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At least 19 recordsLinked to original sources
PubMed2000

Nedocromil sodium for preventing exercise-induced bronchoconstriction.

BACKGROUND: Exercise-induced asthma causes cough, dyspnea, wheeze and chest tightness. Management of focuses on prevention through pharmaco-therapy and alternate strategies. Single use, pre-exercise beta2-agonists and non-steroidal anti-inflammatory agents such as the cromones are the most common treatments. OBJECTIVES: The objective of this review was to assess the effects of a single dose of nedocromil sodium to prevent exercise-induced bronchoconstriction. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register, the Cochrane Controlled Trials Register, Current Contents, review articles, textbooks and reference lists of articles. We also contacted the drug manufacturer and primary authors for additional citations. SELECTION CRITERIA: Randomised trials comparing a single dose of nedocromil sodium with placebo to prevent exercise-induced bronchoconstriction in people over six years of age. DATA COLLECTION AND ANALYSIS: Trial quality assessment and data extraction were conducted independently by two reviewers. Study authors were contacted for confirmation of data. MAIN RESULTS: Twenty randomised controlled trials involving 280 participants were identified. 15-60 min following inhalation of 4 mg nedocromil, the maximum fall in forced expiratory volume in one second due to exercise was improved by 15.6%, (95% CI:13.2 to 18.1) compared to the placebo response. The maximum percentage fall in peak expiratory flow rate was of the same magnitude (weighted mean difference 15.0%; 95% CI 8.3 to 21.6). Nedocromil shortened the time to recover lung normal function from more than 30 minutes with placebo to less than 10 minutes with the drug. The relative magnitude of its effect was greatest in patients with more severe exercise-induced bronchoconstriction (defined as an exercise-induced fall in lung function > 30% from baseline). There were no significant adverse effects reported. REVIEWER'S CONCLUSIONS: Nedocromil sodium used before exercise appears to reduce the severity and duration of exercise-induced bronchoconstriction. This effect appears to be more pronounced in people with severe exercise-induced bronchoconstriction.

Adolescent↗
PubMed1994

Involvement of thromboxane A2 in propranolol-induced bronchoconstriction after allergic bronchoconstriction in guinea pigs.

Although it is well recognized that beta-blockers can induce bronchoconstriction only in patients with asthma, mechanisms of the bronchoconstriction are not well known. We hypothesize that bronchoconstriction induced by beta-blockers may result from inflammatory mediators released by allergic reactions. In this study, we developed a guinea pig model for propranolol-induced bronchoconstriction (PIB) after antigen inhalation and investigated the effect of specific thromboxane (TXA2) receptor antagonists, S-1452 and ONO NT-126, on PIB in passively sensitized and artificially ventilated guinea pigs to determine whether TXA2 is involved in PIB. Propranolol caused bronchoconstriction with 10 mg/ml of propranolol was inhaled 20 min after antigen challenge. On the other hand, propranolol did not produce bronchoconstriction after antigen provocation in nonsensitized guinea pigs or after saline provocation in sensitized animals. Pretreatment of the animals with S-1452 in doses of 0.01 and 0.1 mg/kg and ONO NT-126 in doses of 1.0 and 10 micrograms/kg injected intravenously 15 min after antigen challenge as well as before antigen challenge reduced PIB in a dose-dependent manner. Bronchoconstriction caused by methacholine did not induce PIB. These results suggest that TXA2 has an important role in the pathophysiology of the PIB that develops after the allergic bronchoconstriction.

Administration, Inhalation↗
PubMed1987

Mediators of C5a-induced bronchoconstriction in the guinea pig.

