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PubMed1987

Substance P-inducing massive postmortem bronchoconstriction in guinea pig lungs.

To further examine the role that substance P plays in initiating the observed massive postmortem bronchoconstriction in guinea pig lungs and to explore the role of neural reflex in this airway spasm, six groups of animals were employed: control (n = 6), morphine (n = 6), substance P (n = 5), chronic capsaicin pretreatment + substance P (n = 5), tetrodotoxin (TTX) + acute capsaicin (n = 4), and chlorisondamine + acute capsaicin (n = 5). Pressure-volume curves were performed prior to and following the initiation of artificial pulmonary perfusion with 1% bovine serum albumin and 5% dextran in Tyrode's solution. A decrease in inflation volume (the lung volume between transpulmonary pressure of 0 and 30 cmH2O during inflation) was used as an index of bronchoconstriction. In control animals, inflation volume decreased to 20-30% of the base-line value at 15-30 min of perfusion, indicating massive bronchial constriction during this time period. Morphine (an agent inhibiting substance P release) significantly attenuated the spasm, whereas the presence of substance P in the perfusate markedly enhanced the constriction. Depletion of endogenous substance P by chronic capsaicin pretreatment did not affect exogenous substance P-induced spasm. Acute capsaicin-induced bronchoconstriction was significantly attenuated by TTX but was not affected by the ganglionic blocking agent, chlorisondamine. These data suggest that substance P initiates the massive postmortem bronchoconstriction in guinea pig lungs and that substance P is released by local stimulation of sensory nerve endings via axonal reflex.

Animals↗

PubMed1988

Effects of lung volume, bronchoconstriction, and cigarette smoke on morphometric airway dimensions.

To examine the role of airway wall thickening in the bronchial hyperresponsiveness observed after exposure to cigarette smoke, we compared the airway dimensions of guinea pigs exposed to smoke (n = 7) or air (n = 7). After exposure the animals were anesthetized with urethan, pulmonary resistance was measured, and the lungs were removed, distended with Formalin, and fixed near functional residual capacity. The effects of lung inflation and bronchoconstriction on airway dimensions were studied separately by distending and fixing lungs with Formalin at total lung capacity (TLC) (n = 3), 50% TLC (n = 3), and 25% TLC (n = 3) or near residual volume after bronchoconstriction (n = 3). On transverse sections of extraparenchymal and intraparenchymal airways the following dimensions were measured: the internal area (Ai) and internal perimeter (Pi), defined by the epithelium, and the external area (Ae) and external perimeter (Pe), defined by the outer border of smooth muscle. Airway wall area (WA) was then calculated, WA = Ae - Ai. Ai, Pe, and Ae decreased with decreasing lung volume and after bronchoconstriction. However, WA and Pi did not change significantly with lung volume or after bronchoconstriction. After cigarette smoke exposure airway resistance was increased (P less than 0.05); however, there was no difference in WA between the smoke- and air-exposed groups when the airways were matched by Pi. We conclude that Pi and WA are constant despite changes in lung volume and smooth muscle tone and that airway hyperresponsiveness induced by cigarette smoke is not mediated by increased airway wall thickness.

Airway Resistance↗

PubMed1989

Influence of body temperature on histamine-induced bronchoconstriction in guinea pigs.

The effects of body temperature on histamine-induced bronchoconstriction were investigated in anesthetized, paralyzed, and mechanically ventilated guinea pigs. Four groups of guinea pigs were studied with constant body temperatures of 40, 38, 35, and 32 degrees C, respectively. Histamine was infused for 5 min at a rate of 50 ng.kg-1.s-1. Body cooling from 40 to 32 degrees C augmented the bronchomotor responses to histamine, which eventually rose almost fourfold. The enhancement of histamine-induced bronchoconstriction induced by body cooling was not suppressed by pretreating guinea pigs with 5 mg/kg hexamethonium or 5 mg/kg hexamethonium plus 3 mg/kg atropine; neither was the enhancement of histamine-induced bronchoconstriction suppressed in pithed guinea pigs, demonstrating that the autonomic nervous system is not involved in potentiating bronchoconstriction at low body temperatures. These results suggest that, at low body temperatures, increased airway responsiveness to histamine may be because of some direct effect of temperature on bronchial airway smooth muscle.

