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PubMed1983

Bronchoconstriction: upper airway dilating muscle and diaphragm activity.

The effect of bronchoconstriction on the activity of the diaphragm and the upper dilating airway muscles were studied by administering graded doses of methacholine to anesthetized dogs spontaneously breathing oxygen. The electrical activity of the genioglossus, posterior cricoarytenoid, and alae nasi was compared with that of the diaphragm at different levels of pulmonary resistance. Induced bronchoconstriction was associated with increases in the electrical activity of all muscles examined. Bilateral cervical vagotomy diminished but did not prevent the bronchoconstrictor effects of methacholine. When greater concentrations of methacholine were administered to produce bronchoconstriction comparable with that produced prevagotomy, both genioglossus and diaphragm activity increased. This study indicates that the upper airway muscles and the diaphragm respond to bronchoconstriction. The activation of the upper airway muscles with bronchoconstriction may decrease upper airway resistance serving to partially offset increases in pulmonary resistance and to modulate airflow patterns during bronchoconstriction.

Airway Resistance↗

PubMed1988

Afferent neural pathways in cough and reflex bronchoconstriction.

Cough and bronchoconstriction are airway reflexes that protect the lung from inspired noxious agents. These two reflexes can be evoked both from the larynx and tracheobronchial tree and also from some extrarespiratory sites. Within the airways, certain sites are particularly sensitive to stimulation of cough (larynx and points of proximal airway branching), whereas bronchoconstriction can be triggered from the whole of the tracheobronchial tree. In the larynx, "irritant" receptors with myelinated afferents mediate cough and bronchoconstriction. Little seems to be known about laryngeal nonmyelinated afferents and their reflexes. In the tracheobronchial tree and lung, slowly adapting stretch receptors (SARs) and rapidly adapting stretch receptors (RARs) have opposing effects on airway tone, the former mediating bronchodilation and the latter bronchoconstriction. In cough, on the other hand, they operate concurrently, a mediatory role for RARs and a facilitatory role for SARs. C-fiber endings (bronchial and pulmonary) mediate bronchoconstriction. Inhalation of so-called "selective" C-fiber stimulants induces cough, but excitation of RARs has not been eliminated, and the possibility also exists that the cough is secondary to other lung actions mediated by these nerve endings. Although cough and bronchoconstriction may be mediated by the same type of receptor, they seem to have separate afferent neural pathways.

Afferent Pathways↗

PubMedDate not supplied

Low incidence of paradoxical bronchoconstriction with bronchodilator drugs administered by Respimat Soft Mist inhaler: results of phase II single-dose crossover studies.

BACKGROUND AND OBJECTIVES: Respimat Soft Mist Inhaler (SMI) is an innovative device that offers improved lung deposition and is an environmentally friendly alternative to conventional, chlorofluorocarbon-containing metered-dose inhalers (CFC-MDIs). The aqueous formulations of bronchodilator drugs administered from Respimat SMI contain low concentrations of ethylene diamine tetra-acetic acid (EDTA), a stabilising agent, and benzalkonium chloride (BAC), an antibacterial agent, both of which have been associated with bronchoconstriction when administered via nebulisers. The aim of this retrospective analysis was to compare the incidence of paradoxical bronchoconstriction with bronchodilator drugs administered via Respimat SMI or a CFC-MDI in patients with asthma or chronic obstructive pulmonary disease (COPD). METHODS: Nine randomised, active- and/or placebo-controlled, double-blind, crossover studies, in which asthmatic and COPD patients (n = 444 and n = 216, respectively) received a beta(2)-agonist and/or anticholinergic or placebo via Respimat SMI or CFC-MDI, were included in the analysis. The incidence of conditions indicative of paradoxical bronchoconstriction were collated and divided into four categories: (1) 'bronchospasm'; (2) two or more of the following events: 'other respiratory adverse events', 'rescue medication use' or 'asymptomatic drop in forced expiratory volume in one second' (FEV(1)); (3) either 'rescue medication use' or 'other respiratory adverse event'; (4) 'asymptomatic drop in FEV(1)'. RESULTS: The incidence of adverse events indicative of paradoxical bronchoconstriction was low in those patients using the Respimat SMI device, and similar to that seen in the CFC-MDI group. In addition, the incidence of adverse events indicative of paradoxical bronchoconstriction observed in the Respimat SMI group was similar for BAC + EDTA and BAC-only drug formulations. CONCLUSIONS: These studies demonstrate that, due to the extremely low absolute amounts of BAC and EDTA delivered to the lungs by the device, Respimat SMI is safe with regard to paradoxical bronchoconstriction in patients with asthma or COPD.

