Mode of action of iron(III) chelators as antimalarials. III. Overadditive effects in the combined action of hydroxamate-based agents on in vitro growth of Plasmodium falciparum

Recent studies suggest a significant contribution of the pulmonary circulation to the perfusion of large airways. In this study we used anesthetized ventilated sheep (n = 19) to determine the functional contribution of the pulmonary circulation to airway smooth muscle. We performed sequential intravenous challenge with methacholine chloride (MCh; 0.25-2.5 mg/ml) to determine airway resistance (Raw) changes in the intact animal, after bronchial artery cannulation that essentially removed bronchial arterial delivery of MCh, and in an isolated lung preparation. After blocking the vagal reflex component of this response, we found that intravenous MCh in the intact preparation resulted in an average 2.2 +/- 0.5 cmH2O.l-1.s increase (181%) in Raw. After prevention of bronchial arterial delivery of MCh, Raw increased by 0.8 +/- 0.3 cmH2O.l-1.s (64%; P < 0.01 compared with intact preparation). In the isolated lung preparation, Raw increased by 0.6 +/- 0.2 cmH2O.l-1.s (63%; P < 0.01 compared with intact preparation). These results demonstrate that in sheep, the bronchial artery provides the major route for delivery of intravenously administered agonists to airway smooth muscle. Considering the large dilutional effect of an intravenously administered agonist by the time it reaches the bronchial artery, we conclude that the pulmonary component of agonist delivery to large airways is < 10% and unlikely to play a major physiological role.     

NO does not mediate inhibitory neural responses in sheep airway and bronchial vascular smooth muscle

Endogenous nitric oxide (NO) influences acetylcholine-induced bronchovascular dilation in sheep and is a mediator of the airway smooth muscle inhibitory nonadrenergic, noncholinergic neural response in several species. This study was designed to determine the importance of NO as a neurally derived modulator of ovine airway and bronchial vascular smooth muscle. We measured the response of pulmonary resistance (RL) and bronchial blood flow (Qbr) to vagal stimulation in 14 anesthetized, ventilated, open-chest sheep during the following conditions: 1) control; 2) infusion of the alpha-agonist phenylephrine to reduce baseline Qbr by the same amount as would be produced by infusion of Nomega-nitro-L-arginine (L-NNA), a NO synthase inhibitor; 3) infusion of L-NNA (10(-2) M); and 4) after administration of atropine (1.5 mg/kg). The results showed that vagal stimulation produced an increase in RL and Qbr in periods 1, 2, and 3 (P < 0.01) that was not affected by L-NNA. After atropine was administered, there was no increase in Qbr or RL. In vitro experiments on trachealis smooth muscle contracted with carbachol showed no effect of L-NNA on neural relaxation but showed a complete blockade with propranolol (P < 0.01). In conclusion, the vagally induced airway smooth muscle contraction and bronchial vascular dilation are not influenced by NO, and the sheep's trachealis muscle, unlike that in several other species, does not have inhibitory nonadrenergic, noncholinergic innervation.     

Effects of bronchial vascular engorgement on airway dimensions

Airway vascular engorgement has been suggested to cause luminal narrowing and airflow obstruction. To determine the extent to which changes in bronchial vascular volume could influence airway dimensions, we studied the effects of left atrial pressure elevation on airway morphometry in sheep (n = 17). The bronchial branch of the bronchoesophageal artery was cannulated and perfused with autologous blood (0.6 ml.min-1.kg-1). A balloon-tipped catheter was inserted into the left atrial appendage to elevate left atrial pressure by 10 mmHg, and papaverine was infused into the bronchial artery to eliminate airway smooth muscle tone. Morphological measurements were made from rapidly frozen lungs excised in vivo. Left atrial pressure elevation caused a 79% increase in total vascular area (P = 0.0002). Average airway luminal area was significantly decreased from 86 to 71% of the airway maximal area (P < 0.0001). Noteworthy were the prominent bronchial vessels located within mucosal folds. However, when papaverine was infused during left atrial pressure elevation, despite a comparable total vascular area, luminal narrowing did not occur and remained at 87% of the maximal area (P = 0.6267). In conclusion, we found that engorgement of the bronchial vasculature leads to an increase in the vascular area in regions inside and outside the smooth muscle layer. The associated decrease in luminal area only occurs in the presence of airway smooth muscle tone. This suggests a reflex effect on the airway caused by the vascular engorgement. We conclude that vascular engorgement of the airway wall per se has a negligible effect on airway obstruction.     