Animals↗

PubMed1989

Effect of magnesium sulfate on bronchoconstriction in the lung periphery.

Magnesium sulfate has been shown to be effective clinically as a bronchodilator, but its mechanism of action is unknown. We used a wedged bronchoscope technique to study the ability of MgSO4 at clinically relevant concentrations to attenuate hypocapnia-, acetylcholine- (ACh), and dry air-induced bronchoconstriction in the canine lung periphery. Control experiments demonstrated that consecutive challenges of either hypocapnia or ACh resulted in greater collateral system resistance (Rcs) after the second challenge compared with the first. Intravenous infusion of MgSO4 diminished the maximum response to a second hypocapnic challenge (Rcs = 1.59 +/- 0.29 cmH2O.ml-1.s prechallenge vs. 1.12 +/- 0.20 postchallenge) but had no effect on either ACh- or dry air-induced bronchoconstriction. Serum magnesium levels before MgSO4 administration were 1.59 +/- 0.04 meq/l and rose to 6.20 +/- 0.13 during the infusion. Previous studies demonstrated that nifedipine, like MgSO4 in this study, attenuates hypocapnia-induced bronchoconstriction in the canine lung periphery but has no effect on ACh- or dry air-induced bronchoconstriction. We conclude that these results are consistent with the idea that, like nifedipine, magnesium acts in the airway as a voltage-sensitive calcium channel blocker.

Acetylcholine↗

PubMed1989

A muscarinic agonist inhibits reflex bronchoconstriction in normal but not in asthmatic subjects.

Muscarinic receptors of the M2 subtype, which inhibit acetylcholine release from cholinergic nerves (autoreceptors), have been described in animal and human bronchi in vitro. We investigated whether these receptors may be involved in feedback inhibition of cholinergic reflex bronchoconstriction induced by sulfur dioxide (SO2) in seven nonasthmatic atopic subjects and in six mild asthmatic subjects. In a control experiment, total respiratory resistance (Rrs) was increased by 30 +/- 5% in nonasthmatic and by 60 +/- 18% in asthmatic subjects. In nonasthmatic subjects, pilocarpine, an agonist of muscarinic M2-autoreceptors, increased Rrs by 15 +/- 5% and addition of SO2 increased Rrs to 21 +/- 5% above base line, which was not significantly greater than after pilocarpine alone. Histamine gave a comparable bronchoconstriction (25 +/- 3% increase in Rrs) and SO2 further increased Rrs to 39 +/- 6% above base line (P less than 0.05). Thus pilocarpine appears to inhibit SO2-induced bronchoconstriction in nonasthmatic subjects, and this effect is not explained by an increase in airway tone. In asthmatic subjects, pretreatment with pilocarpine increased Rrs by 31 +/- 8% and SO2 further increased Rrs to 88 +/- 17% above base line. SO2 alone gave a 60 +/- 18% increase in Rrs. Our results suggest that feedback inhibitory muscarinic receptors may be present on cholinergic nerves in normal airways and that there may be a dysfunction of this feedback mechanism in asthmatic airways. This might be contributory to exaggerated cholinergic reflex bronchoconstriction in asthma.

Adult↗

PubMed1993

Neutral endopeptidase inhibitor potentiates allergic bronchoconstriction in guinea pigs in vivo.

