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PubMed1990

Effect of inhaled furosemide on the bronchial response to methacholine and cold-air hyperventilation challenges.

Inhaled furosemide has been recently demonstrated to inhibit the bronchoconstrictive effects of exercise, ultrasonically nebulized distilled water, and antigen challenge. The presumed mechanism of action of these challenges is through mast cell degranulation. We report on the effect of inhaled furosemide on cold-air hyperventilation challenge (CAHC) and methacholine challenge. We studied 10 subjects with mild to moderate asthma in a double-blind, placebo-controlled, crossover study. Inhaled furosemide did not affect FEV1 in the hour after inhalation, and there was no significant difference between placebo or furosemide on the dose of methacholine causing a 20% fall in FEV1. Our results demonstrated inhaled furosemide significantly attenuated the bronchoconstrictive effect at 6 and 9 minutes after CAHC (p less than 0.05 and 0.029, respectively) when furosemide was compared to placebo and approached significance at 12 and 15 minutes after CAHC (p = 0.052 and 0.56, respectively). Inhaled furosemide attenuates CAHC but does not effect methacholine-induced bronchoconstriction.

Administration, Inhalation↗
PubMed1990

Neutrophil chemotactic activity in toluene diisocyanate (TDI)-induced asthma.

We quantitated serum neutrophil chemotactic activity (NCA), which is associated with mast cell or basophil activation, to determine if mast cell or basophil mediators are released during bronchoprovocation-inhalation challenge with subirritant levels of toluene diisocyanate (TDI). Four subjects with suspected TDI-induced asthma and four mite-sensitive subjects with asthma who served as a comparison group were studied. NCA was measured in a multiwell, microchemotaxis chamber. Blood samples were collected, and FEV1 measurements were performed before challenge and at regular intervals during the subsequent 24 hours. Three of four workers clinically sensitive to TDI reacted to a subirritant TDI exposure. There was no increase in NCA during placebo challenges. NCA increased in the three TDI-sensitive workers during early and late asthmatic reactions in quantities proportional to the FEV1 decline. No increase in NCA was found during TDI exposures in the TDI-negative worker. Gel filtration analysis demonstrated the main NCA fraction eluted with macromolecules of an estimated molecular weight greater than 440,000 daltons. This characteristic is compatible with neutrophil chemotactic factor of basophil or mast cell origin. The kinetics of NCA release were similar in mite- and TDI-induced asthmatic reactions. A high correlation (r = 0.97; p = 0.0006) was obtained between the percent decrease in FEV1 during early asthmatic reactions and percent increase in NCA. These observations support the hypothesis that activation of mast cells or basophils is associated with TDI-induced early and late asthmatic reaction.

Animals↗
PubMed1990

A double-blind, randomized study of sodium cromoglycate versus placebo in patients with cystic fibrosis and bronchial hyperreactivity.

To evaluate the effects of sodium cromoglycate (SCG) on patients with cystic fibrosis (CF) and with bronchial hyperreactivity, a long-term, double-blind, placebo-controlled, crossover study was performed. Fourteen patients with CF and without asthma (aged 7 to 29 years) and with bronchial hyperreactivity entered the study. Each patient received 8 weeks of 1% SCG nebulizer solution three to four times daily and 8 weeks of placebo. Seven patients received the treatment in the order SCG/placebo and seven patients in the reverse order. Evaluation of SCG effect was performed every 4 to 8 weeks by (1) clinical assessment of symptoms, (2) clinician and patient/parent opinion, (3) pulmonary function tests, and (4) methacholine provocation tests. After two patients were withdrawn for lack of cooperation, the results were evaluated for treatment effect (SCG versus placebo), period effect (whether SCG was administered first or last), or combination of both. No significant difference was found for these parameters for the clinical assessment of symptoms, the patient/parent and clinician opinion, their subjective preferences, the metacholine challenges, or the pulmonary function tests. The study did not demonstrate any benefit from the use of SCG in patients with CF and with bronchial hyperreactivity and does not support the routine use of SCG in patients with CF.

Adolescent↗
PubMed1990

Metabisulfite oral challenge: incidence of adverse responses in chronic childhood asthma and its relationship with bronchial hyperreactivity.