Adrenergic beta-Agonists↗

PubMed1990

Enhancement of antigen-induced bronchoconstriction in the guinea pig after intravascular complement activation with cobra venom factor.

The purpose of the present studies was to begin to test the hypothesis that the complement system is important for antigen-induced bronchoconstriction in the guinea pig. The effect of the complement-depleting agent cobra venom factor (CVF) on antigen-induced bronchoconstriction in guinea pigs passively sensitized with IgG or IgE antibody to ovalbumin was determined. Intravenous injection of CVF significantly reduced total hemolytic complement activity (CH50), caused a transient decrease in dynamic lung compliance, an increase in pulmonary resistance, and a decrease in circulating white blood cells with a sustained decrease in platelets. Antigen-induced bronchoconstriction was not inhibited in either IgG- or IgE-sensitized guinea pigs depleted of complement. Thus, a role for the complement system as a contributing factor in antigen-induced bronchoconstriction was not supported. On the contrary, our studies revealed an enhanced antigen-induced bronchoconstriction in guinea pigs depleted of complement with CVF. Our studies were then directed towards characterizing the enhanced response to begin to determine the mechanism responsible. The enhanced antigen-induced bronchoconstriction occurred in both IgG- and IgE-sensitized guinea pigs and was most apparent at lower antigen doses. The enhanced response still occurred in animals treated for 5 min with a dose of CVF (10 U) which caused no demonstrable decrease in CH50, a 30% level of conversion of C3, and a normal response to C5a. These data suggested that the enhanced response was not related to the level of C5a responsiveness of the animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗

PubMed1976

Effect of helium on maximal expiratory flow in patients with asthma before and during induced bronchoconstriction.

The effect of breathing helium on maximal expiratory flow at 50 per cent of vital capacity (V50) was studied in 27 patients with asthma during remission and during induced bronchoconstriction. Nine patients gave a history of asthma induced by exercise; two had asthma due to timothy pollen allergy, and the remaining 16 had asthma due to exposure to western red cedar. Bronchoconstriction was induced by exercise in 10 patients, timothy pollen in 4 patients, methacholine in 4 patients, and red cedar in 16 patients. During remission, the increase in V50 with helium (deltaV50He) was greater than 20 per cent in 22 patients who were classified as responders; deltaV50He was less than 20 per cent in the remaining 5 patients, who were classified as nonresponders. There was a significant correlation between the severity of airway obstruction as measured by V50 and the response to helium, both during remission and during induced bronchoconstriction; however, there was no correlation between helium response and specific airway conductance. In general, patients who were responders during remission remained responders during induced bronchoconstriction, and nonresponders remained nonresponders, regardless of the method of challenge or the type of reaction (immediate verus late). There were a few exceptions in which a responder became a nonresponder during severe bronchoconstriction. The results of this study suggest that in most patients with asthma, the site of airway obstruction is likely to be in the large airways and, in most cases, remains constant in an individual asthmatic; however, an asthmatic who is a helium responder may become a nonresponder during severe bronchoconstriction.

Adult↗

PubMed1983

Effect of exercise rate and route of inhalation on sulfur-dioxide-induced bronchoconstriction in asthmatic subjects.

Nine asthmatic subjects exercised at low, moderate, and high work rates on a cycle ergometer while breathing filtered, humidified air with or without 0.5 ppm of sulfur dioxide (SO2) in a double-blind study. Subjects first performed these experiments breathing through a mouthpiece while wearing a noseclip (oral breathing) and then repeated the experiments breathing through a facemask that separated and permitted independent measurement of oral and nasal air flow (oronasal breathing). We determined specific airway resistance before and after exercise by body plethysmography. Inhaled by mouthpiece, 0.5 ppm So2 caused bronchoconstriction at moderate and high but not at low work rates. There was a dose-response relationship between the work rate performed and the degree of bronchoconstriction induced. Inhaled oronasally, 0.5 ppm SO2 caused bronchoconstriction only at the high work rate. These findings demonstrate that So2-induced bronchoconstriction is dependent on the work rate of exercise during exposure, that oronasal breathing is only partially effective in preventing the bronchoconstriction observed with oral breathing, and that oronasal breathing is less effective in preventing bronchoconstriction with high than with moderate exercise at this concentration of SO2.

