Nifedipine aerosol attenuates airway constriction in dogs with hyperreactive airways

We investigated the ability of a calcium channel blocker nifedipine, given as an aerosol, to attenuate bronchoconstriction induced by citric acid, Ascaris antigen, and methacholine in Basenji-Greyhound dogs. citric acid 10% increased pulmonary resistance (RL) 4.2-fold +/- 1.0 (mean +/- SEM) and 1.7-fold +/- 0.7 in untreated and nifedipine-pretreated dogs (P less than 0.05). Dynamic compliance (Cdyn) fell to 0.58 +/- 0.07 and 0.66 +/- 0.07 of control values in untreated and nifedipine-treated dogs, respectively (p greater than 0.05). Ascaris antigen increased RL 5.1-fold +/- 0.83 and 3-fold +/- 0.48 in untreated and nifedipine-treated dogs, respectively (p less than 0.05); Cdyn decreased to 0.33 +/- 0.04 and 0.48 +/- 0.03 in untreated and nifedipine-treated dogs, respectively (p less than 0.05). In 5 dogs challenged with 0.3 mg/ml methacholine, RL increased 6.1-fold +/- 0.7 and 4.4-fold +/- 1.0 in untreated and nifedipine-treated dogs, respectively (p less than 0.05); Cdyn fell to 0.41 +/- 0.-3 and 0.46 +/- 0.07 of control values in untreated and nifedipine-treated dogs (P greater than 0.05). Neither 40% ethanol nor nifedipine-ethanol altered resting RL and Cdyn. We conclude that nifedipine effectively attenuates bronchoconstriction induced by citric acid, Ascaris antigen, and methacholine in dogs with hyperreactive airways.     

The requirement for platelets in allergen-induced late asthmatic airway obstruction. Eosinophil infiltration and heightened airway responsiveness in allergic rabbits

In these studies, we have used an allergic rabbit model to investigate the role of platelets in the late asthmatic response (LAR) by depleting platelets with a guinea pig antirabbit platelet antiserum (APAS). Allergen exposure of immunized rabbits pretreated with normal guinea pig serum (NGPS) to serve as a control resulted in an early- and late-phase obstructive airway response that persisted for 6 h. When the immunized animals were pretreated with APAS, the magnitude of the LAR in terms of dynamic compliance was reduced by 86.2% (p less than 0.03), but there was no difference in the early response curve. Allergen challenge of animals treated with NGPS resulted in an increased bronchial responsiveness to inhaled histamine: PD50 Cdyn geometric mean +/- SEM before, 2.36 mg/ml (3.43-1.64); after, 0.60 mg/ml (0.67-0.54) (p less than 0.01). PD50 RL before, 1.78 mg/ml (2.4-1.32); after, 0.58 mg/ml (0.81-0.47) (p less than 0.05). In contrast, when animals were treated with APAS, there was a significant inhibition of allergen-induced airway hyperresponsiveness to inhaled histamine: PD50 Cdyn geometric mean +/- SEM before, 1.42 mg/ml (2.06-0.98); after, 1.10 mg/ml (1.41-0.86) (p less than 0.4). PD50 RL before, 1.62 mg/ml (2.22-1.39); after, 1.05 mg/ml (1.35-0.82) (p greater than 0.4). Analysis of bronchoalveolar lavage fluid revealed an increase in the number of neutrophils and eosinophils after allergen exposure in control animals (p less than 0.01). However, in animals rendered thrombocytopenic, the number of eosinophils, but not neutrophils, was significantly reduced (p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of nonadrenergic noncholinergic inhibitory nerve stimulation on the allergic reaction in cat airways