Fifty-six children with chronic asthma, 6 to 14 years of age, were studied to evaluate bronchoconstrictive airway responses after ingestion of varying doses of potassium bisulfite administered in one occasion in capsule and in another occasion in solution. With methacholine challenge before and after metabisulfite (MBS) provocation, the relationship of bronchoconstrictive responses and bronchial hyperreactivity was evaluated. Positive bronchoconstrictive responses were observed in only four children after the ingestion of a maximum dose of MBS in capsule and in two children after the ingestion of different doses of MBS solution. A high reactivity to methacholine challenge was present in all the reactive children. After MBS challenge, no additional changes in bronchial reactivity were observed either in the reactors or nonreactors.

Administration, Oral↗
PubMed1990

Duration of the effect of astemizole on histamine-inhalation tests.

The aim of the study was to investigate if astemizole, a new, long-acting antihistamine preparation, has an effect on histamine-inhalation tests and to assess the duration of action of this medication. The study included a group of 15 adult subjects with asthma in a clinically stable state. The subjects all demonstrated mild to severe bronchial hyperresponsiveness (geometric mean provocative concentration causing a 20% fall in FEV1 (PC20) histamine, 0.57; range, 0.20 to 4.7 mg/ml). The first part of the study was a double-blind, 7-day trial of astemizole (10 mg/day) or placebo, assigned in random order for the first eight subjects. The seven subjects entering the trial subsequently were administered active medication only. PC20 histamine was assessed on the 3 consecutive days before starting the trial, on the last day of medication, 3 days later, and once a week thereafter until PC20 returned to baseline. PC20 methacholine was also assessed before the trial and regularly thereafter to ensure functional stability. No significant changes in PC20 histamine were documented in the placebo-treated group, but the four subjects receiving active medication demonstrated marked changes in PC20 histamine (from a tenfold to a greater than 100-fold difference) (p = 0.001). There were no significant differences in changes in PC20 methacholine between the two treatment groups (p = 0.27). The duration of recovery of bronchial response to histamine in all 15 subjects ranged from 12 to 102 days (mean, 42 days) and was in some subjects, longer than the duration of the blocking effect of histamine reactivity found with skin testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1990

Relationship of different serum levels of theophylline on methacholine sensitivity.

With an increased awareness of the importance of bronchial hyperreactivity on the clinical state of asthma, efforts at establishing effective treatment for asthma have been aimed at trying to reduce the level of bronchial hyperreactivity. This study investigated whether or not theophylline at different serum concentrations had any effect on bronchial hyperreactivity, as measured by methacholine challenges. Twelve adult subjects with mild asthma participated. All subjects were atopic and were nonsmokers. Subjects were studied on three separate occasions according to a double-blind, randomized, crossover study design with one of the following medications: two placebo capsules in the morning and evening, a placebo and 250 mg of sustained-release theophylline in the morning and evening, or two 250 mg sustained-release theophylline capsules each morning and evening. Subjects were administered their medication between 5 and 15 days before performing methacholine challenges in the morning at the presumed trough level, and in the afternoon at the presumed peak serum theophylline level. Despite statistically significant differences in the pulmonary function and theophylline levels between the two active dosages (p less than 0.05 for both), there was no difference in methacholine sensitivity at the time of ingestion of the two dosage forms. There was also no correlation between a particular theophylline level and degree of methacholine sensitivity. It was concluded that, although theophylline has significant bronchodilator capability, it has little, if any, effect on bronchial hyperreactivity, as measured by methacholine challenges. Thus, other forms of long-term therapy should be used in reducing bronchial hyperreactivity.

Adult↗
PubMed1990

Comparative protective effect of the inhaled beta 2-agonist salbutamol (albuterol) on bronchoconstriction provoked by histamine, methacholine, and adenosine 5'-monophosphate in asthma.