Adult↗

PubMed2001

Changes in FVC during methacholine-induced bronchoconstriction in elderly patients with asthma: bronchial hyperresponsiveness and aging.

STUDY OBJECTIVE: We evaluated whether aging may produce changes in bronchial hyperresponsiveness, risk of enhanced bronchoconstriction, and changes of bronchoconstriction perception. SETTING: Each subject underwent a methacholine bronchial challenge. Methacholine challenge was stopped when one of the following conditions occurred: (1) plateau of bronchoconstriction; (2) decrease of FEV(1) > 40%; (3) FEV(1) drop below 1 L; or (4) excessive respiratory discomfort. Methacholine dose-response curves were plotted both for FVC and FEV(1). The provocative dose of methacholine causing a 20% decrease in FEV(1) with respect to baseline (PD(20)) and the fall in FVC (DeltaFVC) at PD(20) were computed. The Borg scale was used for scoring the perception of respiratory discomfort. PATIENTS: We compared 17 young asthmatic patients (aged 22 to 45 years) with 17 older asthmatic patients (aged 63 to 78 years) selected on the basis of similar baseline pulmonary function and disease duration. RESULTS: No significant between-group difference was found in PD(20) and in plateau development. Conversely, DeltaFVC was significantly higher in the older group (mean +/- SD, 15.5 +/- 3.9% vs 11.6 +/- 5.5% in younger patients). In addition, DeltaFVC showed a positive linear relationship with age (p = 0.0026). Elderly subjects were less aware of bronchoconstriction during the methacholine challenge (p = 0.04). CONCLUSIONS: In elderly patients with asthma having comparable pulmonary function and disease duration, bronchial responsiveness is not different from that observed in younger asthmatic patients. Nevertheless, in such patients, an age-related tendency to an enhanced bronchoconstriction and a reduced perception of the degree of bronchoconstriction exist.

Adult↗

PubMed1988

Role of arachidonate metabolites in C5a-induced bronchoconstriction.

The complement cleavage product, C5a, causes a bronchoconstriction in the guinea pig as evidenced by a decrease in dynamic lung compliance and an increase in pulmonary resistance. Previous studies had demonstrated that the antihistamine pyrilamine and the cyclooxygenase inhibitor indomethacin inhibited the C5a-induced bronchoconstriction but the leukotriene (LT)D4 antagonist L-649,923 did not. As an extension of those studies, the purpose of the present study was to determine the contribution of specific cyclooxygenase products and/or LTB4 in mediating C5a-induced bronchoconstriction. To assess the role of the various potential mediators, plasma levels of thromboxane (TX)B2, prostaglandin (PG)D2 and PGF2 alpha were monitored. In addition, guinea pigs were treated either with the TX synthetase inhibitor U-63557A, treated with the TX receptor antagonist SQ 29,548 or made tachyphylactic to the bronchoconstrictor actions of LTB4. C5a challenge caused an increase in plasma concentrations of TXB2, which peaked before the maximum of the bronchoconstriction. However, no significant increase in plasma concentrations of PGD2 or PGF2 alpha was seen. Both U-63557A at 80 mg/kg and SQ 29,548 significantly inhibited the C5a-induced bronchoconstriction, whereas 10 mg/kg of U-63557A did not. The inability of 10 mg/kg of U-63557A to inhibit the response could be explained by both incomplete inhibition of TX synthesis as well as possibly by the increased plasma concentrations of the potent bronchoconstrictor PGD2, which occurred with C5a challenge in the presence of U-63557A. In animals tachyphylactic to LTB4, the maximum of the C5a-induced bronchoconstriction was no different from control.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗

PubMed1984

Alteration in osmolarity of inhaled aerosols cause bronchoconstriction and cough, but absence of a permeant anion causes cough alone.