To examine the effect of nonadrenergic noncholinergic (NANC) inhibitory nerve stimulation on the antigen inhalation with allergic animals, changes in pulmonary resistance (RL) and arterial plasma histamine concentration ([H]) caused by inhalation of Ascaris suum antigen were studied in five control (Group A) and five nerve-stimulated (Group B) cats, which were anesthetized and mechanically ventilated. All animals were actively sensitized with Ascaris antigen before the experiment. After cholinergic and beta-adrenergic blockade with intravenously administered atropine (3 mg/kg) and propranolol (2 mg/kg), inhalation of the antigen (1:100 dilution) was performed for 3 min. For Group B, bilateral cervical vagi were stimulated electrically for 1 min before the antigen inhalation and successively every 30 s until 5 min had passed from the onset of inhalation. RL and [H] were determined before, during, and after antigen inhalation in both groups. Baseline RL and [H] did not differ significantly between groups (16.3 +/- 2.2 (mean +/- SE) cm H2O/L/s and 14.0 +/- 0.7 ng/ml, respectively, for Group A; 14.4 +/- 1.3 and 15.6 +/- 2.7, respectively, for Group B). Increases in RL and [H] of Group B after the antigen inhalation were significantly depressed, compared with Group A (p less than 0.01 and p less than 0.05, respectively, two-way ANOVA). The increase in RL 5 min after antigen inhalation was 113 +/- 19% for Group A and 28 +/- 8% for Group B, and the increase in [H] at the same point was 36.3 +/- 9.1 ng/ml for Group A and 4.4 +/- 1.4 ng/ml for Group B.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of a late phase pulmonary response after antigen challenge in allergic sheep

We determined if allergic sheep undergo a dual bronchoconstriction in response to inhalation of antigen and whether these responses could be modified by cromolyn or glucocorticosteroids. In 8 conscious sheep with Ascaris suum hypersensitivity, mean pulmonary flow resistance (RL), dynamic lung compliance (Cdyn), thoracic gas volume (Vtg), and arterial oxygen tension (PaO2) were determined prior to, immediately after, and from 2 through 8 h after and 24 h after inhalation challenge with Ascaris suum antigen. Immediately after antigen challenge, mean specific lung resistance (SRL = RL X Vtg) increased by 750% (p less than 0.01) and mean Cdyn and PaO2 decreased by 55% (p less than 0.01) and 37% (p less than 0.01), respectively. By 5 h after challenge, mean SRL and PaO2 had returned to baseline values, whereas mean Cdyn was still below baseline (-19%, p less than 0.05). At 6.5 h, mean SRL increased again to 245% (p less than 0.01) of baseline and remained significantly elevated through the eighth hour. The average increase in mean SRL for the 6.5- to 8-h postchallenge period was 196%, with concomitant decreases in mean Cdyn and PaO2 of 29% and 10%, respectively. By 24 h, all values had returned to baseline. Control inhalation challenge with ragweed, an antigen to which sheep are not sensitive, did not significantly alter SRL, Cdyn, or PaO2 at any time during the 8-h observation period, indicating that the late response was antigen specific and not caused by circadian rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary antigen challenge in rats passively sensitized with a monoclonal IgE antibody induces immediate but not late changes in airway mechanics

Pulmonary antigen challenge in sensitized individuals results in isolated immediate, isolated late, or dual reactions consisting of both an immediate and late change in airway function. The immediate response appears to be dependent on the presence of IgE antibody and mast cell mediator release. Although the late phase of dual responses is considered to be related to or a continuum of the immediate hypersensitivity response, its precise pathogenesis remains to be determined. To increase both the sensitivity and specificity of analyzing the pathogenesis of IgE-dependent pulmonary responses, we have used a Sprague-Dawley rat model system in which rats are passively sensitized with a murine monoclonal IgE anti-dinitrophenol (DNP) antibody prior to challenge with DNP-bovine serum albumin (DNP-BSA). Pathogen-free rats were injected with IgE or saline in a randomized blinded protocol, and in 24 to 48 h were anesthetized with urethane (1.2 g/kg intraperitoneally) and instrumented to measure lung resistance (RL) and dynamic compliance (Cdyn). Rats were then challenged with aerosolized DNP-BSA (10 mg/ml), and RL and Cdyn monitored through 7 h after challenge. Both RL (0.30 +/- 0.10 versus 0.13 +/- 0.02 cm H2O/ml.sec-1) and Cdyn (0.41 +/- 0.10 versus 0.25 +/- 0.08 ml/cm H2O) were significantly different (p less than 0.05) in sensitized rats compared to control rats immediately after challenge. No late changes were observed in either the treated or control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo bronchodilator activity of nifedipine in the guinea pig