The effect of intravenous injection of C5a on pulmonary resistance and dynamic lung compliance was determined in anesthetized, artificially respirated guinea pigs. A mixture of C5a plus C5ades arg was purified from yeast-activated guinea pig serum and is referred to as C5a. Intravenous injection of C5a caused a dose-related bronchoconstriction as evidenced by a decrease in compliance and increase in resistance. Conversion of the C5a in the mixture to C5ades arg by carboxypeptidase B digestion did not significantly alter the magnitude of the bronchoconstriction. Pharmacological antagonists were employed to determine if histamine, acetylcholine or products of the arachidonate metabolism were mediators of C5a-induced bronchoconstriction. The histamine H1 antagonist pyrilamine inhibited the C5a-induced bronchoconstriction, suggesting the involvement of histamine. The cholinergic receptor antagonist atropine in combination with pyrilamine caused an inhibition of the C5a-induced increase in resistance but not compliance, suggesting acetylcholine does not play a major role in C5a-induced bronchoconstriction beyond its known role in participating in histamine-induced bronchoconstriction. Involvement of arachidonate metabolites was suggested by the ability of the cyclooxygenase inhibitor, indomethacin, to prevent the C5a-induced bronchoconstriction. Because indomethacin also caused a delay in the leukotriene C4 (LTC4)-induced bronchoconstriction, the participation of peptidoleukotrienes in the C5a-induced bronchoconstriction could not be ruled out. The leukotriene antagonists FPL 55712 and L-649,923 were evaluated for their specificity in inhibiting LTC4-induced bronchoconstriction. FPL 55712 was nonselective since it inhibited prostaglandin D2 and histamine-induced bronchoconstriction as well as LTC4-induced bronchoconstriction. L-649,923 inhibited only the LTC4-induced bronchoconstriction and was without effect on the C5a-induced bronchoconstriction, suggesting that peptidoleukotrienes are not important mediators of C5a-induced bronchoconstriction. Using radioimmunoassay, the change in peptidoleukotriene levels detected in plasma during C5a-induced bronchoconstriction was not significantly different from 0. Thus, these studies have quantitated the C5a-induced decrease in dynamic lung compliance and increase in pulmonary resistance and suggest that histamine and cyclooxygenase products, but not peptidoleukotrienes, play a major role in C5a-induced bronchoconstriction.

Acetylcholine↗
PubMed1993

Regulation of NANC neural bronchoconstriction in vivo in the guinea-pig: involvement of nitric oxide, vasoactive intestinal peptide and soluble guanylyl cyclase.

1. We investigated the effect of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and the peptidase alpha-chymotrypsin on non-adrenergic, non-cholinergic (NANC neural) bronchoconstriction induced by electrical stimulation of the vagus nerves and by capsaicin in anaesthetized guinea-pigs in vivo using pulmonary insufflation pressure (PIP) as an index of bronchial tone. We also investigated the contribution of soluble guanylyl cyclase (SGC) to NANC neural relaxant mechanisms. 2. In the presence of atropine and propranolol, electrical stimulation of the vagus nerves induced a frequency-dependent increase in PIP above baseline of 67% at 2.5 Hz, of 128% at 5 Hz and of 230% at 10 Hz. L-NAME (1-50 mg kg-1, i.v.), at doses inducing increases in systemic blood pressure, dose-relatedly potentiated NANC bronchoconstriction. At 10 mg kg-1 i.v., L-NAME significantly (P < 0.05) potentiated NANC bronchoconstriction by a further 106% at 2.5 Hz and a further 147% at 5 Hz but did not potentiate the increase in PIP at 10 Hz. L-NAME did not induce bronchoconstriction in sham-stimulated control animals. D-NAME did not potentiate NANC bronchoconstriction. Raising systemic blood pressure with phenylephrine did not potentiate vagally-induced bronchoconstriction (2.5 Hz). 3. The NO precursor L-arginine, but not D-arginine, (100 mg kg-1, i.v.) significantly reversed the potentiation by L-NAME of NANC bronchoconstriction. L-Arginine alone significantly inhibited neurogenic bronchoconstriction at 10 Hz (by 74%); the inhibition of 25% at 2.5 Hz was not significant. 4. L-NAME did not significantly affect the increases in PIP induced by intravenous substance P. neurokinin A (NKA) or capsaicin. 5. The inhibitor of SGC, methylene blue (10 mg kg', i.v.) potentiated (by 110-140%) NANC neural bronchoconstriction induced by lower frequencies of nerve stimulation and reversed the reduction in PIP induced by the SGC activator, sodium nitroprusside (SNP, 1.05 mg kg- 1, i.v.). SNP significantly (P <0.05) reduced by 65% the bronchoconstriction induced by nerve stimulation at 10 Hz. Methylene blue did not effect baseline PIP in sham-stimulated controls. The airway effects of methylene blue and SNP were not associated with their cardiovascular effects. 6. a-Chymotrypsin (2 units kg-', i.v.) significantly potentiated vagally-induced bronchoconstriction by a further 63% at 2.5 Hz, by a further 95.6% at 5 Hz but did not potentiate the increase in PIP at 10 Hz. alpha-Chymotrypsin also potentiated (by 116%) capsaicin-induced bronchoconstriction. Vasoactive intestinal peptide (VIP, 10 ig kg-' i.v. infused over min) significantly reduced by 70% the increase in PIP induced by NKA (0.1 .Lmol kg-' i.v., infused over 30 s). 7. The combination of a-chymotrypsin (2 units kg-', i.v.) and L-NAME (5 mg kg-', i.v.) significantly potentiated NANC bronchoconstriction by a further 304% at 2.5 Hz, an increase in PIP which was greater than that induced by either a-chymotrypsin or L-NAME alone (P <0.05). 8. We conclude that endogenous NO and a bronchodilator peptide, possibly VIP, released in association with nerve stimulation, as well as activation of soluble guanylyl cyclase, regulate the magnitude of NANC neurogenic bronchoconstriction in guinea-pigs in vivo.