Importance of airway blood flow on particle clearance from the lung

The role of the airway circulation in supporting mucociliary function has been essentially unstudied. We evaluated the airway clearance of inert, insoluble particles in anesthetized ventilated sheep (n = 8), in which bronchial perfusion was controlled, to determine whether airway mucosal blood flow is essential for maintaining surface transport of particles through airways. The bronchial branch of the bronchoesophageal artery was cannulated and perfused with autologous blood at control flow (0.6 ml.min-1.kg-1) or perfusion was stopped. With the sheep in a supine position and after a steady-state 133Xe ventilation scan for designation of lung zones of interest, an inert 99mTc-labeled sulfur colloid aerosol (2.1-microns diameter) was deposited in the lung. The clearance kinetics of the radiolabeled particles were determined from the activity-time data obtained for right and left lung zones. At 60 min postdeposition of aerosol, average airway particle retention for control bronchial blood flow conditions was 57 +/- 7 (SE)% for the right and 53 +/- 8% for the left lung zones. Clearance of particles was significantly impaired when bronchial blood flow was stopped, e.g., right and left lung zones averaged 77 +/- 6 and 76 +/- 7% at 60 min, respectively (P < 0.05). These data demonstrate a significant influence of the bronchial circulation on mucociliary transport of insoluble particles. Potential mechanisms that may account for these results include the importance of the bronchial circulation for nutrient flow, maintenance of airway wall temperature and humidity, and release of mediators and sequelae associated with tissue ischemia.     

Independent modulation of horse airway smooth muscle by epithelium and prostanoids

The effects of epithelial removal and cyclooxygenase inhibition on contractions induced by exogenous acetylcholine (ACh) and electrical field stimulation (EFS) were evaluated in horse tracheal strips and bronchial rings. Epithelial removal potentiated the response to ACh but had no influence on the response to EFS. The effect of epithelial removal was not altered by pretreating the tissues with meclofenamate, a cyclooxygenase inhibitor. In trachealis strips, meclofenamate augmented contractions induced by EFS but not by ACh. In bronchial rings, meclofenamate augmented EFS-induced contraction to a greater extent than ACh-induced contraction. These effects of meclofenamate were epithelium-independent. We conclude that horse airway epithelium produces a relaxant factor that is not a prostanoid. Endogenous prostanoids originating from non-epithelial sites inhibit only cholinergic nerves in the trachea but both parasympathetic nerves and smooth muscle in the bronchi.     

Contractile responses and structure of small bronchi isolated from rats after 20 months' exposure to ozone

Short-term exposure to high concentrations of ozone has been shown to increase airway responsiveness in normal humans and in all laboratory animal species studied to date. While our knowledge concerning the pulmonary effects of single exposures to ozone has increased rapidly over recent years, the effects of repeated exposures are less understood. The goal of the present study was to determine whether airway responsiveness is increased after near-lifetime exposure to ozone. Airway segments representing approximately eighth generation airways were isolated from Fischer 344 rats of both genders that had been exposed for 6 hr per day, 5 days per week for 20 months to 0, 0.12, 0.5, or 1.0 parts per million (ppm) ozone. Circumferential tension development was measured in isolated airways in response to bethanechol, acetylcholine, and electrical field stimulation. Responsiveness of the airways to the contractile stimuli was described by the effective dose or frequency that elicited half-maximum contraction (ED50) and the maximum response. Since ozone exposure is associated with remodeling of peripheral airways, smooth muscle area was determined and tension responses were normalized to the area measurements. Before normalization of tension data to smooth muscle area, neither the ED50 nor maximum response of small bronchi to the contractile stimuli was altered after chronic ozone exposure. Smooth muscle area was greater in airways isolated from animals that had been exposed to 0.5 ppm ozone. After accounting for smooth muscle area, maximum responses of the small bronchi isolated from male rats were significantly reduced after 0.12 and 0.5 ppm ozone. Although not significant statistically, a similar trend was observed in airways isolated from female rats. These results suggest that the increase in airway responsiveness associated with acute ozone exposure does not persist during near-lifetime exposure. Although the mechanism responsible for the adaptation to the effects of O3 on airway responsiveness is unknown, the results indicate that smooth muscle cell function was compromised by the chronic exposure. The mechanism(s) responsible for mediating this effect and the relevance of these results to humans remains to be determined.     

