Controversies in pulmonary medicine. Patients with COPD should be started initially on anticholinergic bronchodilators.
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Adrenergic beta-Agonists↗
Biomedical subjects
A Wanner
Publications and source records attributed to A Wanner.
Binding studies with [3H]cis-methyldioxolane in different tissues. Under certain conditions [3H]cis-methyldioxolane labels preferentially but not exclusively agonist high affinity states of muscarinic M2 receptors.
Special conditions--tricine buffer containing Ca2+ and Mg2+, 22 degrees C (TCM)--allow to label a much higher proportion of muscarinic receptors by [3H]cis-methyldioxolane (CD) than hitherto described (Vickroy et al. 1984a). Taking the maximum number of binding sites, Bmax, of [3H]QNB as 100%, Bmax of [3H]CD amounts to 83% in the rat heart instead of the reported 17%, 33% in the cerebral cortex instead of 6%, 20% in hippocampus and 55% in pons/medulla. In the salivary glands specific binding was negligible. The affinities of a number of muscarinic agonists and antagonists to [3H]CD and [3H]QNB binding sites in different tissues of the rat are compared. Apparent affinities of agonists are much higher in the [3H]CD system, affinities of antagonists are slightly higher in the [3H]QNB system. In both assay systems receptors of heart and pons/medulla membranes seem to have similar drug specificity. They differ somewhat from those in the cortex. Receptors in the salivary glands, however, seem to be completely different from those in the other three tissues. In the heart [3H]CD binding can be abolished almost completely by GppNHp. In the cortex about half of the [3H]CD binding is susceptible to GppNHp. The reduction of binding in the cortex is due to a change in Bmax and not in the dissociation constant KD. Competition of unlabelled pirenzepine with [3H]CD: In heart and pons/medulla only low affinity sites for pirenzepine (M2-receptors) are labelled by [3H]CD.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Bacterial pneumonia stimulates macromolecule secretion and ion and water fluxes in sheep trachea.
In vivo instillation of Pasteurella haemolytica (greater than or equal to 10(7) colony-forming units/kg) into a lobar bronchus of sheep produced bacterial pneumonia by 7 days postinoculation. Infection was verified bacteriologically and histologically. Macromolecule secretion and ion and water fluxes were subsequently measured in tracheal tissues in vitro and were compared with values from sham-infected sheep. Macromolecules were radiolabeled with 35SO4 and [3H]threonine, and we measured the secretion of macromolecule-bound radiolabel onto the mucosa. Unidirectional fluxes of Cl-, Na+, and water were measured with radioactive tracers under open-circuit and short-circuit conditions. Lung infection increased basal secretion of bound 35SO4 (by 189%) and bound [3H]-threonine (by 110%). It significantly increased net Na+ absorption under open- and short-circuit conditions and induced open-circuit net absorption of Cl- and water (16 +/- 29 microliters X cm-2 X h-1). These changes were associated with specific recruitment of neutrophils and elevated levels of arachidonate metabolites (thromboxane B2 and leukotriene B4) in the airways. Thus the bacterial pneumonia-induced changes in tracheal mucus secretion may be the result of airway inflammation.
Animals↗
Autonomic control and mucociliary functions.
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Airway Resistance↗
Effect of ipratropium bromide on airway mucociliary function.
Airway mucociliary dysfunction leading to a depression of mucus transport has been demonstrated in patients with acute and chronic bronchitis, cystic fibrosis, and bronchial asthma; use of bronchodilators that might further impair mucociliary function, therefore, generally has been discouraged. Atropine and ipratropium bromide are cholinergic antagonists that are effective bronchodilators in various clinical settings. Atropine has been shown to block the production of respiratory secretions in response to cholinergic stimulation, but to have no effect on baseline secretions. Atropine has also been clearly demonstrated to depress ciliary beat frequency and to slow airway mucociliary clearance, whereas the short-term and long-term administration of ipratropium bromide at higher than clinically recommended doses seems to lack these effects. No satisfactory explanation has thus far been offered for this difference between the two cholinergic antagonists. Nevertheless, with respect to airway mucociliary function, ipratropium bromide appears to be preferable to atropine in the treatment of obstructive airways disease.
Animals↗
Differences in airway responsiveness to leukotriene D4 in allergic sheep with and without late bronchial responses.
