolated perfused and ventilated guinea-pig lung.

SO2 exposure (50-500 ppm) of isolated, perfused and ventilated guinea pig lungs, via the air passages, caused a concentration-related reduction in dynamic compliance and conductance. No changes in pulmonary perfusion flow was noted at any SO2 concentration. Formed sulfite was detected in lung lavage fluid as well as in the perfusate. Pretreatment of the lungs with a low concentration of SO2 (10 ppm) for 30 min protected against bronchoconstriction by a high concentration of SO2 (250 ppm). A similar protective effect was noted by pretreatment with sodium sulfite (3 mM) in the lung perfusate.

Air Pollutants↗
PubMed1995

Mechanisms of 3-carene-induced bronchoconstriction in the isolated guinea pig lung.

Inhaled 3-carene at a concentration of 5,000 mg/m3 caused bronchoconstriction in isolated, ventilated and perfused guinea pig lungs. This effect was inhibited by the cyclooxygenase inhibitor diclofenac (100 microM) and the thromboxane/prostaglandin endoperoxide-receptor antagonist L-670,596 (1 microM). 3-Carene exposure also increased the amount of thromboxane in the perfusate from the lungs. In cultured calf pulmonary arterial endothelial cells 3-carene caused a dose-related release of arachidonic acid. Thus, the results obtained in this experimental model may have implications in the understanding of the pathophysiology of 3-carene-induced obstructive pulmonary disease in humans.

Animals↗
PubMed1991

Inhibition of allergen-induced bronchoconstriction in sensitized guinea pigs by orally administered allergen.

Crude mite extract (CME) was orally administered to guinea pigs sensitized to CME. It was shown that such treatment reduces the bronchoconstrictive response upon allergen provocation. Isolated tracheae taken from guinea pigs orally administered CME allergen showed less contraction in response to CME as compared to those obtained from sensitized but not orally treated animals. The oral administration of allergens seemed to attenuate the bronchial hyperresponsiveness of sensitized animals to a non-specific chemical stimulus (histamine). IgE antibodies titrated by 8 days passive cutaneous anaphylaxis, and IgG1 and IgG2 antibodies measured by ELISA were comparable in the sera obtained from animals before and after CME treatment.

Administration, Oral↗