We have investigated the ability of salbutamol to protect against bronchoconstriction induced by methacholine, histamine, and adenosine 5'-monophosphate (AMP) in nine subjects with asthma. In a double-blind, placebo-controlled study, salbutamol, 2.5 mg administered by nebulization, increased the geometric mean provocation concentrations of methacholine, histamine, and AMP required to produce a 20% decrease in FEV1 from 0.3 to 2.2, 0.4 to 3.8, and 4.0 to 106.7 mg/ml after placebo and active treatment, respectively (p less than 0.01). Thus, this dose of beta 2-adrenoceptor agonist displaced the concentration-response curves for methacholine, histamine, and AMP to the right in a parallel fashion by 8.8 (0.6 to 29.3)-, 10.3 (1.4 to 33)-, and 26.6 (1.5 to 76.6)-fold, respectively, the difference between the results for AMP and those for histamine and methacholine being statistically significant (p less than 0.01). For six of the nine subjects studied, salbutamol displaced the concentration-response curve for AMP to the right by greater than 50-fold. There was no correlation between bronchodilatation and protection against bronchoconstriction induced by any of the agonists. We conclude that salbutamol protects against bronchoconstriction provoked by methacholine and histamine by functional antagonism, whereas with AMP, an additional activity is demonstrable, possibly involving inhibition of mast cell-mediator release.

Adenosine Monophosphate↗
PubMed1990

Assessment of airway hyperresponsiveness in chronic stable asthma.

Airway reactivity and disease severity were investigated in 24 subjects with stable chronic bronchial asthma. Disease severity was determined by assigning a disease severity score (DSS) representing six clinical and therapeutic parameters. Airway hyperresponsiveness was assessed in two ways: airway reactivity score (ARS) based on the number of positive responses to a question concerning exposure to 22 nonspecific inhaled irritants and methacholine challenge testing and determining the cumulative dose causing a 20% reduction in FEV2 (CMD20). A significant correlation between DDS and CMD20 (r = 0.57; p less than 0.003) and DSS and ARS (r = 0.67; p less than 0.0003) attested to the important influence of airway hyperresponsiveness on disease severity. Significant correlations for ARS with CMD20 (r = -0.60; p less than 0.002) suggested the consistency with which the ARS estimated methacholine hyperresponsiveness. We found no statistically significant correlations between DSS, ARS, or CMD20 and the age of subject, duration of asthma, or other host characteristics. There was not a significant correlation between the degree of airway obstruction and DSS or ARS noted. The results of this investigation demonstrate the value of the use of clinical information for assessing airway hyperresponsiveness and disease severity in patients with chronic stable asthma. Both ARS and DSS are useful clinical tools for estimating methacholine reactivity.

Adult↗
PubMed1991

Airway responsiveness in atopic dermatitis.

Twelve of 123 patients with atopic dermatitis (AD) were screened by questionnaire and spirometry for the absence of smoking, hay fever, and respiratory disorders. Seven of these 12 patients had a positive methacholine challenge test. None of eight patients with another skin disorder, psoriasis, screened in a similar fashion, had a positive methacholine challenge. We conclude that hyperresponsive airways are a frequent finding in patients with AD and that similar mechanisms may account for the cutaneous physiologic and pharmacologic abnormalities that have been observed in AD.

Adult↗
PubMed1992

The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours.

The duration of the protective effect of 50 and 100 micrograms of inhaled salmeterol against methacholine-induced bronchoconstriction was compared with that of 200 micrograms of inhaled salbutamol in 12 patients with asthma with a baseline FEV1 of at least 70% and a provocative concentration of inhaled methacholine causing a 20% fall in FEV1 (PC20) greater than or equal to 8 mg/ml. The study was placebo controlled, double blind, randomized, and crossover. The bronchodilating effect was no longer significant 4 hours after inhalation of salbutamol, whereas the effect was still present 12 hours after administration of 50 and 100 micrograms of salmeterol. All active treatments caused PC20 to increase at 1 hour (p less than 0.05). PC20 (milligrams per milliliter) thus reached 3.7 +/- 0.8 after placebo, 13.8 +/- 3.0 after 50 micrograms of salmeterol, 23.2 +/- 4.7 after 100 micrograms of salmeterol, and 13.9 +/- 3.4 after 200 micrograms of salbutamol. The protective effect of 200 micrograms of salbutamol was no longer significant at 4 hours, whereas both doses of salmeterol protected against methacholine challenge up to 12 hours after inhalation (p less than 0.01). An increased incidence of tremor (2/12) and palpitations (2/12) was recorded after inhalation of 100 micrograms of salmeterol. We conclude that inhalation of 50 or 100 micrograms of salmeterol causes a long-lasting bronchodilatation and protects against methacholine-induced bronchoconstriction for at least 12 hours.