To determine whether endogenous tachykinins are released in allergic airway response to contribute to bronchoconstriction and whether neutral endopeptidase (NEP), which effectively cleaves tachykinins, modulates that bronchoconstriction, we studied the effects of the NEP inhibitor phosphoramidon on bronchoconstriction induced by allergic response in anesthetized guinea pigs. We mechanically ventilated the guinea pigs sensitized with ovalbumin (OVA) in a bodyplethysmograph and measured the pulmonary resistance (RL). We exposed the sensitized guinea pigs to doubling concentrations of OVA aerosols from 2(-5)% (wt/vol) until the transpulmonary pressure increased more than twofold from the baseline. After the final exposure, we exposed them to phosphoramidon (10(-4) M) or its vehicle. Phosphoramidon significantly potentiated the increased RL induced by OVA challenge. Phosphoramidon also significantly potentiated the increased RL in the guinea pigs treated with atropine, but the potentiation was significantly reduced. In contrast, phosphoramidon failed to potentiate the increased RL induced by OVA in guinea pigs pretreated with capsaicin. These results suggest that 1) endogenous tachykinin-like substances are released in allergic airway response and that 2) when endogenous NEP is inhibited in the guinea pig airways in vivo, the substances contribute to bronchoconstriction by partly activating the parasympathetic nerve.

Airway Resistance↗

PubMed1980

Effect of RMI 81968, a combined alpha- and beta-adrenergic receptor blocking agent, on histamine-induced bronchoconstriction in the dog.

The interaction of propranolol and RMI 81968 on histamine-induced bronchoconstriction was studied in the anesthetized dog using the respiratory overflow technique of Konzett and Rössler. Propranolol, 3 and 10 mumol/kg i.v., enhanced histamine-induced bronchoconstriction. In contrast, RMI 81968, at 10 or 30 mumol/kg i.v., had no effect in this test. It is believed that the alpha-receptor blocking component of RMI 81968 prevents the bronchoconstriction induced by beta-adrenergic receptor blockade. The results of this study suggest that RMI 81968 is less likely than propranolol to produce bronchoconstriction in asthmatic patients.

Adrenergic alpha-Antagonists↗

PubMed1979

The role of upper airways in antigen-induced bronchoconstriction.

The bronchoconstrictor effect of antigen was tested in 15 dogs. The upper and the lower airways were sequently exposed through a specially confected endotracheal tube. The antigen was also generally administered through a mouth mask. Bronchoconstriction was induced after each kind of exposure. The results argue for reflex bronchoconstriction. The sensory receptors localized in the upper part of the airways are responsible for about 50% of antigen-induced bronchoconstriction. The decrease of PO2a was less marked following Ascaris suum extract aerosol administration to the upper part of the airways. Control measurements demonstrated the reproducibility of antigen-induced bronchoconstriction.

Aerosols↗

PubMed1984

Influence of a minimal surgical transection around the trachea on bronchoconstriction in cats.

The influence of a minimal surgical transection around the trachea on ACH- and allergen-induced bronchoconstriction was studied in a series of 21 cats. A significant smaller bronchoconstriction was observed after surgical transection around the trachea. The trachea isolation itself induced a smaller nonsignificant bronchoconstrictive response. This diminished response of the airways after this surgical intervention assumes an interruption of syncytial connections, which alters the response to bronchoconstricting stimuli of the whole bronchial system. The exact role of these syncytial connections has yet to be clarified.

Acetylcholine↗

PubMed1988

C5a-induced bronchoconstriction: absence of a role of circulating white blood cells and platelets.

C5a causes an intense bronchoconstriction when injected intravenously into the guinea pig. The present study was designed to determine if circulating white blood cells or platelets were important target cells for the induction of bronchoconstriction on intravenous injection of C5a. To accomplish this, we examined the effect of C5a on numbers of circulating cells as well as the effect of depletion of various circulating cell populations on C5a-induced bronchoconstriction. Intravenous injection of C5a caused a precipitous drop in circulating granulocytes which preceded the maximum bronchoconstrictor response. The levels of circulating platelets and mononuclear cells were unchanged by intravenous injection of C5a. Depletion of either white blood cells or platelets did not significantly alter either the maximum bronchoconstrictor response to C5a or the time course of the response. Thus, these studies suggest that C5a-induced bronchoconstriction in the guinea pig is not dependent on an interaction of C5a with circulating white blood cells or platelets.