A comparison of sensory nerve function in human, guinea-pig, rabbit and marmoset airways

We have investigated the role of sensory nerves in regulating airway smooth muscle function in the guinea-pig, marmoset, rabbit and man. Tissue levels of the sensory neuropeptides CGRP and substance P in the airways of the guinea-pig were significantly greater compared with the rabbit and marmoset. The relative order of tissue content was guinea-pig > rabbit = marmoset. Marmoset bronchial and tracheal preparations responded weakly to exogenously administered substance P and neurokinin A but contracted to methacholine and demonstrated atropine-sensitive cholinergic responses. In marmoset, rabbit and human airway preparations, capsaicin mediated weak contractile responses to exogenously administered capsaicin. However, high concentrations of capsaicin elicited a relaxation response that was epithelium-independent, cyclo-oxygenase-insensitive, not involving nitric oxide and not dependent on the activation of capsaicin-sensitive afferents. These results suggest that rabbit and marmoset airways respond functionally in a similar way to human airway preparations and maybe more relevant than guinea-pig airways with regard to understanding the role of sensory neuropeptides in airways.     

Isometric and isotonic contractions in airway smooth muscle

Canine tracheal smooth muscle was used as an in vitro model of smooth muscle in intrapulmonary airways to determine whether active tension curves derived from isometric and isotonic muscles are similar, and thus resemble striated muscle in this respect. Isometric, isotonic after-loaded, and isotonic free-loaded contractions elicited at different lengths and loads, were analysed. The data demonstrate that length-tension (L-T) diagrams were different in these various types of contractions for electrically and carbachol driven tracheal smooth muscles strips. In general, at any given length active tension is less in isotonic and free-loaded modes of contraction as compared with isometric. We conclude that the ability to actively develop tension at a given length in airway smooth muscle depends on the mode of contraction.     

Dibutyryl cGMP raises cytosolic concentrations of Ca2+ in cultured nodose ganglion neurons of the rabbit

Airway hyperresponsiveness in asthma has been attributed to impaired ability of deep inspiration (DI) to stretch airway smooth muscle. We have retested this hypothesis by comparing the responses to methacholine of 10 asthmatic and 10 control subjects. After each dose subjects breathed tidally without deep inspiration for 4 min, followed by a forced partial expiration from which flow was measured at a constant volume, 35% baseline VC (Vp 35). This index is independent of both DI and increases in end-inspiratory lung volume (EILV). EILV increased significantly more in the asthmatic group than in the control group (15.0 versus 2.5% of baseline VC, p = 0. 019), a factor that if not taken into account would tend to mask the difference in the two responses. Comparisons were made after a cumulative dose of 50 microg methacholine, which was the highest dose common to all subjects. The asthmatic response was significantly greater than that seen in the control group, with reductions to 25.9 and 72.1% of baseline Vp 35, respectively (p = 0. 0007). We conclude that the sensitivity of asthmatic airways to methacholine is greater than that of normal airways even when DI is prohibited. Therefore, the hyperresponsiveness of asthmatic airways is not attributable simply to an inability of DI to stretch airway smooth muscle.     

Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchial remodeling, and airways obstruction

Interleukin-11 is a pleotropic cytokine produced by lung stromal cells in response to respiratory viruses, cytokines, and histamine. To further define its potential effector functions, the Clara cell 10-kD protein promoter was used to express IL-11 and the airways of the resulting transgene mice were characterized. In contrast to transgene (-) littermates, the airways of IL-11 transgene (+) animals manifest nodular peribronchiolar mononuclear cell infiltrates and impressive airways remodeling with subepithelial fibrosis. The inflammatory foci contained large numbers of B220(+) and MHC Class II(+) cells and lesser numbers of CD3(+), CD4(+), and CD8(+) cells. The fibrotic response contained increased amounts of types III and I collagen, increased numbers of alpha smooth muscle actin and desmin-containing cells and a spectrum of stromal elements including fibroblasts, myofibroblasts, and smooth muscle cells. Physiologic evaluation also demonstrated that 2-mo-old transgene (+) mice had increased airways resistance and non-specific airways hyperresponsiveness to methacholine when compared with their transgene (-) littermates. These studies demonstrate that the targeted expression of IL-11 in the mouse airway causes a B and T cell-predominant inflammatory response, airway remodeling with increased types III and I collagen, the local accumulation of fibroblasts, myofibroblasts, and myocytes, and obstructive physiologic dysregulation. IL-11 may play an important role in the inflammatory and fibrotic responses in viral and/or nonviral human airway disorders.     