Allergic sheep respond to inhaled Ascaris suum antigen with either acute and late bronchial obstructions (dual responders) or only acute bronchoconstriction (acute responders). In this study we tested the hypothesis that one factor which may distinguish between these two populations is the difference in sensitivity to a specific mediator of airway anaphylaxis, leukotriene (LT) D4 (a major component of slow reacting substance of anaphylaxis). We postulated that if the hypothesis was correct then dual responders should demonstrate increased airway responses to inhaled LTD4 and that this increased responsiveness should also be reflected by a more severe response to inhaled antigen. To test this we used animals from both groups with the same degree of non-specific airway responsiveness to carbachol and determined their airway responses to controlled inhalation challenges with synthetic LTD4 and Ascaris suum antigen. Airway responsiveness to carbachol was determined by measuring the change in specific lung resistance (SRL) to increasing concentrations of carbachol aerosol, and then identifying, by linear interpolation, the provocative carbachol concentration which produced a 150% increase (PC150) in SRL. Airway responses to LTD4, and antigen were determined by measuring the percentage change in SRL after a controlled inhalation challenge with either aerosol. Airway responsiveness to carbachol was not different between the two groups. There was, however, a difference (p less than 0.05) in the airway response to the same dose of LTD4 in the two groups. Dual responders showed a 297 +/- 72% increase in SRL as compared to a 90 +/- 13% increase in SRL in the acute responders. Dual responders also showed a greater immediate and more prolonged response to antigen than did acute responders. These results suggest that increased responsiveness to LTD4 may be one factor which may distinguish dual responders from acute responders.
Airway Resistance↗
The effect of an orally active leukotriene D4/E4 antagonist, LY171883, on antigen-induced airway responses in allergic sheep.
Leukotriene (LT) D4 is a putative mediator of allergic asthma: inhaled LTD4 produces early and late increases in specific lung resistance (SRL) and slows tracheal mucus velocity (TMV) similar to inhaled antigen. In this study we examined the effects of an orally active LTD4/LTE4 antagonist, LY171883 [1-less than 2-Hydroxy-3-propyl-4-less than 4-(1H-Tetrazol-5-yl) Butoxy greater than Phenyl greater than Ethanone], on early and late changes in SRL and TMV following airway challenge with Ascaris suum antigen in conscious allergic sheep. SRL and TMV were measured before and up to 8 h and 24 h after antigen challenge after either LY171883 (30 mg/kg, p.o. 2 h before challenge) or placebo pretreatment. After placebo pretreatment antigen challenge resulted in significant early (483% over baseline) and late (221% over baseline) increases in SRL (n = 9). LY171883 pretreatment, however, significantly reduced the early increase in SRL (163% over baseline) and blocked the late response. LY171883 did not prevent the antigen-induced fall in TMV from 5-8 h post challenge (n = 6), but TMV recovered more rapidly in the drug trial returning to baseline values by 24 h. These results suggest that the generation of LTD4, and its metabolite LTE4, during airway anaphylaxis contributes to the early increase in SRL and is important for eliciting the late increase in SRL as well as contributing to the fall in TMV.
Acetophenones↗
Effects of 0.5 ppm ozone on glycoprotein secretion, ion and water fluxes in sheep trachea.
We studied the effects of ozone (O3) exposure on airway mucus secretion. Sheep were exposed in vivo to 0.5 ppm O3, 4 h/day for 2 days (acute, n = 6), 6 wks (chronic, n = 6) or 6 wks + 1 wk recovery (chronic + recovery, n = 6). Secretion of glycoproteins (radiolabeled with 35SO4 and [3H]threonine), and transepithelial fluxes of Cl-, Na+ and water were subsequently measured in tracheal tissues in vitro, and were compared with values from control, unexposed sheep (n = 8). Acute O3 exposure increased basal secretion of sulfated glycoproteins (P less than 0.05), but had no effect on ion fluxes. Chronic exposure reduced basal glycoprotein secretion, but increased net Cl- secretion. Under open-circuit conditions, chronic exposure also induced net water secretion (P less than 0.05). With 7 days recovery, basal glycoprotein secretion (predominantly sulfated) was greatly increased above control, while the increased net secretion of Cl- and of water persisted (P less than 0.05). Histology of the airways indicated that acute exposure induced moderate hypertrophy of submucosal glands in the lower trachea (P less than 0.05), while chronic exposure (with and without recovery) induced a large hypertrophy of submucosal glands in both upper and lower trachea (P less than 0.05). Without recovery, however, the gland cells were devoid of secretory material, whereas with recovery they were full of secretory material. This suggests that the decreased glycoprotein secretion with chronic exposure alone resulted from incomplete replenishment of intracellular stores after 6 wks of stimulation. We conclude that both short- and long-term O3 exposure causes airway-mucus hypersecretion.