Airway Resistance↗
PubMed1993

Regulation of neuropeptide release from pulmonary capsaicin-sensitive afferents in relation to bronchoconstriction.

An isolated perfused lung model was developed in which the mechanisms of regulation of sensory neuropeptide overflow and bronchoconstrictor responses evoked by antidromic vagal nerve stimulation or various irritants could be studied. For further comparison, non-adrenergic non-cholinergic (NANC) bronchoconstriction was also studied in guinea-pig isolated bronchus and in vivo. In the isolated guinea-pig lung, spontaneous strong postmortem bronchoconstriction occurred; this had to be overcome by the beta 2-adrenoceptor agonist terbutaline. Vagal stimulation, capsaicin, resiniferatoxin (RTX), nicotine, and pH 5 buffer all caused sensory peptide release and bronchoconstriction via a capsaicin-sensitive mechanism. Bradykinin and histamine also stimulated sensory peptide release but evoked bronchoconstriction mainly via capsaicin-resistant mechanisms. Stimulation at low frequency (1 Hz) caused similar degree of sensory nerve activation (peptide release in perfused lung and NANC bronchial contraction in bronchus) as stimulation at 10 Hz. Dactinomycin and the non-peptide SR 48968 selectively blocked the bronchoconstriction induced by neurokinin 2 (NK2) receptor agonists and also depressed that induced either by vagal stimulation or capsaicin, with no prejunctional effect on the overflow of calcitonin gene-related peptide (CGRP). Furthermore, SR 48968 inhibited the bronchoconstriction to citric acid aerosol. The NK1 antagonist CP 96345 had only marginal effects on NANC bronchoconstriction. Tetrodotoxin (TTX) and omega-conotoxin (CTX) inhibited neuropeptide release and bronchoconstriction caused by vagal stimulation or a low concentration of capsaicin but only marginally attenuated the effects evoked by a high concentration of capsaicin, or nicotine. Prejunctional alpha 2-adrenoceptor or opiate receptor activation inhibited the neuropeptide release and bronchoconstriction induced by vagal stimulation or a low concentration of capsaicin. Ruthenium red had a selective inhibitory effect on the overflow of neuropeptides [CGRP, neurokinin A (NKA)] and bronchoconstriction induced by capsaicin and its analogue RTX but not on responses induced by vagal stimulation, nicotine, bradykinin and histamine. It also inhibited CGRP and NKA release and bronchoconstriction caused by pH 5 buffer in lung, as well as cough and nasal irritation provoked by citric acid in vivo. The capsaicin receptor antagonist capsazepine inhibited peptide (CGRP, NKA) release and bronchoconstriction produced by capsaicin but not that evoked by vagal stimulation, nicotine and bradykinin, suggesting selectivity. Citric acid (in vivo) and pH 5 buffer (in vitro) produced bronchoconstriction via activation of capsaicin-sensitive sensory nerves. Interestingly, capsazepine also markedly depressed peptide overflow and bronchoconstriction caused by pH 5 buffer in isolated guinea-pig lung.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Acute bronchoconstriction is not a stimulus for sympatho-adrenal activation in asthmatic or healthy subjects.