We administered histamine subcutaneously to anesthetized guinea pigs to induce prolonged bronchoconstriction and then tested the effect of intravenously administered nifedipine on pulmonary resistance (RL) and dynamic compliance (Cdyn). One mg of subcutaneously administered histamine caused RL to increase by an average of more than 250% and Cdyn to fall on average to 26% of baseline; mean RL remained more than twice baseline, and mean Cdyn remained less than half baseline for 80 min. Intravenously administered nifedipine 3 micrograms/kg and ethanol (diluent) administered 25 min after histamine had no effect on RL but caused a slightly greater fall in Cdyn than in the control animals treated with histamine alone. Nifedipine 30 micrograms/kg, however, exhibited significant bronchodilator activity: 35 min after nifedipine 30 micrograms/kg, RL decreased on average to 41 +/- 17% above baseline (p less than 0.02), and Cdyn increased to 49 +/- 5% below baseline (p less than 0.0001). By comparison, isoproterenol (0.3 to 3.0 micrograms/kg) caused bronchodilation of more rapid onset (within 1 min) and shorter duration of action (approximately 10 min). Thus, we were able to demonstrate bronchodilator activity of nifedipine in vivo, as had been predicted by in vitro studies of guinea pig and human tracheal strips. These results would appear to justify continued exploration of the potential role for calcium channel blockers in the treatment of obstructive lung disease.     

Antigen-coated sepharose beads induce airway eosinophilia and airway hyperresponsiveness in cynomolgus monkeys

A method of inducing sustained airway eosinophilia and airway hyperresponsiveness in primates has been developed. Our method utilizes a series of intratracheal instillations of Ascaris suum-coated sepharose 4B beads (3 x 10(5] administered once a week for four weeks. Five cynomolgus monkeys (Macaca fascicularis) demonstrating a naturally occurring skin and respiratory sensitivity to Ascaris suum extract were studied. Airway cell composition was measured by bronchoalveolar lavage (BAL), and airway responsiveness was determined as the bronchoconstrictor response to inhaled methacholine. Ascaris suum bead administration resulted in a transient increase in total cells recovered by BAL (2.4 +/- 0.4 to 8.7 +/- 2.5 x 10(5) cells/ml, p less than 0.05) and a selective increase in BAL eosinophils (17 +/- 6 to 916 +/- 158 x 10(3) cells/ml, p less than 0.05). Increases in airway responsiveness were concurrent with the increase in airway eosinophils. These observations show that airway eosinophilia is associated with airway hyperresponsiveness in primates. Furthermore, this new model is a novel experimental system in which the underlying mechanisms in the pathogenesis of airway hyperresponsiveness can be investigated.     

Antigen-induced airway inflammation and hyper-responsiveness does not enhance airway responses to a subsequent antigen challenge in rats