Airway Resistance↗

PubMed1987

The contribution of histamine to immediate bronchoconstriction provoked by inhaled allergen and adenosine 5' monophosphate in atopic asthma.

In order to investigate the contribution of histamine to bronchoconstriction provoked by inhaled allergen and adenosine monophosphate (AMP), we have observed the effects of prior treatment with the potent H1-receptor antagonists, terfenadine and astemizole. Nine mild, atopic asthmatics underwent inhalation challenge tests on 6 separate days with histamine, allergen extract, and AMP using single concentrations previously shown to produce a 30% fall in FEV1. For each agonist, bronchoprovocation was performed 3 h after treatment with either terfenadine 180 mg or matched placebo, and airway caliber assessed by measurement of FEV1 over a period of 45 min. AMP challenge was also performed after prior treatment with astemizole. After placebo, histamine produced rapid bronchoconstriction, reaching a maximum within 5 min and returning to within 10% of baseline at 25 min. Pretreatment with terfenadine abolished the bronchoconstrictor response to histamine completely. In contrast, bronchoconstriction provoked by allergen after placebo was slower in onset and sustained during the 45 min of observation. Terfenadine only partially inhibited this response to allergen by 50 +/- 10% (mean +/- SEM) with the maximal effect being observed within the first 5 to 8 min of challenge. AMP inhalation provoked rapid bronchoconstriction similar in time course to that of histamine, and this reaction was inhibited by 86 +/- 8.1% by terfenadine. Astemizole produced inhibition of the response to AMP that was almost identical to that of terfenadine. On the basis of in vitro studies, we interpret these differential effects of terfenadine as reflecting the contribution of histamine to the various airway challenges.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Monophosphate↗

PubMed1987

An animal model for adenosine-induced bronchoconstriction.

The inhalation of adenosine is known to cause bronchoconstriction in asthmatic patients. A thorough study of the possible role of this purine nucleoside in the pathogenesis of asthma has been hampered by the lack of a suitable animal model. We have studied the bronchial effects of adenosine in an in vivo rat model. The intravenous injection of 0.1 to 10 micromoles/kg body weight of adenosine causes in BDE-rats an increase in lung resistance and decrease in dynamic compliance. Study of the potency of various adenosine analogs suggests that the bronchial adenosine receptor belongs to the A2-type. The bronchoconstriction caused by adenosine is inhibited by atropine, methysergide, sodium cromoglycate, nedocromil sodium, and ketotifen. Xanthines in doses of 5 and 15 mg/kg body weight have no significant effect on the adenosine-induced bronchoconstriction. These results suggest that adenosine causes bronchoconstriction by stimulating postsynaptic vagal nerve endings and mast cells.

Adenosine↗

PubMed1987

The roles of pH and ionic species in sulfur dioxide- and sulfite-induced bronchoconstriction.

Sulfur dioxide (SO2) and sulfites are well-described causes of bronchoconstriction in persons with asthma that are chemically related and, therefore, may share a common mechanism of action. When either sulfur species dissolves in aqueous solutions, a pH-dependent equilibrium is established predominantly among bisulfite ion (HSO3-), sulfite ion (SO3=), and SO2. In addition, hydrogen ions may be released. To assess the relative bronchoconstricting potencies of these chemical forms and the role of acidity caused by the release of hydrogen ions in SO2- and sulfite-induced bronchoconstriction, we administered to 10 asthmatic subjects nebulized sodium sulfite (Na2SO3) solutions at pH 9 containing 95% sulfite, at pH 6.6 containing 80% bisulfite, and at pH 4 containing 99% bisulfite but greater than an order of magnitude more SO2 than the pH 6.6 solutions. Subjects inhaled increasing concentrations of aerosolized Na2SO3 at each pH during 1 min of tidal breathing. Subjects also breathed buffered acetic acid aerosols with the same acidity of the pH 4 Na2SO3 solutions to control for the airway effects of acid aerosols. To assess sensitivity to SO2 gas, subjects inhaled increasing concentrations of SO2 during eucapneic hyperpnea. Bronchoconstrictor response was assessed by measuring specific airway resistance (SRaw) before and after each challenge. Nine of the 10 subjects developed bronchoconstriction after inhaling the Na2SO3 aerosols at all 3 levels of pH and the SO2 gas. The mean concentration of Na2SO3 solution calculated to increase SRaw by 100% above baseline was significantly different (p less than 0.01) at the various levels of pH: pH 4 (0.17 mg/ml) less than pH 6.6 (0.49 mg/ml) less than pH 9 (2.10 mg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1988