Bronchoconstriction has been found to cause little sympathoadrenal activation in asthmatic patients. It has been questioned whether this is due to blunted sympatho-adrenal reactivity in asthmatics or if bronchoconstriction is a stimulus for sympatho-adrenal activation at all. We therefore compared sympatho-adrenal responses in eight asthmatic patients and 12 healthy subjects by measurements of plasma adrenaline and noradrenaline concentrations before, during and after methacholine-induced bronchoconstriction. Significant bronchoconstriction was obtained in eight of the healthy subjects and in all of the asthmatics. Considerably higher concentrations of methacholine were required to evoke bronchoconstriction in the healthy subjects but the relative magnitudes of bronchoconstriction were similar in the two groups: peak expiratory flow (PEF) decreased by approximately 24 and approximately 28% and specific airway conductance (sGaw) decreased by approximately 68 and approximately 70% in asthmatics and controls, respectively). Methacholine-induced bronchoconstriction did not alter plasma catecholamine levels significantly in either group. In addition, plasma concentrations of catecholamines and neuropeptide Y-like immunoreactivity (NPY-LI) were measured before and during bronchoconstriction induced by histamine or allergen in 8 and 5 asthmatic subjects, respectively. Plasma noradrenaline, adrenaline and NPY-LI remained unchanged up to 30 min after bronchoconstriction induced by histamine or allergen. We, therefore, conclude that bronchoconstriction is not a stimulus for sympatho-adrenal activation and that the lack of an adrenaline response to bronchoconstriction is not likely to be related to NPY release.

Acute Disease↗
PubMed1995

Role of substance P in cough during bronchoconstriction in awake guinea pigs.

To examine the role of substance P (SP) in cough during bronchoconstriction, we studied the effects of an aerosolized beta-adrenoceptor agonist, procaterol, and a specific inhibitor of SP (NK1) receptor, FK 888, on bronchoconstriction and cough induced by aerosols of histamine and acetylcholine (ACh) in unsensitized guinea pigs and by those of ovalbumin (OA) antigen in guinea pigs sensitized to OA. Intensity of bronchoconstriction was evaluated by the time to onset of bronchoconstriction after the inhalation of bronchoconstrictors. Both procaterol (10(-6) to 10(-4) M, 2 min) and FK 888 (10(-7) to 10(-5) M, 2 min) dose dependently decreased the number of coughs and increased the time to onset of bronchoconstriction induced by histamine (10(-2) M, 15 s). Procaterol attenuated histamine-induced cough only at the concentrations effective to inhibit bronchoconstriction. However, FK 888 at concentrations of 10(-7) and 10(-6) M decreased the number of coughs without effect on bronchoconstriction. Likewise, the inhibitory effects of procaterol (10(-5) M, 2 min) on the number of coughs were parallel to those on bronchoconstriction induced by ACh (10(-1) M, 15 s) and OA antigen (0.1% concentration, 30 s), but FK 888 (10(-6) M, 2 min) decreased the number of coughs without effect on bronchoconstriction induced by them. The number of coughs induced by histamine (10(-2) M, 15 s) was inhibited by systemic capsaicin treatment and enhanced by phosphoramidon (10(-5) M, 5 min) without effect on bronchoconstriction. (ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effects of milrinone, sulmazole and theophylline on adenosine enhancement of antigen-induced bronchoconstriction and mediator release in rat isolated lungs.

The effects of adenosine and some of its analogues on bronchoconstriction and mediator release were studied in isolated lungs of actively sensitized rats. The influence of two novel cardiotonic drugs, milrinone and sulmazole on these adenosine-induced effects was compared with that of theophylline, a well known adenosine antagonist. Adenosine (ADO) and its analogues N-ethyl-carboxamide-adenosine (NECA) and R-phenyl-isopropyladenosine (R-PIA), dose-dependently enhanced antigen-induced bronchoconstriction. The enhancement of anaphylactic bronchoconstriction by adenosine and its analogues was accompanied by a rise in histamine release. The rank order of potency for adenosine and analogues with respect to enhancement of anaphylactic bronchoconstriction, was NECA greater than or equal to R-PIA greater than ADO. An unequivocal classification of the adenosine receptor involved, was therefore not possible. Dipyridamole and S-(p-nitrobenzyl-6-thioinosine) (NBTI), both inhibitors of adenosine uptake, had no inhibitory influence on the adenosine-induced enhancement of anaphylactic bronchoconstriction, indicating that this enhancement is mediated by an extra-cellular receptor. Theophylline, milrinone and sulmazole inhibited the enhancement of anaphylactic bronchoconstriction, without affecting preformed mediator release. Theophylline and sulmazole were both more effective as inhibitors of adenosine-enhanced bronchoconstriction than as inhibitors of antigen-induced bronchoconstriction, suggesting adenosine antagonism. Milrinone was equi-effective as inhibitor of both types of bronchoconstriction. Since adenosine antagonism has been associated with the side effects of theophylline it will be interesting to further investigate the therapeutic merits of novel cyclic nucleotide phosphodiesterase inhibitors in the treatment of asthma.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1998