Brown-Norway (BN) rats develop airway hyper-responsiveness and lung eosinophilia 18-24 h after ovalbumin (OA) challenge. We hypothesized therefore that allergen-induced airway inflammation would further enhance airway responses to a subsequent antigen challenge. Animals were sensitized to both OA and bovine serum albumin (BSA) and, 14 days later, challenged by aerosols with both antigens 24 h apart. Measurements of pulmonary resistance (RL) were made for 8 h after the second antigen challenge and bronchoalveolar lavage (BAL) was performed. Animals were divided into three groups and received two challenges as follows: saline-BSA (n=9), OA-saline (n=8) and OA-BSA (n=10). Sensitization was confirmed by measurements of specific OA-IgE and BSA-IgE. Early responses [determined as the highest value of RL within the first 30 min after the challenge] were absent in all study groups. The late responses [determined from the area under the RL versus time curve from 120 to 480 min after the challenge] were significantly greater in animals challenged with BSA (15.16+/-3.86) compared to saline (3.76+/-4.09; P<0.05). However previous exposure to OA did not further increase the late response in animals subsequently challenged with BSA (20.11+/-3.67) despite enhanced airway responsiveness to LTD4 at this time point. BAL eosinophils and lymphocytes were significantly increased following BSA challenge in previously OA-challenged animals, compared to numbers retrieved from animals previously exposed to saline (P<0.05). These data indicate that previous exposure to OA did not further increase the LR to a second antigen challenge despite substantial increases in airway inflammatory cells and airway hyper-responsiveness to LTD4.     

Effect of acute and chronic antigen inhalation on airway morphology and responsiveness in actively sensitized rats.

Bronchial hyperresponsiveness (BHR) is a major characteristic of bronchial asthma. The pathogenesis of BHR remains to be fully elucidated, but is considered to be closely linked to airway inflammation. Animal models might provide us with useful data for a better understanding of the interrelationship between these phenomena. In the present study we investigated the effect of a single and chronic exposure to inhaled antigen on bronchial responsiveness and airway morphology in actively sensitized Brown Norway rats. Immunization to ovalbumin (OA) did not cause airway inflammation, but induced a small, transient decrease in bronchial responsiveness to 5-hydroxytryptamine (5HT) on Day 10, which returned to baseline on Day 16. By 24 h after a single exposure to aerosolized OA, a significant decrease in the provocative concentration of 5HT causing a 50% increase in lung resistance (PC50RL 5HT) was observed, compared with immunized, saline-exposed animals (7.7 +/- 0.8 versus 10.8 +/- 1.0 micrograms/kg). This was accompanied by the influx of neutrophils and few eosinophils in bronchoalveolar lavage fluid. Repeated daily or intermittent exposure to aerosolized OA enhanced airway inflammation, characterized by the presence of neutrophils, eosinophils, and lymphocytes in bronchoalveolar lavage fluid. Histologic analysis revealed patchy inflammatory infiltrates, located predominantly around bronchi and bronchioli. Despite these inflammatory changes, bronchial responsiveness was not significantly different from that of control animals. We therefore conclude that the induction of airway inflammation is not always associated with BHR.     

Mechanisms of late hemodynamic and airway dynamic responses to endotoxin in awake sheep

The mechanism of sustained alterations in pulmonary hemodynamics and lung mechanics after endotoxin infusion in sheep remains unclear. We examined the effects of metaproterenol, propranolol, atropine, and ibuprofen on pulmonary artery pressure (Ppa), dynamic compliance (Cdyn), resistance to airflow across the lungs (RL), specific airway conductance (SGaw), and alveolar-arterial oxygen difference (delta AaPO2) (room air) given 2.5 h after endotoxemia (except for propranolol, which was given 1 h after metaproterenol) in awake sheep. Atropine infusion had no effect on any of the variables measured. Ibuprofen infusion immediately reduced mean Ppa from 31 +/- 2 (mean +/- SEM) to 24 +/- 2 cm H2O (p less than 0.05). Metaproterenol and ibuprofen immediately increased Cdyn and SGaw and decreased RL to near baseline (p less than 0.05). No intervention affected delta AaPO2 (p greater than 0.05). In sheep treated with metaproterenol, propranolol immediately returned lung mechanics (p less than 0.05) to premetaproterenol levels without affecting delta AaPO2 (p greater than 0.05). Ibuprofen reduced lung lymph thromboxane-B2 towards baseline levels (p less than 0.05). We conclude that endotoxemia causes prolonged bronchoconstriction and pulmonary hypertension in sheep, which is largely mediated by constrictor prostanoids rather than by cholinergic mechanisms and is reversible with ibuprofen given 2.5 h after endotoxin.     