Animals↗
In vivo estimation of tracheal wall water: effects of histamine and carbachol.
Based on double-indicator-dilution principles we developed and validated a new method of measuring water content in the tracheal wall by inscribing time-concentration curves with the inert gas, helium and the water-soluble gas, dimethylether. In the trachea of conscious adult sheep the measurable water volume of the wall over a 15-cm length ranged between 0.50 and 0.70 ml. The tracheal radius calculated from helium volume and known tracheal length ranged between 7.4 and 9.3 mm. The corresponding measurable "water depth" ranged between 63 and 82 microns. Changes in bronchial blood flow had no consistent influence on tracheal water volume. The intravenous injection of histamine (4 micrograms/kg) increased mean water depth to between 122 and 134% of base line (P less than 0.001), whereas the intravenous injection of carbachol (4 micrograms/kg) had no effect on water depth. The production of large amounts of airway secretions produced by carbachol were removed prior to inscription of the indicator-dilution curves. These findings indicate that the double-gas-indicator technique is capable of measuring in vivo the volume of a water compartment in the tracheal wall and that this volume is increased by histamine. This method may be applicable in human subjects.
Airway Obstruction↗
Effects of induced bronchoconstriction on pulmonary blood flow.
Allergic bronchoconstriction may be associated with hemodynamic alterations due to changes in respiratory mechanics (or the associated changes in arterial blood gas composition) or the cardiovascular effects of chemical mediators. In an attempt to differentiate between these two possible mechanisms, we obtained measurements of hemodynamics, respiratory mechanics, and O2 consumption (VO2) in nine asymptomatic adult ragweed asthmatics before and after inhalation challenge with either ragweed extract or methacholine. We measured specific airway conductance (sGaw) by body plethysmography, pleural pressure with an esophageal balloon catheter, pulmonary blood flow (Q) and VO2 by a rebreathing technique, and heart rate. For a similar degree of bronchoconstriction after the two types of challenge (mean +/- SD sGaw 0.06 +/- 0.03 and 0.05 +/- 0.02 cmH2O-1 . s-1, P = NS), mean Q increased by 29 and 29%, and mean VO2 by 33 and 37% 15-20 min after ragweed and methacholine, respectively. Since heart rate did not change, there was a concomitant increase in mean stroke volume by 25 and 35%, respectively (P less than 0.05). The respiratory pleural pressure swings during quiet breathing and the rebreathing maneuver and the work of breathing during rebreathing also increased to a similar degree after the two types of challenge. These observations suggest that, if chemical mediators are released into the circulation during antigen-induced bronchoconstriction, their blood concentrations are too low for appreciable cardiovascular effects. The increase in rebreathing cardiac output during allergic and nonallergic bronchoconstriction is probably due to increases in intrathoracic pressure swings and in the work of breathing.
Adult↗
Ciliary responsiveness in allergic and nonallergic airways.
Allergic asthma is associated with airway (smooth muscle) hyperresponsiveness to several chemical mediators of anaphylaxis; however, it is not known whether this is accompanied by mucociliary hyperresponsiveness. The purpose of this study was therefore to determine if airway ciliary activity, a component function of mucociliary clearance, exhibits exaggerated responses to prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), and leukotriene D4 (LTD4) in allergic sheep when compared with nonallergic sheep, and the effects of LTD4 are direct or involve the generation of cyclooxygenase products of arachidonate metabolism. Ciliary beat frequency (CBF) was measured in a perfusion chamber with a microscopic technique using tracheal epithelial cells obtained from brushing of "allergic" (positive cutaneous reaction and previous bronchospastic response to inhaled specific antigen) and "nonallergic" (negative cutaneous reaction, no previous inhalation challenge with antigen) sheep. Mean base-line CBF was not different among the groups; PGE1, PGE2, and LTD4 induced dose-dependent increases in CBF, and these increases were not different in allergic and nonallergic sheep. At the highest agonist concentration the mean increase in CBF from base line varied between 13 and 16% (P less than 0.05). The ciliostimulatory effect of LTD4 was significantly blunted by both the sulfidopeptide leukotriene antagonist FPL-55712 and the cyclooxygenase inhibitor indomethacin. These results suggest that allergic sheep fail to exhibit ciliary hyperresponsiveness to selected chemical mediators of anaphylaxis and the ciliostimulatory effect of LTD4 depends on the activation of cyclooxygenase and possibly the generation of prostaglandins.