Role of adrenergic nervous system in cigarette smoke-induced bronchoconstriction in guinea pigs.

The goal of this study was to clarify the role of the adrenergic nervous system in bronchoconstriction induced by exposure to cigarette smoke in guinea pigs. Artificially ventilated animals were exposed to 160 puffs of smoke for 8 min. Bronchoconstriction was assessed as a percentage of the baseline total pulmonary resistance (RL). The effects of pretreatment with phentolamine (0.1 mg/kg, i.v.), propranolol (1 mg/kg, i.v.), and/or atropine (1 mg/kg, i.v.) were evaluated. Exposure to cigarette smoke caused significant bronchoconstriction. Phentolamine, an alpha-adrenoceptor antagonist, significantly inhibited cigarette smoke-induced bronchoconstriction, while propranolol, a beta-adrenoceptor antagonist, significantly enhanced it. Combined use of these compounds further enhanced the bronchoconstriction. All of modulations of the bronchoconstriction by adrenoceptor antagonists were completely abolished by pretreatment with atropine. Phentolamine and/or propranolol had no effect on the bronchoconstriction induced by inhaled acetylcholine. Pretreatment with yohimbine (0.5 mg/kg, i.v.), a selective alpha2-adrenoceptor antagonist, showed modulatory effects similar to those of phentolamine on cigarette smoke-induced bronchoconstriction. These results suggest that cigarette smoke-induced bronchoconstriction is regulated by the prejunctional modulation of the cholinergic system via alpha- and beta-adrenoceptors. This mechanism may be modulated by the autoregulation of adrenergic nerves via the alpha2-autoreceptor.

Acetylcholine↗
PubMed2000

Frequency and determinants of exaggerated bronchoconstriction during shortened methacholine challenge tests in epidemiological and clinical set-ups.

The European Respiratory Society guidelines on bronchial provocation testing have proposed time-saving procedures, which may lead to unwanted exaggerated responses. The frequency and determinants of exaggerated bronchoconstriction in response to methacholine inhalation testing in clinical and epidemiological settings have not been assessed. The authors evaluated: 1) the prevalence of exaggerated bronchoconstriction, 2) its relation to time-saving measures (starting methacholine concentration and skipping concentrations); and 3) associations between such reactions and risk factors, respiratory symptoms and/or lung function parameters. Clinical (n=408) and epidemiological (n=711) groups were included. Exaggerated bronchoconstriction was defined as either a fall > or =20% following saline or a > or =30% fall in forced expiratory volume in one second (FEV1) after methacholine inhalations. Cases were compared with two groups of subjects: 1) with measurable bronchial responsiveness (MBR); and 2) without MBR. In the epidemiological group, 84 subjects (12%) presented exaggerated bronchoconstriction. Skipped concentrations accounted for an exaggerated bronchoconstriction in 18 of these. In the clinical group, 41 subjects (10%) experienced exaggerated reactions. Skipped concentrations accounted for an exaggerated bronchoconstriction in five of these. The provocative concentration of methacholine causing a 20% fall in FEV1 values were marginally lower in subjects with exaggerated bronchoconstriction. Questionnaire analysis in epidemiological subjects showed some symptoms of asthma and rhinitis to be more prevalent in cases than in subjects without MBR. In conclusion, methacholine inhalation tests with time-saving measures result in a 10% risk of exaggerated bronchoconstriction as defined in this study and bronchial responsiveness is more prominent in subjects with exaggerated bronchoconstriction.

Adult↗
PubMed1995

Effect of a selective thromboxane A2 receptor antagonist BAY u3405 on antigen-, leukotriene C4- and leukotriene D4-induced bronchoconstriction in guinea pigs.