Inhibition of methacholine-induced bronchoconstriction in patients with chronic obstructive pulmonary disease.

Patients with COPD have increased airway responsiveness to pharmacologically induced bronchoconstriction when compared with normal healthy subjects. We questioned whether an inhaled bronchodilator such as isoproterenol would benefit patients with COPD by inhibiting inducible bronchoconstriction. Ten patients with COPD were found to be more sensitive to methacholine by inhalation bronchial challenge testing than were normal control subjects. (PD35 = 58 +/- 110 versus 238 +/- 220 cumulative dose units). Neither group as a whole demonstrated significant inhibition of methacholine-induced bronchoconstriction by prior inhalation of isoproterenol (200 micrograms at mouth). However, within the COPD group, there was a significant negative correlation between both baseline lung function and airway responsiveness (PD35-SGaw) with inhibition of methacholine-induced bronchoconstriction. (r = -0.8, p less than or equal to 0.003). This suggests that those patients with COPD and significantly reduced lung function (%FEV1 less than 50%) demonstrate airway hyperresponsiveness to a degree recorded in asthma and may benefit from therapy that inhibits airway responsiveness.

Aerosols↗

PubMed1988

Mechanism of platelet activating factor-induced bronchoconstriction in humans.

The inhalation of platelet activating factor (PAF) produces bronchoconstriction in normal and asthmatic subjects. To identify the mechanism by which PAF-induced bronchoconstriction occurs in humans, bronchoprovocation testing was performed in 7 subjects (3 normal, 4 with mild asthma) after pretreatment with phosphate-buffered saline (PBS), atropine, chlorpheniramine, or indomethacin. We determined the nebulizer concentration of PAF which reduced specific airway conductance (SGaw) 35% (PC35 SGaw) and the slope of the PAF dose-response curve. Atropine produced baseline bronchodilatation (SGaw increased 50%), while chlorpheniramine and indomethacin had no effect on baseline pulmonary function. Atropine increased airway responsiveness to PAF: the PC35 SGaw decreased 40% (p less than 0.05) and the slope of the PAF dose-response curve increased 86% (p less than 0.05). In contrast, chlorpheniramine inhibited the airway response to PAF: the PC35 SGaw increased 87% (p less than 0.05), while the slope of the PAF dose-response curve decreased an insignificant 37%. Indomethacin did not affect either measurement. Chlorpheniramine also prevented the PAF-induced facial flushing and feeling of warmth; atropine and indomethacin did not. These results suggest that PAF-induced bronchoconstriction in humans is mediated at least in part by histamine release, not by cholinergic or cyclooxygenase-dependent mechanisms. Other indirect effects, such as the release of sulfidopeptide leukotrienes, or a direct effect on airway smooth muscle may also contribute to PAF-induced bronchoconstriction. Why atropine heightened the airway response to PAF is unclear.

Adolescent↗

PubMed1988

The mechanism of tachykinin-induced bronchoconstriction in the rat.

