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PubMed1988

The relationship between bronchial responsiveness to methacholine and bronchial responsiveness to histamine in asthmatic subjects.

There is widespread belief that methacholine responsiveness in asthmatic subjects is closely related to histamine responsiveness, and that the two agents may be used interchangeably in the measurement of non-specific bronchial responsiveness (NSBR). Because this view has been challenged, we have examined the repeatability of measurements of bronchial responsiveness to methacholine and histamine and the relationship between them, in groups of 20 adult asthmatic subjects. Bronchial responsiveness was expressed as the cumulative dose (in both micrograms and mmols) provoking a 20% fall in FEV1 (PD20). The predicted 95% confidence limits for the second PD20 measurement of a further pair were within the range 0.5-2.0 x first PD20 for both agents. When the two agonists were compared in the same subjects, a significant difference in potency was noted (ratio of geometric means PD20.methacholine to PD20.histamine 2.19 [micrograms], 3.43 [mmols]; p = 0.0003). Furthermore, the variance of the differences of the pairs of log PD20.methacholine and PD20.histamine measurements was found to be significantly greater than that of either the paired methacholine measurements or the paired histamine measurements (p less than 0.01). We conclude firstly that methacholine is a less potent bronchoconstrictor than histamine and secondly that, while inhalation tests with either agent broadly reflect the degree of NSBR, they measure different phenomena and cannot be used interchangeably even after allowance is made for the difference in potency.

Adult↗
PubMed1989

Comparison of in vitro drug responses in airways of atopic dogs with and without in vivo airway hyperresponsiveness.

For comparison with previous studies in greyhounds and in the Basenji-Greyhound dog model of asthma (BG), basenji dogs were studied under identical conditions with respect to airway responsiveness to inhaled methacholine, cutaneous responses to intradermal antigen injection, and the sensitivity of isolated trachealis muscle to methacholine and isoproterenol. The relaxant effect of isoproterenol was assessed in trachealis muscle precontracted with methacholine (ED50). The basenji dogs resembled the BG dogs in that they showed multiple positive skin tests. Further, trachealis muscle showed a markedly reduced sensitivity to methacholine (pD2 6.64 +/- 0.10) (+/- S.E.) in vitro. However, basenji dogs resembled the greyhounds in requiring high concentrations of methacholine aerosols to produce a 2-fold increase in pulmonary resistance (1.68 mg/ml +/- 1.21). Thus, there were no significant correlations between sensitivity to methacholine in vitro and airway responsiveness to methacholine in vivo; however, the reduced sensitivity to methacholine in vitro in both basenji and BG dogs may be related to the marked atopy characteristic of both groups. In vitro sensitivity to isoproterenol was correlated (r = 0.82) with the concentration of methacholine needed to elicit the test contraction, but isoproterenol sensitivity in BG dogs was significantly less (p = .0027) than that predicted by the common regression line. This deficit in beta adrenergic function in trachealis muscle unrelated to atopy may be important in the in vivo airway hyperresponsiveness of BG dogs.

Aerosols↗
PubMed1989

Relaxation of human peripheral airway smooth muscle in vitro does not correlate with severity of chronic airflow limitation in vivo.

We tested the hypothesis that a defect in relaxation of peripheral airway smooth muscle contributes to chronic airflow limitation in chronic obstructive pulmonary disease (COPD). Twenty subjects underwent lung function measurements prior to thoracotomy. Lung tissue was obtained during surgery and bronchiolar segments were dissected. Smooth muscle function was measured isotonically in organ baths, using L-isoprenaline and the adenylate cyclase activator forskolin. Segments were precontracted with methacholine. Of the 20 subjects, 10 fulfilled the ATS criteria for COPD and had airflow limitation. There was no significant relationship between the degree of airflow limitation in vivo and the sensitivity or maximal response of peripheral airway muscle to methacholine, L-isoprenaline or forskolin in vitro. Furthermore, we found no differences between the mean contractile- and relaxation responses of airways from subjects with versus those without COPD and airflow limitation. Lung tissue from patients who regularly used beta-adrenergic drugs (n = 3) and/or steroids (n = 3) exhibited responses in vitro similar to those from subjects without medication. These results suggest that airflow limitation in COPD is not associated with an impaired relaxability of peripheral airway smooth muscle.

Adult↗
PubMed1989

The effect of oral prostaglandin E1 on airway responsiveness in asthmatic subjects.