Canine parainfluenza type 2 bronchiolitis increases histamine responsiveness in beagle puppies

Histamine hyperresponsiveness with viral bronchiolitis may depend on previous exposures to viruses or to other pathogens. We studied 32 outbred beagle puppies 80 to 155 days of age who were raised in isolation and who were specific pathogen-free. Puppies were inoculated with canine parainfluenza type 2 (CPI2, n = 8), Bordetella bronchiseptica (Bb, n = 7), or both CPI2 and Bb (CPI2-Bb, n = 9). Control puppies (C, n = 8) were not inoculated. The puppies were anesthetized with sodium thiopental (5 mg/kg) and chloralose (80 mg/kg) and were ventilated mechanically. Lung resistance (RL), dynamic lung compliance (Cdyn), functional residual capacity (FRC), and responsiveness to aerosolized histamine were measured 3 days prior to inoculation (Day -3), on the day of inoculation (Day 0), and on Days 3-4, 6, 8-10, and 12-14 after inoculation. Histamine responsiveness was measured as: (1) the concentration of histamine base that increased RL to 150% (PC 150% RL) or decreased Cdyn to 75% (PC 75% Cdyn) of the response to saline (RL sal and Cdyn sal, respectively), and (2) the change in RL or Cdyn after inhalation of 11 mg/ml of histamine when compared with RL sal and Cdyn sal. On Day 0 there were no significant (p greater than 0.05) differences among groups with regard to age-corrected weights, FRC, RL, Cdyn, or histamine responsiveness. Control puppies remained healthy, and their pulmonary function and histamine responsiveness did not change. CPI2-Bb puppies increased RL and decreased FRC on Day 3-4, and were moderately ill and histamine-hyperresponsive on Day 3-4 and on Day 6.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute canine adenovirus 2 infection increases histamine airway reactivity in beagle puppies

Acute infection with canine adenovirus was studied in 23 specific pathogen-free outbred beagle puppies (median age = 78 days, range = 67 to 86 days) to determine its effects on pulmonary function and airway responsiveness to aerosolized histamine. The following groups were studied: uninoculated (n = 6, Control); inoculated with canine adenovirus type 2 (CAV2) (n = 11, Infected); and subclinical spontaneous infection with CAV2 (n = 6, Subclinical). While anesthetized with chloralose and mechanically ventilated, lung function and responsiveness to aerosolized histamine were measured 3 days before inoculation (Day -3), the day of inoculation (Day 0), and 3 to 4 (Day 3-4), 6 (Day 6), 8 to 10 (Day 8-10), and 12 to 14 (Day 12-14) days after inoculation. Histamine responsiveness was assessed by calculating the provocation concentration of histamine diphosphate to increase lung resistance (RL) to 150% (PC 150% RL), or decrease dynamic lung compliance (Cdyn) to 75% (PC 75% Cdyn) of the response to saline [RL(sal) and Cdyn(sal), respectively]. Arterial blood gases, functional residual capacity (FRC), specific static lung compliance (spCst), RL, Cdyn, and histamine responsiveness were not significantly different on Day 0 among the groups (p greater than 0.05). Control and Subclinical puppies remained healthy, had a mean weight gain of 0.7 kg, and did not change their histamine responsiveness during the study period. Infected puppies developed moderate to severe clinical illnesses, had poor weight gain, and were histamine hyperresponsive on Days 3-4 and 6. One infected puppy died on Day 3-4, and two died on Day 6 of their illness.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antigen-induced mediator release in primates.