We studied the effect of a selective thromboxane (TX) A2 receptor antagonist BAY u3405 on prostanoid-, leukotriene (LT) C4, LTD4- and antigen-induced bronchoconstriction in nonanesthetized guinea pigs in vivo. Oral administration of BAY u3405 inhibited bronchoconstriction induced by inhaled TXA2 mimetic U46619, prostaglandin (PG) D2 and PGF2 alpha. BAY u3405 also decreased the bronchoconstriction induced by inhaled LTC4 and LTD4. Intraperitoneal administration of TXA2 synthetase inhibitor OKY-046 did not affect PGD2- and PGF2 alpha-induced bronchoconstriction, but attenuated LTC4- and LTD4-induced bronchoconstriction. BAY u3405 and OKY-046 decreased antigen-induced bronchoconstriction in actively sensitized guinea pigs. These results indicate that BAY u3405 not only inhibits TXA2-, PGD2- and PGF2 alpha-induced bronchoconstriction that is mediated through a TXA2 receptor but also decreases LTC4. LTD4- and antigen-induced bronchoconstriction which is mediated in part through TXA2 synthesis. These results suggest that BAY u3405 might be useful in controlling prostanoid-induced bronchoconstriction in asthma.

Animals↗
PubMed1998

Perception of respiratory symptoms after methacholine-induced bronchoconstriction in a general population.

In an epidemiological study, methacholine-induced bronchoconstriction was used as a physical illustration of the sensations associated with asthma. The objective of this study was to assess whether familiarity with these sensations could be used as a measure of asthma prevalence. Eight hundred and seventy six subjects aged 20-44 yrs completed a respiratory questionnaire and a measurement of airway responsiveness (the provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD20)). Subjects were asked about their perception of, familiarity with and description of the respiratory sensations experienced at the time of maximal bronchoconstriction. The questionnaire-derived lifetime prevalences of wheeze, chest tightness and undue breathlessness were 43, 35 and 22% respectively. Asthma medication was used by 8% and the lifetime prevalence of diagnosed asthma was 12%. Quantifiable levels of airway responsiveness were measured in 34%, and airway responsiveness in the range considered to be consistent with untreated active asthma was present in 21%. Bronchoconstriction was perceived by 59%. Perception of bronchoconstriction was associated with the magnitude of bronchoconstriction, younger age, female sex and questionnaire-reported symptoms. Of subjects able to perceive bronchoconstriction, 58% reported previous experience of (familiarity with) the associated respiratory sensations. Familiarity with the sensations of bronchoconstriction was associated with questionnaire-reported symptoms, diagnosed asthma and increasing levels of airway responsiveness. There was poor agreement between the respiratory symptoms reported by questionnaire before the methacholine test and the words used to describe respiratory sensations induced by the test. Familiarity with the sensations of methacholine-induced bronchoconstriction has all the appropriate associations of a measure of asthma prevalence and may be a useful adjunct to symptom questionnaires and airway responsiveness measurements in epidemiological studies. A sizeable number of subjects can be identified with intermediate levels of airway responsiveness, who are able to perceive bronchoconstriction and are familiar with the sensations associated with it, yet who are not recognized to suffer from asthma.

Adult↗
PubMed1991

[Effects of Y-20811, a specific thromboxane A2 synthetase inhibitor, on chemical mediator-induced bronchoconstriction in guinea pigs].

We investigated the effects of Y-20811 on chemical mediator-induced bronchoconstriction and the release of chemical mediators into lung perfusion fluid during arachidonic acid (AA)-induced bronchoconstriction in guinea pigs. Y-20811 (0.01-1 mg/kg, i.v.), like acetylsalicylic acid or indomethacin, dose-dependently suppressed arachidonic acid- and LTD4-induced bronchoconstriction, and it (1 mg/kg, i.v.) also inhibited PAF-induced bronchoconstriction in guinea pigs. However, at a dose of 1 mg/kg, i.v., it was inactive against the bronchoconstriction induced by histamine, serotonin and acetylcholine in guinea pigs. Y-20811 (0.3-10 mg/kg) administered orally also prevented the LTD4-induced bronchoconstriction in a dose-dependent manner. This protective effect of Y-20811 (10 mg/kg, p.o.) persisted for at least 24 hr. Y-20811 (10 mg/kg, p.o.) also inhibited antigen-induced bronchoconstriction in guinea pigs passively sensitized with anti-ovalbumin guinea pig serum and pretreated with mepyramine. In the perfused and ventilated guinea pig lungs, Y-20811 inhibited AA-induced bronchoconstriction, decreased the release of TXA2 (estimated as TXB2) and increased the release of PGE2 into the perfused lung fluid, significantly (TXB2 and PGE2 were measured by HPLC). Therefore, Y-20811 suppressed various stimulant-induced bronchoconstrictions through the decrease of TXA2 production and the increase of PGE2 production. Thus, Y-20811 should prove useful as an anti-asthmatic drug.