Prostaglandin E1 (PGE1) is a bronchodilator in humans, but the effect of this prostaglandin on airway responsiveness in asthmatic subjects is not known. The purpose of this study was to examine the effect of oral PGE1 treatment on airway responsiveness to inhaled histamine and methacholine in asthmatic subjects. The subjects had inhalation tests performed on separate study days over a period of 2 weeks. PGE1 (200 micrograms 4 times daily) or placebo was taken in a double-blind fashion for 4 consecutive days. Each week, after three days of treatment, a histamine or methacholine inhalation test was performed on one day, followed by an inhalation test with the alternative agonist the following day. Baseline forced expired volume in 1 s (FEV1) values were similar before each inhalation test on each study day (P = 0.81). However, both histamine and methacholine airway responsiveness decreased following PGE1 treatment. The mean provocative concentration of histamine causing a 20% fall in FEV1 (PC20 histamine) on the placebo day was 1.47 mg/ml (%SD 3.05) and was 2.35 mg/ml (%SD 2.72) (p less than 0.005) during PGE1 treatment period. Similarly the PC20 methacholine was 1.84 mg/ml (%SD 2.30) on the placebo day and was 2.53 mg/ml (%SD 2.06) during PGE1 treatment period (p = 0.025). This study demonstrates that oral PGE1, administered in doses which did not change airway caliber, can reduce airway responsiveness in mild asthmatics.

Administration, Oral↗
PubMed1988

Leukotriene generation and small airway smooth muscle responsiveness in human lung.

The hypothesis was tested that endogenous leukotriene (LT) production in the lung causes desensitisation of airway smooth muscle to LT. The synthesis of LTB4, C4, D4 and E4 by human lung tissue, obtained at thoracotomies, after stimulation with Ca-ionophore was assessed by HPLC. Functional studies of small airway smooth muscle from the same tissue specimens were carried out using LTC4 and methacholine as the contracting agents. Generation of LTB4, C4, D4 and E4 was 453 +/- 82, 84 +/- 15, 71 +/- 27 and 40 +/- 16 pmol/g fresh tissue respectively (mean +/- S.E.M., n = 10). All airway smooth muscle preparations responded to LTC4 in a concentration dependent way with a -log EC20 of 8.56 +/- 0.13, a -log EC50 of 7.95 +/- 0.08 and a Tmax of 82 +/- 11 mg force/mg tissue weight, corresponding to 79 +/- 4% of the maximal response to methacholine (mean +/- S.E.M.; 27 preparations from 10 patients). No correlations were found between any of the functional parameters (-logEC20, -logEC50, Tmax to LTC4 and methacholine) and the amounts of LT's generated by the lung tissue. Furthermore airway smooth muscle contractility was not significantly reduced after repeated exposure of bronchiolar strips to LTC4 in vitro. These findings suggest that the responsiveness of human peripheral airway smooth muscle to LT is not related to the capacity of the lung tissue to synthetize LT.

Humans↗
PubMedDate not supplied

Dopamine-induced relaxation of the guinea-pig isolated jejunum is not mediated through dopamine receptors.

The possible involvement of specific dopamine receptors in the relaxing effect of dopamine in the guinea-pig isolated jejunum has been investigated. The relaxing effect of dopamine does not show the tachyphylaxis phenomenon and it is present in preparations from guinea-pigs pretreated with reserpine. These results indicate that dopamine has a direct action. Comparison of the effect of dopamine with those of other dopamine receptor agonists, i.e. apomorphine, bromocriptine and the DA1 selective fenoldopam, were made to calculate potency ratios. Since apomorphine, bromocriptine and fenoldopam were shown to relax the guinea-pig jejunum, partly behaving as indirectly acting agents, comparisons were made on reserpine-pretreated guinea-pigs. It has been found that apomorphine is 2.5 times, fenoldopam 3 times and bromocriptine 20 times more active than dopamine in relaxing the guinea-pig jejunum. The order of potency is different from that found in other dopamine receptors containing tissues. The effects of the dopamine receptor blockers, haloperidol and cis-alpha-flupenthixol and the DA1 selective blocker SCH 23390 on the relaxing effect of dopamine were also studied. The relaxing effect of dopamine was not reduced by haloperidol, cis-alpha-flupenthixol and SCH 23390. It is concluded that specific postjunctional dopamine receptors are not involved in the relaxing action of dopamine. Since dopamine is known to interact with alpha- and beta-adrenoceptors in a variety of tissues, the effects of the alpha-adrenoceptor blocker phentolamine and the beta-adrenoceptor blocker propranolol on the relaxing effect of dopamine were also studied. Noradrenaline has been used to check the responsiveness of the tissue. Phentolamine did not block the responses to dopamine and propranolol was able only to partially reduce responses to dopamine, at concentrations higher than those at which it antagonized noradrenaline. Mechanisms other than dopamine, alpha- or beta-receptor activation should be involved in the relaxing effect of dopamine in the guinea-pig jejunum.