We examined the release of bronchoactive mediators into the airways of allergic primates during the acute response to specific antigen inhalation. Twelve adult male cynomolgus monkeys (Macaca fascicularis) with a naturally occurring respiratory sensitivity to inhaled Ascaris suum extract were anesthetized and intubated for each study. Respiratory system resistance (Rrs) and dynamic lung compliance (CLdyn) were measured before and after antigen inhalation, and the release of mediators into the airways was assessed by bronchoalveolar lavage (BAL). BAL samples were concentrated approximately 5-fold before quantitation of LTC4 and PGD2 by RP-HPLC and radioimmunoassay and histamine by a fluorometric assay. Antigen inhalation resulted in a 40-fold increase in BAL levels of i-LTC4 (1.5 +/- 0.7 to 41.6 +/- 12.7 ng, p less than 0.01), a 10-fold increase in i-PGD2 (2.4 +/- 0.9 to 25.9 +/- 5.5 ng, p less than 0.01), and a 20-fold increase in BAL histamine (1.0 +/- 1.5 to 21.4 +/- 2.3 micrograms, p less than 0.01). Dexamethasone (n = 7) inhibited the antigen-induced increase in BAL i-LTC4 (71 +/- 6%, p less than 0.01) and i-PGD2 (52 +/- 8%, p less than 0.05) while weakly inhibiting histamine release (43 +/- 10%). Indomethacin (n = 7) had a variable effect on i-LTC4 levels (6 +/- 51%), strongly inhibited i-PGD2 (88 +/- 9%, p less than 0.01), and had no effect on histamine release (25 +/- 8%). Pretreatment with iodoxamide tromethamine significantly blocked the release of each mediator, but mepyramine, an H1 antagonist, had no effect on mediator release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphometry of the airways during late responses to antigen challenge in the rat

To quantitate the structural changes in the airways that contribute to the late bronchial response (LR) to antigen challenge we killed six Brown-Norway rats, sensitized to ovalbumin (OA) and challenged by aerosol, during the LR and compared the dimensions of the intraparenchymal airways with those of six control animals. Lungs were rapidly frozen with liquid nitrogen and fixed in Carnoy's solution. Paraffin sections were stained with hematoxylin-phloxine-saffron. At the time of the LR (382 +/- 39 min after OA challenge), RL increased from the baseline value (0.067 +/- 0.034 cm H2O.ml-1.s) by 0.107 +/- 0.03 cm H2O.ml-1.s (p less than 0.05). RL did not change significantly in the control rats. The lumen size and the wall area of all membranous airways were measured and were corrected for airway size by dividing by the basement membrane length squared (BM2). There was no increase in airway wall area in OA-challenged animals. However, the lumen of large airways (BM: 2.0 to 2.99 mm) was significantly less for the OA-challenged animals (0.039 +/- 0.0055 mm2) than for the control animals (0.058 +/- 0.0063 mm2; p less than 0.05). In six additional rats, the distribution of mast cells (MC) in the bronchial tree was determined. Tissues were fixed with Carnoy's solution and stained with a modified May-Grunwald-Giemsa stain. There were significantly more MC in the large airways than in medial or small airways. We conclude that smooth muscle constriction of large airways and not airway wall edema accounts for the LR in the rat. The distribution of the mast cells corresponds closely to the site of bronchoconstriction.     

Effect of maturation on topographic distribution of bronchoconstrictor responses in large diameter airways of young swine.

We studied the effect of maturation on the topographic distribution of airway constriction in Generations 0 (trachea) through 6 in fourteen 2-wk-old swine (2ws) and sixteen 10-wk-old swine (10ws) in vivo and in excised airways from seven 2ws and seven 10ws in vitro. Animals were anesthetized with chloralose-urethane and received beta-adrenergic blockade and vagotomy prior to generation of random-order, dose-response curves with i.v. methacholine (MCh) and histamine (His) or serotonin (5HT) given intravenously. Lung resistance (RL) was measured, and airway diameter was assessed by tantalum bronchograms obtained at functional residual capacity for each dose of agonist. Baseline RL was substantially greater in 2ws (48 to 62 cm H2O/L/s) than in 10ws (9 to 11 cm H2O/L/s; p less than 0.001 for all groups). Intravenous infusion of 10(-6) mol/kg MCh caused a 416 +/- 110% increase in RL in 2 ws and a 314 +/- 32% increase in RL in 10 ws (p = NS); airway diameter (Daw) decreased by 10 +/- 1% (Generation 2) to 27 +/- 4% (Generation 6) in 2ws and from 8 +/- 2 (Generation 2) to 17 +/- 4% in 10ws. Intravenous infusion of 10(-6) mol/kg His caused a 513 +/- 85% increase in RL in 2ws and a 276 +/- 17% increase in RL in 10 ws (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide synthase inhibition augments acute allergic reactions in the pig airways in vivo.