Role of nitric oxide on cholinergic component of bronchial tone in pig

In vitro studies demonstrated that stimulation of intrinsic nerves of airway smooth muscle results in a predominantly contractile response, followed by a relaxant response which involves cholinergic, adrenergic and non-adrenergic non-cholinergic (NANC) nerve activation. Thus, in this paper it is determined whether endogenous nitric oxide (NO) modulates cholinergic neurotransmission in isolated pig airway smooth muscle. Bronchial rings were suspended in organ baths for isometric measurement of tension and the contractions were induced using electrical field stimulation (EFS) techniques. Then, the effects of L-NG-nitroarginine (L-NOARG, 10 microM), an inhibitor of NO synthase, and L-arginine (L-ARG, 1 mM), a precursor of NO synthesis, were evaluated. The cholinergic contractions induced by electrical field stimulation (EFS: 60 V, 2 ms, 60 Hz) of pig lobar bronchial preparations increased (29%) in the presence of L-NOARG (10 microM). This effect may be released by nerves in pig large airways during EFS.     

Inhibitory nerve distribution and mediation of NANC relaxation by nitric oxide in horse airways

The distribution of inhibitory nerves and the mediator of the inhibitory nonadrenergic noncholinergic (iN-ANC) nervous system were investigated in smooth muscle preparations from seven regions of equine airways. In tissues incubated with atropine and precontracted with histamine, electrical field stimulation produced frequency-dependent relaxation, and the magnitude of the relaxation decreased from trachea to central bronchi and was absent in peripheral airways. The degree of relaxation in bronchi was not simply a function of bronchial size or generation. Propranolol inhibited part of the relaxation only in the cranial trachealis. After propranolol, NG-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, eliminated the remaining relaxation in all preparations. This effect was reversed by L-arginine, the NO precursor, but not by D-arginine. Exogenous NO concentration dependently relaxed trachealis. These results indicate that: 1) adrenergic innervation is limited to cranial trachealis, 2) iNANC nerves supply the trachea and central bronchi, and 3) NO mediates iNANC function.     

Pharmacological characterization of the muscarinic receptor subtype mediating contraction of human peripheral airways

The postjunctional muscarinic receptors mediating contraction of human bronchial smooth muscle have been characterized using four nonselective muscarinic receptor agonists and eight subtype selective and nonselective muscarinic antagonists. Carbachol, methacholine, oxotremorine M and (+)-cis-dioxolane all caused concentration-related contractions of human bronchial smooth muscle with a rank order of potency (pD2) of (+)-cis-dioxolane (7.3 +/- 0.2) > oxotremorine M (6.7 +/- 0.2) > carbachol (6.4 +/- 0.1) > methacholine (5.8 +/- 0.2, n = 5 for all). Maximum contractions were not significantly different between agonists, whether expressed as absolute my tension changes or as a percentage of the maximum response to 0.3 mM histamine. Antagonist apparent affinities (pKB) were determined against carbachol-induced contractions and the following rank order was obtained; 4-DAMP (9.4 +/- 0.3) > or = atropine (9.1 +/- 0.1) > zamifenacin (7.6 +/- 0.1) > hexahydrosiladifenidol (HHSiD; 7.1 +/- 0.1) > or = himbacine (7.0 +/- 0.3) > or = pirenzepine (6.8 +/- 0.2) > para-fluoro-hexahydrosiladifenidol (p-F-HHSiD; 6.7 +/- 0.1) > methoctramine (5.3 +/- 0.2). This rank order of antagonist affinities is consistent with activation of M3 receptors. The affinities of HHSiD, p-F-HHSiD and zamifenacin were, however, lower than those reported in guinea pig trachea.     

Regulation of GLUT1 in response to cellular stress

We assessed the effect of smooth muscle contraction and relaxation on airway lumen subtended by the internal perimeter (Ai) and total cross-sectional area (Ao) of human bronchial explants in the absence of the potential lung tethering forces of alveolar tissue to test the hypothesis that bronchoconstriction results in a comparable change of Ai and Ao. Luminal area (i.e., Ai) and Ao were measured by using computerized videomicrometry, and bronchial wall area was calculated accordingly. Images on videotape were captured; areas were outlined, and data were expressed as internal pixel number by using imaging software. Bronchial rings were dissected in 1.0- to 1.5-mm sections from macroscopically unaffected areas of lungs from patients undergoing resection for carcinoma, placed in microplate wells containing buffered saline, and allowed to equilibrate for 1 h. Baseline, Ao [5.21 +/- 0.354 (SE) mm2], and Ai (0.604 +/- 0.057 mm2) were measured before contraction of the airway smooth muscle (ASM) with carbachol. Mean Ai narrowed by 0.257 +/- 0.052 mm2 in response to 10 microM carbachol (P = 0.001 vs. baseline). Similarly, Ao narrowed by 0.272 +/- 0.110 mm2 in response to carbachol (P = 0.038 vs. baseline; P = 0.849 vs. change in Ai). Similar parallel changes in cross-sectional area for Ai and Ao were observed for relaxation of ASM from inherent tone of other bronchial rings in response to 10 microM isoproterenol. We demonstrate a unique characteristic of human ASM; i.e., both luminal and total cross-sectional area of human airways change similarly on contraction and relaxation in vitro, resulting in a conservation of bronchiolar wall area with bronchoconstriction and dilation.     