To determine whether cough and bronchoconstriction result from alterations in the osmolarity or alterations in the ion concentration of inhaled aerosols and to determine if the specific ions in the aerosol are important, we had 9 subjects with mild asthma inhale various solutions while we recorded cough and measured specific airway resistance. To evaluate the effects of altering osmolarity and ion concentration separately, we administered aerosols of hypo-osmolar distilled water (0 mosm), iso-osmolar sodium chloride (308 mosm), iso-osmolar dextrose in water (308 mosm), hyperosmolar sodium chloride (1,232 mosm), and a hyperosmolar solution of dextrose and sodium chloride (1,232 mosm). To evaluate cough without bronchoconstriction, we had the subjects inhale metaproterenol before inhaling the same aerosols. To determine whether the absence of a specific ion was important in causing cough or bronchoconstriction, we had the subjects inhale iso-osmolar solutions of sodium bromide, sodium gluconate, and lysine monohydrochloride. We found that alteration in osmolarity away from iso-osmolarity of inhaled aerosols is a stimulus for bronchoconstriction in subjects with mild asthma. Absence of ions in the presence of iso-osmolarity is not a stimulus for bronchoconstriction, but the absence of a permeant anion is a stimulus for cough. Thus, we found that the responses of cough and bronchoconstriction to inhaled aerosols can be separated.

Adult↗

PubMed1982

[Role of vagus nerves in bronchoconstriction induced by chemical mediators].

The role of the vagal reflex in bronchoconstriction induced by histamine, acetylcholine, serotonin, and PGF2 alpha was investigated in anesthetized dogs using a complete vagal blockade by cooling. We devised a thermode for vagal cooling. The vagal cooling was performed by circulating cold water through the thermode attached to fit snugly around the bilateral cervical vagus nerves. Airway musculature response was measured as a change in ventilation overflow with a modification of the Konzett-Rössler method. Drugs were injected close intraarterially into the right bronchial artery and inhaled into the airway. Afferent impulses of the vagus nerve were abolished by cooling at 0 degree C. When the vagus nerves were cooled to 0 degree C, the ventilation overflow decreased. On the other hand, when the nerves were rewarmed, the ventilation overflow increased again. Bronchoconstriction was produced by close intraarterial injection of histamine, acetylcholine, serotonin, or PGF2 alpha at a dosage of 10 microgram each. The bronchoconstrictions produced by these agents were inhibited by vagal cooling. The bronchoconstrictions induced by histamine, acetylcholine, and serotonin were all 0.00125%, and that by PGF 2 alpha was 0.001%. Inhalations for 10 min were also inhibited by vagal cooling. These findings indicate that the thermode devised in this study is useful for vagal cooling and that vagally mediated bronchoconstriction is a relatively major component of bronchoconstriction induced by chemical mediators.

Acetylcholine↗

PubMed2001

Bradykinin causes inhibition of methacholine-induced bronchoconstriction in vivo in mice.

In this study the influence of bradykinin on airway responses was investigated in anaesthetised and ventilated mice. Airway resistance in mice was monitored using whole body plethysmography. Intravenous (i.v.) administration of bradykinin (4-40 microg/kg) did not cause a direct effect on airway resistance. Also pretreatment with propranolol (1 mg/kg, i.v.), atropine (1 mg/kg, i.v.) or indomethacin (5 mg/kg, i.v.) did not result in any effect of intravenous bradykinin on baseline airway resistance. However, i.v. bradykinin (4-40 microg/kg) caused a dose-dependent inhibition of the (0.5 mg/kg, i.v.) methacholine-induced bronchoconstriction, with an ED50 value of 3.4 +/- 0.4 microg/kg. The maximal inhibition of the bronchoconstrictor response to methacholine was 65.5 +/- 2.0%. The inhibition of the methacholine-induced bronchoconstriction by bradykinin could be prevented by treatment with the B2 receptor antagonist icatibant (Hoe 140, 0.13 mg/kg, i.v.). Also pretreatment with either propranolol (1 mg/kg, i.v.), L-NAME (30 mg/kg, i.v.) or indomethacin (5 mg/kg, i.v.) completely blocked the inhibition of the methacholine-induced bronchoconstriction by bradykinin. The inhibition of the methacholine-induced bronchoconstriction after bradykinin was not affected by the NK1 receptor antagonist RP 67580 (17.5 microg/kg, i.v.). In conclusion, the results of this study demonstrate that bradykinin causes a dose-dependent inhibition of the methacholine-induced bronchoconstriction in vivo in mice. This response is B2 receptor-mediated and at least involves the activation of beta-adrenoceptors and the synthesis of nitric oxide and cyclo-oxygenase products.