Alprostadil↗
Indomethacin and FPL-57231 inhibit antigen-induced airway hyperresponsiveness in sheep.
We compared the development of antigen-induced airway hyperresponsiveness (AHR) 24 h after challenge with Ascaris suum antigen in allergic sheep with acute (n = 7) and with dual (n = 7) airway responses and then attempted to modify this AHR. Cholinergic airway responsiveness was determined by measuring the carbachol dose required to increase specific lung resistance (sRL) 150% (i.e., PC150). Subsequently the sheep were challenged with antigen and sRL was measured at predetermined times to document the presence or absence of a late response. PC150 was redetermined 24 h later followed by bronchoalveolar lavage (BAL) to assess inflammation. Only dual responders developed AHR (PC150 decreased, P less than 0.05). There were no significant differences in BAL between the two groups. Six dual responders were then, on separate occasions (greater than or equal to 3 wk), pretreated with placebo, indomethacin (2 mg/kg iv), or a leukotriene antagonist, FPL-57231 (30 mg inhaled). Neither agent significantly affected the acute response to antigen. Only FPL pretreatment blocked the late response, but both agents blocked the antigen-induced AHR 24 h later. BAL at 24 h showed no significant differences. These results indicate that only dual responders develop AHR 24 h after antigen challenge. This AHR appears independent of the late increase in sRL or the severity of pulmonary inflammation. AHR appears to be sensitive to agents that interfere with the early release or actions of cyclooxygenase and lipoxygenase metabolites in dual responders.
Airway Resistance↗
Mucociliary clearance in the trachea.
Tracheal mucociliary clearance is governed by the interplay between ciliary activity and secretory functions of the epithelium. These functions are altered transiently by various physiologic and injurious stimuli, and chronically in asthma, chronic bronchitis, cystic fibrosis, and other forms of airway disease. In general, these conditions are associated with a depression in mucociliary clearance that may predispose to respiratory infections and the accumulation of secretions.
Animals↗
Impairment of tracheal mucociliary clearance but not ciliary beat frequency by a combination of low level ozone and sulfur dioxide in sheep.
We used conscious sheep to determine the effect of a combined exposure to ozone (O3) and sulfur dioxide (SO2) on tracheal mucus velocity (TMV) and ciliary beat frequency (CBF). TMV was measured in vivo by tracking the movement of radiopaque particles which had been deposited on the tracheal mucosa. CBF of tracheal epithelial cells, obtained by brushing, was measured in vitro with phase contrast microscopy. On two separate occasions, six sheep were exposed by mask to either a combination of 0.3 ppm O3 and 3 ppm SO2 or air (control) for 5 h on each of three consecutive days. TMV and CBF were measured prior to the first exposure, and immediately and 24 h after the last exposure. The combination of O3 and SO2 depressed mean TMV by 40% immediately after and by 25%, 24 h after exposure. Both values were different from the corresponding values after air exposure (p less than 0.05). However, this depression in TMV was not associated with an impairment in CBF. We conclude that in conscious sheep, exposure to a combination of low level O3 and SO2 causes a depression in TMV, and changes in CBF are probably not a primary cause of this mucociliary dysfunction.
Animals↗
Effects of methylxanthines on airway mucociliary function.
Mucociliary interaction and hence mucus clearance in the airways is governed by ciliary activity and the depth and rheologic properties of periciliary fluid and mucus. Therefore, a defect in one or more of these component functions must be responsible for the impairment of mucociliary clearance in patients with a variety of airway diseases. Methylxanthines stimulate ciliary beat frequency, augment net ion secretion with a substantial increase in water flux toward the lumen, and promote mucus secretion in the lower airways. The net result is an enhancement of mucociliary clearance. This beneficial action of methylxanthines on mucociliary function may complement their effects on bronchoconstriction and respiratory muscle dysfunction in patients with chronic bronchitis, cystic fibrosis, and bronchial asthma.
Aminophylline↗
Production of early and late pulmonary responses with inhaled leukotriene D4 in allergic sheep.