Animals↗
PubMed1978

Role of platelets in aspirin-sensitive bronchoconstriction in the guinea-pig; interactions with salicylic acid.

1 The bronchoconstriction caused in the guinea-pig by arachidonic acid (AA), bradykinin, adenosine diphosphate (ADP) and adenosine triphosphate (ATP) was correlated with effects on platelets. ATP and ADP produced a brief thrombocytopenia and AA a more prolonged one. Bradykinin had no effect on platelets.2 Aspirin inhibited bronchoconstriction and thrombocytopenia produced by AA and part of the bronchoconstriction produced by ATP, but had no effect against ADP. Thrombocytopenia produced by ADP and ATP was not affected by aspirin or indomethacin.3 Platelet depletion by antiserum prevented bronchoconstriction in response to ADP and to ATP, but not in response to bradykinin or to AA, showing that platelets are not involved in aspirin-sensitive bronchoconstriction. Infusions of ADP reduced bronchoconstriction and thrombocytopenia in response to ADP itself and to ATP, but not to AA. Bronchoconstriction by ADP or ATP involves an action on platelets. Only that due to ATP is partially dependent on the activity of prostaglandin synthetase.4 ATP induced aggregation in vitro in guinea-pig platelet-rich plasma (PRP). Rabbit PRP responded only when ATP was first incubated with guinea-pig plasma. The aggregating compound formed was probably ADP, since it was destroyed by apyrase. Its formation was not inhibited by aspirin or indomethacin, indicating that aspirin inhibits ATP-induced bronchoconstriction by a different mechanism.5 The aggregating effect of ATP on guinea-pig platelets was inhibited by concentrations of apyrase that block ADP-induced aggregation, and potentiated by lower concentrations of apyrase.6 Adenosine 5'-tetraphosphate did not aggregate platelets in vivo or in vitro. In vitro aggregation occurred when apyrase was added, suggesting transformation into ADP. Adenosine 5'-tetraphosphate and apyrase inhibited aggregation due to ADP, but failed to affect that due to AA. This suggests that aggregation involving products of prostaglandin synthesis does not require ADP.7 Salicylic acid did not interfere with bronchoconstriction or aggregation due to AA, but prevented inhibition by aspirin when the weight ratio, salicylic acid:aspirin was 4:1. Salicyclic acid may be useful in studies of potential inhibitors of thromboxane A2 synthesis and of thromboxane A2-dependent processes in vivo and in vitro.

Adenosine Diphosphate↗
PubMed1988

Cough and bronchoconstriction mediated by capsaicin-sensitive sensory neurons in the guinea-pig.

Neural pathways involved in cough and reflex bronchoconstriction and the effects of drugs on these airway reflexes have been studied in unanaesthetised guinea-pigs exposed to aerosols of citric acid (0.13-0.78 M), capsaicin (30 microM), nicotine (9.2 mM) and histamine (0.9 mM). The number of coughs was counted during the first 3 min of exposure and the time to onset of signs of dyspnea, as an indication of bronchoconstriction, was measured. Citric acid produced bronchoconstriction and dose-dependently increased the number of coughs. Capsaicin produced both cough and bronchoconstriction. Nicotine mainly produced cough and histamine bronchoconstriction. Pretreatment of adult guinea-pigs with capsaicin (50 mg kg-1 s.c.) produced a long-lasting (greater than or equal to 10 weeks) depletion of substance P- and calcitonin gene related peptide-like immunoreactivities in the sensory nerves of the larynx, tracheobronchial tree and lung. In capsaicin-treated animals, citric acid (0.39 M) and capsaicin (30 microM) caused neither cough nor bronchoconstriction. Nicotine (9.2 mM) and mechanical stimulation still produced cough, and histamine (0.9 mM) bronchoconstriction. It is concluded that in guinea-pigs both capsaicin-sensitive (probably C-fibre endings) and capsaicin-resistant (probably rapidly adapting stretch receptors) afferent neurons may be involved in cough and reflex bronchoconstriction.