The mammalian tachykinins substance P (SP) and neurokinin A (NKA) are known to be present in sensory airway nerves of animals and humans. We studied the effect of mammalian and nonmammalian tachykinins on the conducting airways of anesthetized, mechanically ventilated Fisher 344 rats. Dose-dependent increases in lung resistance and decreases in dynamic compliance occurred after the intravenous administration of eledoisin (E), kassinin (K), NKA, and SP. E, K, and NKA were more potent bronchoconstrictors than was SP. Neurokinin B (NKB) caused a similar decrease in dynamic compliance, but had no effect on lung resistance. This order of potency suggests a predominance of NK-2 receptors in the rat airways. Both atropine and the 5-hydroxytryptamine antagonist methysergide largely reduced the bronchoconstriction induced by E and SP. Vagotomy did not change this reaction, whereas pretreatment with the ganglion blocker hexamethonium slightly enhanced the bronchoconstrictor action of E and SP. Sodium cromoglycate and nedocromil sodium, 2 drugs that can inhibit mediator release from inflammatory cells, significantly reduced the bronchoconstrictor action of NKA. Ketotifen, an antihistamine with mast-cell-stabilizing properties, significantly reduced the bronchoconstriction induced by E, whereas the H1-receptor antagonist clemastine had no effect. We conclude that tachykinins cause bronchoconstriction in rats largely by an indirect mechanism, involving both acetylcholine and 5-hydroxytryptamine. We suggest that tachykinins cause bronchoconstriction by stimulation of postganglionic vagal nerve endings and mast cells.

Airway Resistance↗

PubMed1989

The role of pirenzepine-sensitive (M1) muscarinic receptors in vagally mediated bronchoconstriction in humans.

In a double-blind randomized study, we compared the effects of the M1-selective muscarinic receptor antagonists pirenzepine and the nonselective antagonist ipratropium bromide on bronchoconstriction induced by inhaled sulfur dioxide (SO2) and methacholine in atopic volunteers. Both inhaled pirenzepine (70 micrograms) and ipratropium bromide (7 micrograms) significantly inhibited vagally mediated bronchoconstriction by SO2 to the same extent (p less than 0.02). However, at this dose, pirenzepine had no effect on methacholine-induced bronchoconstriction, whereas ipratropium bromide gave significant protection (p less than 0.02). This indicates that vagally mediated bronchoconstriction in humans can be inhibited by blockade of pirenzepine-sensitive (M1) muscarinic receptors probably present on a different site from muscarinic receptors at the neuromuscular junction and presumably localized to parasympathetic ganglia. Pirenzepine may be useful in investigating ganglionic function and could be beneficial therapeutically in airway disease.

Administration, Inhalation↗

PubMed1989

Effect of a leukotriene antagonist, LY171883, on cold air-induced bronchoconstriction in asthmatics.

Isocapnic hyperpnea (ISH) of cold air induces bronchoconstriction in many asthmatic subjects. Although this response is well described, it is unclear whether this bronchoconstriction is related to the release of bronchoactive mediators. We examined whether pretreatment with LY171883, a competitive antagonist of leukotriene D4 activity via LTD4 receptors, reduced the bronchospastic response to cold air ISH in asthmatics using a randomized, double-blind, two-phase crossover design. In 20 subjects, 2 wk of treatment with either LY171883 600 mg twice a day or placebo did not result in a change in FEV1 (3.45 +/- 0.21 L placebo versus 3.59 +/- 0.20 L LY171883; p greater than 0.05). Nineteen subjects underwent cold-air ISH; LY171883 increased the geometric mean respiratory heat loss required to reduce the FEV1 by 20% (PD20RHE) from 1.00 kcal/min with placebo to 1.24 kcal/min with LY171883 (p less than 0.05). A similar difference was noted when responses were expressed as a function of minute ventilation. LY171883 produced greater shifts in the PD20RHE in more reactive subjects (r = 0.69, p less than 0.002). Among 11 different symptom scores recorded by 18 subjects, there was a significant decrease in daytime chest tightness with LY171883 (p less than 0.03). The increase in PD20RHE while the subjects received LY171883 is consistent with the hypothesis that LTD4 becomes available during cold-air ISH and may mediate bronchoconstriction. The small magnitude of the effect on the PD20RHE may be due to the role of other mediators in cold-air-induced bronchoconstriction or, alternatively, to an inadequate blockade of LTD4 effects.

Acetophenones↗