Airway Resistance↗

PubMed1991

Role of leukocyte depletion in noncholinergic bronchoconstriction of guinea pigs.

To test the role of leukocytes in the activation of afferent C-fibers in the lung, 33 guinea pigs, 18 control and 15 experimental or leukocyte depleted, were used. The leukocyte depletion was accomplished with an intraperitoneal injection of cyclophosphamide (100 mg/kg) 96 h prior to the study. On the day of the study, bronchial constriction was produced either by exsanguination (n = 17) or by capsaicin injection (16 micrograms/kg, i.v.) (n = 16) in anesthetized-paralyzed animals. Venous blood samples were collected for leukocyte counts. At 1-30 min following the above treatment, the maximal expiratory flow maneuver was performed and a decrease in the maximal expiratory flow at 50% baseline total lung capacity (Vmax50) was used as an index of bronchoconstriction. The leukocyte count decreased significantly following the pretreatment with cyclophosphamide [an average of 6217 +/- 612 (control) vs. 2242 +/- 334/mm3 (experimental)]. Exsanguination caused a gradual decrease in Vmax50 with time, indicating a temporal increase in bronchoconstriction. Capsaicin injection, on the other hand, caused an immediate (1 min) marked bronchoconstriction, which attenuated gradually with time. At a specific time point, leukocyte depletion did not produce any significant change in Vmax50 compared to the control group for both types of bronchoconstrictions. Based on these results, we conclude that leukocytes may play an insignificant role in the bronchoconstriction caused by the activation of afferent C-fibers in guinea pig lungs under our experimental conditions.

Animals↗

PubMed1991

Role of the axon reflex in capsaicin-induced bronchoconstriction in guinea pigs.

To study the axon reflex as a contributing factor to capsaicin-induced bronchoconstriction in vivo, 30 guinea pigs weighing 325 +/- 7 g were randomly divided into four groups: Group 1, control (n = 6); Group 2, bupivacaine (n = 11); Group 3, tetrodotoxin (TTX, n = 10); and Group 4, tachykinin depletion (n = 3). Each animal was anesthetized with pentobarbital sodium, cannulated with a tracheal cannula and venous catheter, paralyzed with gallamine triethiodide, and artificially ventilated. All animals were treated with atropine and phenoxybenzamine, and a ganglionic blocking agent (chlorisondamine) was given to about half of the animals. Capsaicin (16 micrograms/kg) was intravenously injected to induce bronchoconstriction. Immediately upon the capsaicin being induced each animal exhibited a decrease in vital capacity, maximal expiratory flow and respiratory compliance, as well as a more than six-fold increase in residual volume, indicating severe bronchoconstriction. Then, the airway spasm decreased gradually toward the baseline values. The animals in Group 4 indicated a complete abolishment of the capsaicin-induced bronchoconstriction, whereas Group 2 and Group 3 displayed a significantly attenuated constriction at 15 to 20 min after capsaicin injection. Administration of chlorisondamine did not alter the capsaicin-induced bronchospasm. Since it is known that bupivacaine and TTX block nerve conduction, the data suggest that the axon reflex plays a significant role in the late phase of bronchoconstriction, which is apparently mediated via tachykinins.

Animals↗

PubMed1993

Axon reflex in resiniferatoxin-induced bronchoconstriction of guinea pigs.