The aim of this study was to examine the effects of nitric oxide synthase inhibition on antigen- and histamine-induced acute airway reactions, in order to clarify the possible modulating role of NO. Twelve specific-pathogen-free pigs (sensitized with Ascaris suum antigen) were challenged with an antigen aerosol during mechanical ventilation and anaesthesia. Six pigs were pretreated with N(G)-nitro-L-arginine (L-NA, 10 mg x kg(-1)), a NO synthase inhibitor, 30 min before challenge. In separate experiments, seven sensitized pigs received histamine (5 mg) aerosols before and after L-NA treatment. It was found that pretreatment with L-NA resulted in an enhanced airways resistance response to antigen (areas under the curve 0-90 min were (mean+/-SEM) 1,119+/-160 versus 555+/-56 (cmH2O x L(-1) x s(-1) x min for controls, p<0.05 (Mann-Whitney U-test), whereas this response to histamine was not affected by L-NA. Moreover, L-NA pretreatment significantly enhanced total protein (1.85+/-0.43 versus 0.31+/-0.06 g x L(-1), p<0.01) and histamine levels (42.8+/-16.0 versus 2.6+/-0.8 nM, p<0.05) in bronchoalveolar lavage fluid 45 min after antigen challenge. In conclusion, this study showed that N(G)-nitro-L-arginine enhanced reactions occurring during the acute allergic reaction in pigs in vivo. This indicates a protective role of nitric oxide, which might occur through downregulation of histamine release from mast cells rather than a direct bronchodilating effect of nitric oxide.     

Endogenous tachykinins in antigen-induced acute bronchial responses of guinea pigs.

Because tachykinins (TKs) cause severe bronchoconstriction in humans and animals, this study was carried out to examine whether depletion of TKs can prevent or ameliorate antigen-induced immediate bronchial constriction. Forty-five guinea pigs were randomly divided into six groups: control, antigen challenge, TK depletion + antigen challenge, ganglionic (Ggl) blockade, Ggl blockade + antigen challenge, and TK depletion + Ggl blockade + antigen challenge. Control animals received no treatment. Animals of all antigen challenge groups were sensitized with ovalbumin 10 days before the study. TK depletion was performed via 5-day pretreatment of capsaicin, which began 11 days before the study. On the day of the study, pulmonary resistance (RI), dynamic compliance (Cdyn), and breathing patterns were measured for 15 min just before (baseline) and for 30 min after intravenous injection of either saline (control) or ovalbumin (antigen challenge). In controls, saline injection did not produce any significant change within 30 min, whereas antigen challenge significantly increased RL at 4-15 min and significantly decreased Cdyn at 6-15 min, suggesting antigen-induced bronchoconstriction. Following TK depletion, antigen challenge produced pulmonary changes similar to those without depletion. Ggl blockade reduced RL and breathing frequency, and increased Cdyn and tidal volume; the blockade, however, did not significantly alter (in terms of % baseline) antigen challenge-induced changes in RL, Cdyn, or breathing patterns. These results suggest that TKs and reflexes via Ggl do not appear to be important contributing factors for antigen-induced immediate bronchial constriction in this animal model.     