Effects of load and tone on the mechanics of isolated human bronchial smooth muscle

Isotonic and isometric properties of nine human bronchial smooth muscles were studied under various loading and tone conditions. Freshly dissected bronchial strips were electrically stimulated successively at baseline, after precontraction with 10(-7) M methacholine (MCh), and after relaxation with 10(-5) M albuterol (Alb). Resting tension, i.e., preload determining optimal initial length (Lo) at baseline, was held constant. Compared with baseline, MCh decreased muscle length to 93 +/- 1% Lo (P < 0.001) before any electrical stimulation, whereas Alb increased it to 111 +/- 3% Lo (P < 0.01). MCh significantly decreased maximum unloaded shortening velocity (0.045 +/- 0.007 vs. 0.059 +/- 0.007 Lo/s), maximal extent of muscle shortening (8.4 +/- 1.2 vs. 13.9 +/- 2.4% Lo), and peak isometric tension (6.1 +/- 0.8 vs. 7.2 +/- 1.0 mN/mm2). Alb restored all these contractile indexes to baseline values. These findings suggest that MCh reversibly increased the number of active actomyosin cross bridges under resting conditions, limiting further muscle shortening and active tension development. After the electrically induced contraction, muscles showed a transient phase of decrease in tension below preload. This decrease in tension was unaffected by afterload levels but was significantly increased by MCh and reduced by Alb. These findings suggest that the cross bridges activated before, but not during, the electrically elicited contraction may modulate the phase of decrease in tension below preload, reflecting the active part of resting tension.     

Ageing is associated with reduced basal and stimulated release of nitric oxide by the coronary endothelium

Our previous studies have shown that heparin, a competitive inhibitor of inositol triphosphate receptors, inhibits airway anaphylaxis in vivo. In the present study, we tested the hypothesis that heparin blocks immunologically induced tracheal smooth muscle (TSM) contraction in vitro. TSM was obtained from sheep allergic to Ascaris suum antigen, and was suspended in an organ bath containing oxygenated (95% O2, 5% CO2) Krebs-Henseleit buffer at 39 degrees C. After an equilibration period, the tissues were treated with heparin dissolved in 10 microliters DMSO, at concentrations of 1, 10, or 100 U/ml (final concentration in the bath). Two types of controls were used: vehicle (10 microliters DMSO)-treated tissues and tissues treated with the anti-asthmatic nedocromil sodium (10(-5) M). After 30 min pretreatment, tissues were challenged with 10, 30 and 100 microliters of antigen. Contractions induced by antigen were expressed as percentage of the contraction elicited by the maximum effective concentration of acetylcholine (ACh, 10(-2) M). Antigen produced dose-dependent increases in tension, which were blocked by heparin and nedocromil sodium; maximal inhibition was 43 and 52%, respectively. Neither heparin nor nedocromil sodium affected the dose-response curve or the maximum response to Ach. The addition of the heparin preservative (benzyl alcohol) did not reverse ACh-induced contractions, or inhibit antigen-induced contractile responses. These results suggest that heparin blocks immunologically induced TSM contraction, without affecting the contractile response to the airway smooth muscle agonist, ACh. This action of heparin is similar to that of the anti-asthmatic nedocromil sodium and may be related to inhibition of mast cell mediator release.     