To study the role of the axon reflex in resiniferatoxin (RTX)-induced bronchoconstriction in vivo, 32 guinea pigs weighing 292 +/- 7 g were randomly divided into five groups: Group 1, control (n = 6); Group 2, chlorisondamine (n = 6); Group 3, tetrodotoxin (TTX, n = 6); Group 4, local capsaicin application (n = 6); and Group 5, systemic capsaicin application (n = 8). Chlorisondamine was used to interrupt ganglionic transmission while TTX was employed to block nerve impulse conduction. In Group 4, capsaicin was locally applied to both cervical vagus nerves 30 min prior to the study whereas capsaicin was given subcutaneously for 5 days starting 9 days before the study in Group 5. Each animal was anesthesized with pentobarbital sodium, cannulated with a tracheal cannula and venous catheter, paralyzed with gallamine triethiodide, and artificially ventilated. All the above animals were treated with atropine (0.2 mg/kg) and phenoxybenzamine (0.5 mg/kg). Resiniferatoxin (2 micrograms/kg) was injected intravenously to induce airway constriction. Immediately upon injection of RTX (at 1 min), each animal in the control group exhibited decreases in maximal expiratory flow, dynamic respiratory compliance, and total lung capacity, indicating severe bronchoconstriction. Then the airway spasm ameliorated gradually with time. Animals in Groups 3 and 4 indicated partial abolishment, while those in Group 5 showed complete abolishment, of the RTX-induced bronchoconstriction. On the other hand, the animals in Group 2 did not display any significant alteration in the RTX-induced bronchospasm. Furthermore, we tested RTX-induced bronchoconstriction in 5 additional animals not pretreated with either atropine or phenoxybenzamine. Compared with the data above, no significant differences in RTX-induced respiratory changes were found. Since it is known that TTX blocks nerve conduction, the data suggest that the TTX-sensitive reflex (the axon reflex) via afferent C-fibers plays a significant role in the RTX-induced bronchoconstriction, which is apparently mediated via tachykinins.

Analysis of Variance↗

PubMed1995

Effect of a 5-lipoxygenase inhibitor, AL-3264, on propranolol-induced bronchoconstriction in guinea-pigs.

The administration of propranolol can provoke bronchoconstriction in asthmatic patients. We hypothesized that such bronchoconstriction may result from the inflammatory mediators released by an allergic reaction. We investigated the effect of AL-3264, a 5-lipoxygenase inhibitor, on propranolol-induced bronchoconstriction (PIB) after antigen inhalation in passively sensitized and artificially ventilated guinea-pigs. Our goal was to determine whether products of arachidonate 5-lipoxygenase are involved in such PIB. Bronchoconstriction occurred when 10 mg/ml of propranolol was inhaled 20 min after antigen challenge. Pretreatment with AL-3264 given in intravenous doses of 0.01 and 0.1 mg/kg 15 min after the antigen challenge significantly reduced PIB in a dose-dependent manner. Pretreatment with 0.1 mg/kg of AL-3264 10 min before antigen challenge significantly inhibited both the immediate allergic bronchoconstriction and PIB, although the effect was minimal. Results suggest that arachidonate 5-lipoxygenase products (such as leukotriene B4, C4, D4 or E4) are involved in the pathophysiology of PIB but their contribution may be small. Further studies using selective antagonists for each of these leukotrienes are needed to clarify their role.

Acrylamides↗

PubMed2005

Low incidence of paradoxical bronchoconstriction in asthma and COPD patients during chronic use of Respimat soft mist inhaler.

Respimat Soft Mist Inhaler (SMI) is a new-generation inhaler that offers improved lung deposition compared with chlorofluorocarbon metered dose inhalers (CFC-MDIs). Bronchodilators administered via Respimat SMI are preserved and stabilised with low concentrations of benzalkonium chloride and ethylene diamine tetra-acetic acid, both of which have been reported to cause dose-related paradoxical bronchoconstriction. The aim of this analysis was to compare the incidence of paradoxical bronchoconstriction after chronic use of bronchodilators via Respimat SMI and CFC-MDI. Data from three clinical trials, in which patients with asthma or chronic obstructive pulmonary disease (COPD) received ipratropium bromide alone or in combination with fenoterol hydrobromide, or placebo via Respimat SMI or CFC-MDI for 12 weeks, were included in the analysis. In order to evaluate the risk of paradoxical bronchoconstriction, we identified four respiratory events that might have occurred within 30 min of inhalation on four test days; these were: 'bronchospasm', 'other respiratory adverse events', 'rescue medication use' and 'asymptomatic drop in FEV(1) 15% from baseline'. In total, 631 asthma and 1538 COPD patients participated in the three studies. No occurrences of bronchospasm were reported with Respimat SMI on any test day. Overall, the incidence of respiratory events possibly indicative of paradoxical bronchoconstriction was low and similar for both devices. There was no increase in the incidence of events during 12 weeks' treatment. Delivery of bronchodilators by Respimat SMI is safe with regard to paradoxical bronchoconstriction during chronic use in patients with asthma or COPD.