Adrenergic alpha-Antagonists↗
PubMed2005

Bronchial challenge, assessed with forced expiratory manoeuvres and airway impedance.

OBJECTIVE: The Methacholine concentration at which a 20% decrease of the forced expiratory volume in 1s (PC20_FEV1) or a 40% increase in airway resistance (PC40_Rrs6) occur are accepted indicators for airway hyperresponsiveness. We hypothesised that the level of detection of bronchial hyperresponsiveness will differ between the two methods. METHODS: The response to Methacholine was assessed by forced oscillation technique (FOT) and spirometry in 20 stable hyperresponsive asthmatics. The effects of repeated lung function measurements on respiratory muscle fatigue were measured from maximal inspiratory mouth pressure (MIP). After each dose, patients scored their perception of dyspnoea on a BORG scale. Differences in patient's burden were measured by comparing the BORG-score at PC40_Rrs6 (BORG-PC40_Rrs6) and at PC20_FEV1 (BORG-PC20_FEV1). Reproducibility was also evaluated. RESULTS: The PC20_FEV1-values were 2.2 (0.4) doubling dose higher as compared to the PC40_Rrs6 (P<0.001). The mean BORG-score at PC40_Rrs6 was 1.7 points lower as compared to the BORG-score at PC20_FEV1 (P<0.001). The difference (mean(sd)) between the PC20_FEV1 of measurement 1 and 2 was -0.1 (1.4) doubling dose, and -0.3 (2.7) doubling dose for PC40_Rrs6. The MIP after Methacholine provocation was 1.0(0.2) kPa lower as compared to the MIP before the challenge test (P<0.001), suggesting respiratory muscle fatigue. CONCLUSION: Measuring PC40_Rrs6 shortens the challenge test and lowers the concentrations of bronchoconstrictor agents as compared to measurements of PC20_FEV1. The FOT-method was less strenuous for patients. In spite of the fact that the reproducibility is two-fold worse than measuring PC20_FEV1, it still remains quite acceptable at a mean of 0.3 doubling dose. The respiratory muscle strength was deteriorated after the challenge test.

Adult↗
PubMed1978

Cholinergic supersensitivity of the iris sphincter in Adie's tonic pupil.

In patients with unilateral Adie's syndrome, we compared the relative supersensitivity of the tonic pupil to methacholine hydrochloride (Mecholyl 2.5%) and pilocarpine 0.125%. We tested a large series of patients and photographed the pupils before and 30 minutes after the eyedrops. In a group of 36 patients, Mecholyl was positive in 64% of the tests; and in a group of 20 patients, pilocarpine 0.125% was positive in 80% of the tests. Eight patients who failed to show supersensitivity with Mecholyl were tested with pilocarpine and five of the eight were shown to be supersensitive. We concluded that pilocarpine, in this concentration is not only an adequate substitute for Mecholyl 2.5%, but is a more sensitive testing substance in unilateral cases, simply because it has a slightly stronger miotic action.

Adie Syndrome↗
PubMed1987

M2 muscarinoceptor-associated ionophore at the cat adrenal medulla.

Atropine and pirenzepine displaced 3H-quinuclydinyl-benzylate binding and inhibited methacholine-evoked catecholamine release with a similar order of potencies, atropine being 200 fold more potent than pirenzepine. In contrast to high-K, methacholine-evoked 45Ca uptake or catecholamine release were not blocked by (+)PN200-110. Bay-K-8644 did not modify the secretory response to methacholine either in the presence of Ca or Sr but potentiated K-evoked secretion. In depolarized glands, methacholine still evoked its usual secretory response. The results suggest that muscarinic stimulation of cat adrenal chromaffin cells stimulates Ca entry though an ionophore other than voltage-dependent Ca channels; such ionophore seems to be chemically operated through a M2 muscarinoceptor.

Adrenal Medulla↗
PubMed1997

Econazole, miconazole and SK & F 96365 inhibit depolarization-induced and receptor-operated contraction of guinea-pig isolated trachea in vitro.