Animals↗
PubMed1996

Prevention of lidocaine aerosol-induced bronchoconstriction with intravenous lidocaine.

BACKGROUND: Lidocaine applied topically provokes bronchoconstriction in persons with hyperreactive airway disease. The authors questioned whether intravenous lidocaine would prevent lidocaine-aerosol induced bronchoconstriction. They compared the effects of lidocaine administered intravenously and by the aerosol route on baseline airway tone, and on the prevention of histamine-induced bronchoconstriction in five Basenji-Greyhound dogs. METHODS: Dogs were pretreated with either intravenous or aerosol lidocaine followed by histamine aerosol challenge. On separate days, dogs were pretreated with intravenous lidocaine, followed by aerosol lidocaine administration at similar doses. Airway caliber was assessed using high-resolution computed tomography. Data were analyzed by two-way analysis of variance. Serum lidocaine concentrations were obtained. RESULTS: Histamine alone decreased the airway area by 32 +/- 3%. Lidocaine administered intravenously or by the aerosol route significantly inhibited histamine-induced bronchoconstriction. There was no significant difference between the two routes in preventing histamine-induced bronchoconstriction. At the dose that inhibited histamine-induced bronchoconstriction, lidocaine administered by the aerosol route decreased baseline airway area by 27 +/- 3% (P < 0.01), whereas intravenous lidocaine had no effect. Intravenous lidocaine prevented lidocaine aerosol-induced bronchoconstriction, and the combination of intravenous and aerosol lidocaine significantly dilated the airways by 20 +/- 5% (P < 0.01 compared with control). CONCLUSIONS: An intravenous bolus of lidocaine prevents the initial bronchoconstriction induced by lidocaine when administered as an aerosol.

Aerosols↗
PubMed1999

Prostaglandin E1 produces spasmolytic effects on histamine-induced bronchoconstriction in dogs.

OBJECTIVE: In this study, we evaluated the spasmolytic effect of intravenous prostaglandin (PG) E1 on histamine-induced bronchoconstriction with a direct visualization method using a superfine fiberoptic bronchoscope. SETTING: A university research laboratory. SUBJECTS: Mongrel dogs. INTERVENTIONS: The bronchial cross-sectional area (BCA) of mongrel dogs was measured by a direct visualization method using a superfine fiberoptic bronchoscope. Bronchoconstriction was elicited with histamine (H) infusion: 10 microg/kg iv bolus + 500 microg/kg/h continuous iv. The first protocol (n = 7) was designed to determine the effects of intravenous bolus of PGE1: 0 (saline), 0.01, 0.1, 1.0 and 10 microg/kg on H-induced bronchoconstriction. BCA was assessed before and 30 min after starting the H infusion and 5 min after each dose of intravenous PGE1. The second protocol was designed to determine whether continuous intravenous infusion of PGE1 reverses H-induced bronchoconstriction. In the PG group (n = 6), PGE1 was continuously infused at 0.1 microg/kg/min (20 mL/hr). In the control group (n = 6), saline was administered at a rate of 20 mL/hr iv. BCA was assessed before and 30 min after starting the H-infusion and at 5, 10, 30 and 60 min after commencing the PGE1 or saline infusion. Arterial blood was obtained simultaneously for measurement of plasma concentrations of epinephrine and norepinephrine by gas chromatography mass spectrometry. MEASUREMENTS AND MAIN RESULTS: In the first protocol, PGE1 produced a dose-dependent increase in the percentage of BCA and 10 microg/kg of PGE1 almost fully reversed the H-induced bronchoconstriction. Plasma catecholamines did not change significantly. In the second protocol, continuous infusion of PGE1 produced a time-dependent reversal of H-induced bronchoconstriction (percentage of BCA increased to 80.0+/-9.0% 60 min after the start of PGE1 infusion), whereas saline infusion did not reverse the bronchoconstriction. Plasma catecholamines did not change significantly in either group. CONCLUSIONS: Both intravenous bolus and continuous intravenous infusion of PGE1 reversed the H-induced bronchoconstriction. PGE1 may be used safely for patients with the hyperreactive airway and might be useful as a therapeutic agent for these patients.

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