Administration, Inhalation↗

PubMed1996

Dysfunctional muscarinic M2 autoreceptors in vagally induced bronchoconstriction of conscious guinea pigs after the early allergic reaction.

We studied the function of autoinhibitory muscarinic M2 receptors on vagal nerve endings in the airways of conscious, unrestrained, ovalbumin-sensitized guinea pigs after the early and late allergic reaction. For this purpose, the effects of the selective muscarinic M2 receptor antagonist gallamine were examined on unilateral vagus nerve stimulation-induced bronchoconstriction, which was determined as an increase in basal respiration amplitude, measured as changes in pleural pressure. Under control conditions, i.e., before antigen challenge, a significant increase in the pleural pressure was found after inhalation of 0.1 mM and, even more pronounced, 1.0 mM gallamine, at medium stimulation frequencies (2-16 Hz), leading to a leftward shift of the frequency-response curve. After inhalation of 10 mM of gallamine, a complete reversal of the left-shift was observed and the frequency-response curve was depressed. However, 6 h after challenge with ovalbumin (i.e., after the early allergic reaction) no increase in nerve stimulation-induced bronchoconstriction by gallamine was found; a decrease in this bronchoconstriction was again observed with the highest concentration. At this moment, bronchial responsiveness to histamine was enhanced 4.5-fold compared to control, i.e., prior to antigen provocation. Both after the late allergic response (24 h after challenge; 1.6-fold histamine hyperresponsiveness) and 4 days after allergen challenge (normal histamine responsiveness) the gallamine-induced potentiation of the bronchoconstriction was restored, similar to the responses under control conditions. The results clearly demonstrate that prejunctional muscarinic M2 receptors control bronchoconstriction in conscious, unrestrained guinea pigs in vivo. Furthermore, these autoinhibitory receptors appear to be completely dysfunctional after the early allergic phase, but their function is largely restored after the late phase. The results indicate that dysfunction of autoinhibitory muscarinic M2 receptors might contribute to the strongly enhanced responsiveness to histamine after the early allergic response.

Allergens↗

PubMed1999

Effect of DP-1904, a thromboxane synthetase inhibitor, on antigen- and spasmogen-induced bronchoconstriction in rodents.

The effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetra-hydronaphthalene-2-car boxylic acid hydrochloride], a selective thromboxane synthetase inhibitor, was examined on antigen- and spasmogen-induced bronchoconstriction in rodents. Oral administration of DP-1904 (1, 3, 10 mg/kg) as well as OKY-046 (sodium (E)-3[4-(1-imidazolylmethyl)-phenyl]-2-propanoate, 100 mg/kg), significantly inhibited immunoglobulin G-mediated bronchoconstriction in actively sensitized guinea pigs. Immunoglobulin E-mediated bronchoconstriction in actively sensitized rats was also inhibited by both DP-1904 (1, 10 mg/kg) and OKY-046 (100 mg/kg). DP-1904 (3-30 mg/kg) and OKY-046 (30 mg/kg) suppressed leukotriene D4-induced bronchoconstriction in guinea pigs. In these models, the endogenous levels of thromboxanes significantly increased following the stimulus (antigen and leukotriene D4). DP-1904 (10 mg/kg) inhibited the increase in thromboxane level in both plasma and bronchial alveolar lavage fluid. These actions of DP-1904 persisted for more than 12 h, indicating a long-lasting effect of DP-1904 on bronchoconstriction. The results showed that the biological activity of DP-1904 in our rodents models is more potent than that of OKY-046 (Ozagrel), which is available as an anti-asthma agent in Japan.

Acetylcholine↗