Certification and occupational health nursing. An historical perspective

BACKGROUND: The bronchodilator agent is an important drug for patients with chronic obstructive pulmonary disease. Methacholine is a popular bronchial provocative agent. Although the major acting site of bronchodilator, methacholine and upper respiratory tract infection (URI) has been evaluated in some studies, the sites are still in debate. This study investigated the exact major acting sites. METHODS: Thirty subjects participated in this study. Episodes of URI were identified by a questionnaire. Spirometry, bronchial provocative test with methacholine, and five minutes' inhalation of a mixture of helium and oxygen (HeO2) were done on day one. Spirometry, bronchodilator test, with five minutes' inhalation of HeO2 and expiratory flow-volume (F-V) curve were performed on another day. The change of pre- and post-HeO2 VEMax50 was calculated as delta VEMax50. The pre- and post-bronchodilator VEMax50 and delta VEMax50 differences were counted to decide the acting site of bronchodilator. After bronchial provocative test with methacholine, the volume of isoflow (VisoV) was estimated from pre- and post-HeO2 F-V curve to establish the acting site of methacholine. RESULTS: This study indicated that small airways are the major acting sites of bronchodilators, large airways are the major acting sites of methacholine and URI affects mainly large airways. Although airway hyperresponsiveness is more severe in subjects with positive methacholine response, the recovery of spirometry values is not significantly different between the methacholine-positive and -negative groups. CONCLUSIONS: The major acting sites of the bronchodilator, methacholine, and URI are the small, large and large airways, respectively. Bronchial hyperresponsiveness is not a cause of quick restoration of spirometry values in subjects with positive methacholine response.     

Distribution of SP- and CGRP-like immunoreactive nerve fibers in the lower respiratory tract of neonatal foals: evidence for loss during development

The lungs of neonatal foals contain many nerves immunoreactive for substance P and calcitonin gene-related peptide. These nerves are closely associated with the epithelium, bronchial and pulmonary vessels and the airway smooth muscle of all intrathoracic airways, including non-cartilaginous bronchioles. Activation of sensory nerves in the respiratory epithelium could thus potentially affect, via local axon reflexes, vascular and respiratory smooth muscle in neonatal equine airways. Nerves immunoreactive for these peptides are much more widely distributed within the lung than in adult horses; they may thus play a trophic role before birth, or contribute to the post-natal adaptation to breathing.     

The inhibition of yohimbine injected intrathecally on electroacupuncture-induced analgesia and release of beta-endorphin from rat brain

No study has investigated the effects of ethanol on bronchial responsiveness in patients with alcohol-induced asthma, although acetaldehyde, which is a metabolite of ethanol and is thought to be a main factor in alcohol-induced asthma, causes both bronchoconstriction and bronchial hyperresponsiveness. The purpose of this study was to investigate the direct action of ethanol on the airway in patients with alcohol-induced asthma. First, we investigated the bronchial response to inhalation of ascending doses (5, 10, and 20%) of ethanol in nine patients with alcohol-induced asthma. Then, the bronchial responsiveness to methacholine was measured in 14 patients who were pretreated with saline or 20% ethanol in a double-blind, randomized, placebo-controlled, crossover fashion. Ascending doses of inhaled ethanol caused no significant changes in FEV1. The methacholine concentrations producing a 20% fall in FEV1 (PC20-MCh) after 20% ethanol (0.769 mg/ml, GSEM 1.514) were significantly (P = 0.0357) higher than those after saline (0.493 mg/ml, GSEM 1.368). This indicates that ethanol has a reducing effect on nonspecific bronchial responsiveness in patients with alcohol-induced asthma; this paper is the first report on the effects of ethanol on bronchial responsiveness.     

Reflex bronchial vasodilation in dogs evoked by injection of a small volume of water into a bronchus

Injection of water into a lobar bronchus stimulates airway C-fibers and rapidly adapting receptors and evokes airway defense reflexes. To determine whether this stimulus also evokes a reflex increase in bronchial blood flow (Qbr), we injected 1-2 ml of water into a lobar bronchus in anesthetized dogs. Injection decreased arterial pressure but increased Qbr from 9 +/- 1 to 21 +/- 3 ml/min. The increase had a latency of 6-8 s and reached a peak after approximately 20 s; Qbr returned to control after 60-90 s. Airway mucosal blood flow, measured by colored microspheres, increased in proportion to Qbr. In contrast, flow in an adjacent intercostal artery that did not supply the airway decreased slightly. Injection of isosmotic saline had little effect. In 13 of 16 dogs, the water-induced increase in Qbr was abolished by cutting or cooling the cervical vagus nerves and hence was entirely dependent on centrally mediated vagal pathways. When the vagus nerves were intact, about one-third of the vasodilator response remained after pharmacological blockade of muscarinic and adrenergic receptors. We conclude that in dogs the defense response to water in the lower airways includes a large increase in Qbr that is partly due to activation of nonadrenergic noncholinergic autonomic pathways.