Administration, Inhalation↗
PubMed1987

Calcium uptake into guinea-pig trachealis: the effect of epithelium removal.

Removal of the epithelium from preparations of guinea-pig airways in vitro increases the responsiveness of the smooth muscle of normal and ovalbumin-sensitized animals to a number of contractile agents. To determine if epithelium removal results in an increase in Ca2+ entry into the smooth muscle, the effect of removing the epithelium on Ca2+ uptake into the trachealis smooth muscle was studied using a modified La3+-technique. KCl increased Ca2+ uptake in the presence and absence of the epithelium in control and sensitized animals. Methacholine did not promote Ca2+ uptake, whether or not the epithelium was present, in either control or sensitized animals. Ovalbumin did not stimulate Ca2+ uptake into the trachealis of sensitized animals. These results indicate that the increase in responsiveness of airway smooth muscle seen on epithelium removal is not a consequence of a facilitation of Ca2+ entry into the muscle. The increased responsiveness to methacholine in control animals, and to ovalbumin in preparations in tension studies in epithelium-free tissues from sensitized animals, cannot be explained by an increased availability of extracellular Ca2+ into the muscle, but, rather may reflect some other effect of the epithelium-derived modulatory factor.

Animals↗
PubMedDate not supplied

Internal Ca2+ mobilization and secretion in bovine adrenal chromaffin cells.

Since secretion from intact bovine adrenal chromaffin cells in response to depolarization by nicotine is triggered by a rise in the concentration of intracellular Ca2+ ([Ca2+]i) to about 200-300 nM above basal, it has been assumed that the failure of the inositol 1,4,5-trisphosphate (InsP3)-mobilizing muscarinic agonists to induce secretion reflects the fact that the 50 nM rise in [Ca2+]i they elicit is insufficient to trigger the exocytotic machinery. A recent report, however, has demonstrated that some of the nicotine-induced rise in [Ca2+]i could originate from the InsP3-releasable Ca2+ store. The role of this Ca2+ store in secretion from bovine adrenal chromaffin cells is therefore unclear. In order to investigate in more detail the role of the InsP3-sensitive Ca2+ store in secretion from these cells, we have used a combination of an InsP3-mobilizing muscarinic agonist and the sesquiterpene lactone thapsigargin (TG), which releases internal Ca2+ without concomitant breakdown of inositol lipids or protein kinase C activation, to examine the events which follow depletion of the releasable Ca2+ store in these cells. Monitoring [Ca2+]i using Fura-2 demonstrated that TG released Ca2+ from the InsP3-sensitive store and, additionally, that the Ca2+ response to TG was composed of two distinct, temporally separated, components: a) a slow (1 min) increase in [Ca2+]i to approximately 50 nM above basal that was independent of extracellular Ca2+ and b) the maintenance of this level at a new steady-state that was dependent on the continual entry of extracellular Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMedDate not supplied

Does beta-adrenoceptor activation stimulate Ca2+ mobilization and inositol trisphosphate formation in parotid acinar cells?

The effects of the beta-adrenoceptor agonist, isoprenaline, on Ca2+ mobilization and inositol phosphate formation in parotid acinar cells were examined. Isoprenaline (2 microM) failed to increase cytosolic [Ca2+] in acinar cells, as measured by Fura-2 fluorescence, even in the presence of a phosphodiesterase inhibitor. Likewise, neither the 8-bromo nor the dibutyryl derivatives of cAMP (both at 2 mM concentration) increased [Ca2+]i. However, in confirmation of results previously published, a higher concentration of isoprenaline (200 microM) increased cytosolic [Ca2+]i of rat parotid acinar cells, from 104 +/- 4 nM to 151 +/- 18 nM. The increase in [Ca2+]i in response to isoprenaline, while transient in the absence of extracellular Ca2+, was sustained in Ca2(+)-containing medium. This isoprenaline-stimulated Ca2+ signal was more potently antagonized by phentolamine than by propranolol, suggesting that the higher concentration of isoprenaline activated alpha-adrenoceptors. Furthermore, the Ca2+ signal generated in response to the alpha-adrenoceptor agonist, phenylephrine, also was blocked by the same concentrations of propranolol necessary to block the effects of isoprenaline, suggesting that propranolol may block alpha-adrenoceptors under certain experimental conditions. The high concentration of (-)isoprenaline (200 microM) also increased inositol (1,4,5) trisphosphate and inositol (1,3,4) trisphosphate formation 45% within 30 s. Analogous to the increase in intracellular Ca2+, the formation of inositol phosphates stimulated by isoprenaline was more potently antagonized by the alpha-adrenoceptor antagonist, phentolamine, than by the beta-adrenoceptor antagonist, propranolol, again suggesting that isoprenaline interacts with alpha-adrenoceptors on parotid cells. Thus, the effects of isoprenaline on [Ca2+]i do not appear to be mediated by cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1990