Econazole, miconazole, SK & F 96365 and nifedipine inhibited Ca2+- and depolarization-induced and receptor-operated contraction of guinea-pig isolated trachea. Econazole, miconazole and SK & F 96365 inhibited histamine- and methacholine-induced tracheal contraction more than nifedipine. Nifedipine was more potent in inhibiting KCl-induced contraction. Nifedipine, salbutamol and theophylline, but not econazole, miconazole or SK & F 96365, relaxed KCl, histamine-, and methacholine-precontracted trachea. It appears that in the guinea-pig tracheal smooth muscle, econazole, miconazole and SK & F 96365 behave differently from nifedipine, theophylline and salbutamol. Econazole, miconazole and SK & F 96365 are thus introduced as novel antagonists of receptor-operated airway smooth muscle contraction.

Animals↗
PubMed1978

Bronchial hyperreactivity in cystic fibrosis and asthma.

We studied 113 patients with CF and compared their responsiveness to inhaled methacholine to that of 50 asthmatic children and 26 normal children. Positive responses to MCh occurred in 51% of the patients with CF and 98% of those with asthma. There was a significant correlation between a positive response to MCh in CF and poor pulmonary function. There was no relationship between allergic rhinitis or positive allergen skin tests and a positive MCh response. Dose-response curves and time course to MCh challenge differed in CF and asthma. Bronchial hyperreactivity is thus common in CF but is different from that in asthma.

Adolescent↗
PubMed1979

Lung function in children following repair of tracheoesophageal fistula.

Lung function and bronchial reactivity by methacholine challenge were studied in 24 patients seven to 18 years after repair of type I tracheoesophageal fistula. Only one patient had no abnormalities of the variables tested. Thirteen patients had obstructive airways disease, five had a restrictive defect, and 15 had a positive methacholine challenge. It is postulated that continuing subclinical aspiration of esophageal contents causes lung damage and renders the airways hyperreactive.

Adolescent↗
PubMed1981

Increased incidence of bronchial reactivity in children with a history of bronchiolitis.

To assess bronchial reactivity in children who have had bronchiolitis, we studied 48 children by challenging them with methacholine nine or ten years after admission to hospital with bronchiolitis. Pulmonary function was also evaluated. Fifty-seven percent of children studied had bronchial hyperreactivity. Thirty-three percent of first-degree relatives of those with a positive MCH challenge had a positive response. There was a significant correlation between the occurrence of a positive MCH challenge and a history of recurrent bronchiolitis. Pulmonary function tests demonstrated lower flow rates in the positive responders. Fourteen children had a history of asthma or wheezing, but this did not appear to be severe or frequent, and few required long-term therapy. There appears to be a strong genetic component in the prevalence of bronchial reactivity in these children. Bronchial hyperreactivity may be a risk factor in the development of COPD.

Bronchi↗
PubMed1985

Comparison of cold air, ultrasonic mist, and methacholine inhalations as tests of bronchial reactivity in normal and asthmatic children.

The sensitivity and specificity of cold air, ultrasonically nebulized distilled water mist (USM), and standard methacholine (MCH) challenges were studied in 21 children with asthma (mean age 11.5 years) and 12 normal children (mean age 14.2 years). The cold air challenge consisted of successive 3-minute periods of hyperventilation during which incremental volumes of subfreezing air (mean temperature -16 degrees C) were inhaled. To perform the USM challenge, subjects inhaled increasingly larger volumes of nebulized distilled water while breathing tidally. The specificity of both nonpharmacologic challenges was found to be 100%, whereas that of MCH was only 83%. The sensitivity of the cold air and USM tests was 57% and 71%, respectively, compared with 95% obtained with MCH challenge. We conclude that cold air and USM challenges are promising alternatives to the MCH challenge, and may be superior to it if optimal standard testing protocols are defined.

Adolescent↗
PubMed1975

Intermittent catheterization and bladder rehabilitation in spinal cord injury patients.

A review was made of 111 spinal cord injury patients who underwent bladder rehabilitation. The essential mode of treatment was intermittent catheterization. About 91 per cent of the patients were free of the catheter after 3 to 168 days of intermittent catheterization. Acute patients given an initial dosage of 30 to 40 mg. bethanechol chloride 3 times daily for 2 to 3 weeks recovered reflex activity in almost half the period (average of 32 days compared to 79 days). Modified sphincterotomy at the bladder neck was performed in 10 patients. This procedure improved the results to 98 per cent catheter-free reflex bladder status in the group of patients.

Follow-Up Studies↗