Kinetics of the recovery from bronchial obstruction due to hyperventilation of cold air in asthmatic subjects

The timecourse of recovery from bronchial obstruction due to inhaled cold air was studied in eight adult asthmatic subjects. On the first visit, bronchial responsiveness to inhaled histamine was assessed. On the other two visits, after assessment of baseline lung resistance (RL) and spirometry, dry cold (-20 degrees C) air was inhaled for three minutes. RL was monitored continuously until its return to baseline +/- 20%. The baseline concentration of histamine causing a 20% fall in FEV1 (PC20) varied from 0.03 to 5.9 mg.ml-1. The mean maximum increase in RL was 2-fold (2.03 +/- 0.41) and was reached 2-11 min after the challenge. RL values were linearly correlated to time (r2 values greater than 0.80 in 14/16 instances). The two slopes of recovery were not significantly different. Slopes of recovery and total time of recovery (14-55 min) varied greatly between subjects. No relationship was found between baseline airway calibre, bronchial hyperresponsiveness and maximal increase in baseline RL on the one hand and the slopes of recovery on the other.     

Effect of platelet-activating factor on aerosol histamine responsiveness in awake sheep

Platelet-activating factor (PAF), a potent proinflammatory ether lipid, has been proposed as a potential mediator of airway hyperresponsiveness. We studied the effect of a single intravascular bolus of synthetic PAF (0.5 microgram/kg) on airway responsiveness to aerosolized histamine in 8 chronically instrumented awake sheep. Lung mechanics were assessed by whole-body plethysmography. Histamine dose-response curves were performed before and 4 h after PAF administration. PAF induced a 60% fall in dynamic compliance and a three-fold increase in resistance to air flow across the lung within 5 min. All animals tested became more responsive to aerosol histamine 4 h after PAF as evidenced by a fall in ED65Cdyn from 9.45 mg/ml before to 4.34 mg/ml. There was no correlation between the initial Cdyn or the Cdyn measured just prior to the second bronchial challenge and the calculated alteration in responsiveness. Animals displaying the greatest initial responsiveness to aerosol histamine also manifested the greatest alteration in lung mechanics after intravascular PAF (r = 0.92). We conclude that PAF consistently alters lung mechanics and increases airway responsiveness in awake sheep, and aerosol histamine responsiveness correlates with the maximal response to intravenous PAF.     

Variability of pulmonary responsiveness to aerosolized histamine in normal rabbits

Considerable between-subject variability in pulmonary responsiveness to histamine has been reported in normal human subjects, dogs, guinea pigs, and rhesus monkeys, but rabbits have not been studied. We determined the between- and within-rabbit variability of pulmonary histamine responsiveness in 34 anesthetized and mechanically ventilated New Zealand White rabbits. In 30 rabbits, 5 breaths of aerosolized histamine were delivered in 9 increasing concentrations ranging from 0.01 to 100 mg/ml. Eleven of 30 rabbits were rechallenged with histamine on 1-4 additional occasions over a 3-week period. In the remaining 4 rabbits, 9 doses of distilled H2O were aerosolized to determine the degree of spontaneous variability in measurements of lung resistance (RL) and dynamic lung compliance (Cdyn). We defined an increase in RL of greater than 50% of baseline (TD50RL) and a decrease in Cdyn of greater than 25% of baseline (TD25Cdyn) as being significant based on observations in these 4 rabbits. These limits exceeded the 99.9 percentile of spontaneous variability in RL and Cdyn. Pulmonary responsiveness to histamine varied widely, with a greater than 10,000-fold range in TD50RL and a 1,000-fold range in TD25Cdyn between the most and least sensitive rabbits. The variability of this responsiveness was log-normally distributed. It was not correlated with age, sex, or baseline RL and Cdyn. In contrast, within-rabbit responses to histamine challenge were quite reproducible. Five of 30 rabbits were killed at the conclusion of their histamine challenges for pathologic examination of their lungs. No evidence of airway inflammation was found.(ABSTRACT TRUNCATED AT 250 WORDS)