Calcium efflux across the plasma membrane of rat parotid acinar cells is unaffected by receptor activation or by the microsomal calcium ATPase inhibitor, thapsigargin.

The rate of Ca2+ extrusion across the plasma membrane of rat parotid acinar cells was determined by measuring the decay of the intracellular calcium concentration, [Ca2+]i, following the addition of EGTA to agonist stimulated cells. In the presence of extracellular Ca2+, the muscarinic cholinergic receptor agonist, methacholine, rapidly increased [Ca2+]i (peaking within 5 s), which then decreased to a higher steady state level. This elevated steady state level was dependent on extracellular Ca2+ concentration. Likewise, thapsigargin, a non-phorbol ester tumor promoter that does not increase inositol phosphates, gradually increased [Ca2+]i, peaking within 1 min and then declining to a new elevated plateau level which was also dependent on extracellular Ca2+. [Ca2+]i, elevated by methacholine or thapsigargin, was rapidly decreased by the addition of EGTA by a process the kinetics of which depended on the value of [Ca2+]i before the addition of EGTA. That is, [Ca2+]i increased as a function of the extracellular Ca2+ concentration and also the apparent half-time for Ca2+ extrusion following the addition of EGTA to cells was increased as the [Ca2+]i increased. This presumably reflects the saturable nature of the Ca2+ extrusion mechanism. The steady state [Ca2+]i in cells stimulated with methacholine or thapsigargin in nominally Ca2+ free medium was similar to the steady state [Ca2+]i in unstimulated cells in normal, Ca2(+)-containing medium. Under these similar [Ca2+]i conditions, stimulated and unstimulated cells showed a similar time course of decay upon addition of EGTA. In addition, neither methacholine nor phorbol myristate acetate decreased the sustained elevation of [Ca2+]i induced by ionomycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Continuous automated assay of alpha-amylase release from superfused rat salivary gland.

A method of continuous automated amylase assay is described. This relies on the absorption of iodine by starch to produce a blue color that can be quantified colorimetrically. Digestion of the starch by amylase released from parotid tissue slices reduces the intensity of the color formed, allowing quantification of the amylase released. The assay in sensitive to 0.05 U/amylase/ml and linear up to 13 U/ml. Typical tissue responses to acetyl-beta-methylcholine and isoprenaline are presented.

Amylases↗
PubMed1985

Measurement of human small airway smooth muscle function in vitro with the bronchiolar strip preparation.

The technique by which human bronchiolar strips are prepared is described in detail. The biological viability of the preparations after storage at 4 degrees C overnight and the reproducibility of contractile responses to KCl and methacholine were examined in lung tissue from six patients. Measurements were performed on the first and second day after surgical resection. On both days, most bronchioles showed an increase in contractility. The responses on the first day were not different from those on the second day. No significant changes in time were found for pD2 and slope of the methacholine dose-response curves. The variability of responses between patients was significantly larger than between strips within patients. The pD2 was the best reproducible parameter.

Bronchi↗
PubMed1987

Comparison of isometric and isotonic responses of human small airway smooth muscle in vitro.

The difference between isometric and isotonic responses of human small airway smooth muscle to a number of pharmacological agonists was studied. The isotonically measured sensitivity to methacholine was 1.4 times less than the isometrically measured value (p less than 0.05), and similar small discrepancies were found for histamine, leukotriene, prostaglandin F2 alpha, isoproterenol, and theophylline. Maximal isometric force and isotonic shortening after methacholine were linearly related (p less than 0.01). The between-methods difference is relatively small. Because the difference was of similar magnitude and in the same direction in all tissues studied, it is of little practical importance for conventional pharmacological experiments.

Bronchi↗