Some allergic sheep respond to inhalation of Ascaris suum antigen with both immediate and late increases in airflow resistance (late response). The mechanism of the late response is unknown but recent evidence suggests that the initial generation of slow-reacting substance of anaphylaxis (SRS-A) immediately after antigen challenge is a necessary pre-requisite for the physiologic expression of this late response. Based on this evidence we hypothesized that airway challenge with leukotriene D4 (LTD4), an active component of SRS-A would produce acute and late airway responses in allergic sheep similar to those observed with antigen. In five allergic sheep with documented early and late pulmonary responses to Ascaris suum antigen, inhalation of leukotriene D4 aerosol (delivered dose (mean +/- SE) 0.55 +/- 0.08 ug) resulted in significant early and late increases in specific lung resistance (SRL). In three allergic sheep which only demonstrated acute responses to antigen, LTD4 aerosol (delivered dose 0.59 +/- 0.09 ug) only produced an acute increase in SRL. In the late responders pretreatment with aerosol cromolyn sodium (1 mg/kg) did not affect the acute response but blunted the late increase in SRL. Pretreatment with aerosol FPL-57231 (1% w/v solution) completely blocked both the acute and late responses. These data support the hypothesis that initial release of LTD4 in the airways of sensitive animals is important for the physiologic expression of the late response.
Aerosols↗
Prolonged bronchial obstruction after a single antigen challenge in ragweed asthma.
Some patients with allergic asthma exhibit late-phase responses to inhalation challenge with specific antigen. However, the duration of these responses is difficult to determine because of diurnal variations in airway function, a common phenomenon in patients with asthma. We therefore examined the pattern and duration of pulmonary function in six asymptomatic patients with a history of ragweed asthma and a documented late-phase response after specific and nonspecific bronchial challenge and compared them to responses after control challenge with normal saline. On 3 different days, specific airway conductance (SGaw) and gas distribution by the single breath nitrogen test were measured before (9:00 A.M.) and hourly for 24 hours after inhalation challenge with either normal saline, ragweed extract, or histamine at concentrations sufficient to decrease SGaw immediately by 35% or more. The fluctuations in SGaw after saline and histamine were considerable but failed to follow a typical diurnal or biphasic pattern. There was no difference in mean SGaw between the histamine and saline challenges from 1 to 24 hours after inhalation. In contrast, ragweed challenge produced a typical late-phase response followed by partial recovery of mean SGaw. However, mean SGaw remained subsequently lower than after saline challenge throughout the remaining observation period with fluctuations about this lower level. Gas distribution demonstrated marked intra- and intersubject variations and was therefore not different among the three challenges at any time of measurement. These observations suggest that a single specific but not nonspecific bronchial challenge causes prolonged airflow obstruction in subjects with allergic asthma that lasts 24 hours or longer, independent of variations in baseline airway function.
Airway Obstruction↗
Effects of histamine on bronchial artery blood flow and bronchomotor tone.
The effects of aerosolized 5% histamine (10 breaths) on bronchial artery blood flow (Qbr), airflow resistance (RL), and pulmonary and systemic hemodynamics were studied in mechanically ventilated sheep anesthetized with pentobarbital sodium. Histamine increased mean Qbr and RL to 252 +/- 45 and 337 +/- 53% of base line, respectively. This effect was significantly different from base line for 30 min after challenge. The histamine-induced increase in RL was blocked by pretreatment with the histamine H1 receptor antagonist, chlorpheniramine, whereas the histamine-induced elevation in Qbr was prevented by the H2 antagonist, metiamide. Both responses were blocked only when both antagonists were present. Changes in Qbr were not directly associated with alterations in systemic and pulmonary hemodynamics or arterial blood gas composition. In vitro histamine caused a dose-dependent contraction of ovine bronchial artery strips that was prevented by H1 antagonist. The H2 agonist, impromidine, caused relaxation of precontracted arterial strips and was more potent and efficacious than histamine, whereas H1 agonists failed to elicit a relaxant response. Thus these findings indicate that histamine aerosol induces a vasodilation in the bronchial vascular bed; histamine has a direct effect on Qbr that is independent of alterations in RL, systemic and pulmonary hemodynamics, or arterial blood gas composition; and, histamine-induced bronchoconstriction is mediated predominantly by H1-receptors, whereas increased Qbr is controlled predominantly by H2-receptors, probably located in resistance vessels. This local effect of histamine on Qbr may have important implications in the pathophysiology of bronchial asthma and pulmonary edema.
Animals↗