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PubMed1989

Effect of inhaled ipratropium bromide on methacholine and exercise provocation in asthmatic children.

To determine whether doses of ipratropium bromide (IB) greater than those usually administered by aerosol (75-250 micrograms) give a greater degree of protection from exercise-induced asthma (EIA) in children, 12 patients with chronic asthma, ages 7-13 yr, were challenged with methacholine and exercise after inhalation of saline or 125, 250, 500, and 750 micrograms of IB on different days. A small and similar bronchodilation (mean increase over baseline: 5.26%) was observed 60 min after the administration of each dose of IB. IB prevented the bronchoconstriction caused by methacholine in all doses we used without statistically significant differences between them. All doses gave an all-or-none protection from EIA. Mean percent fall in FEV1 after exercise was 36.8, 18.3, 23.7, 27.1, and 23.2 following inhalation of saline or 125, 250, 500, or 750 micrograms of IB, respectively. The degree of protection from EIA was not correlated with the bronchodilation caused by IB. We suggest that muscarinic mechanisms are only partly responsible for the pathogenesis of EIA in children. Their importance varies among subjects and also may be variable in the same subject. Alternative mechanisms may be responsible for bronchoconstriction.

Administration, Inhalation↗
PubMed1993

Lung function and bronchial challenges in infants: repeatability of histamine and comparison with methacholine challenges.

UNLABELLED: Limited information exists regarding the repeatability of lung function and bronchial challenge tests using the rapid thoracic compression technique (RTC) in infants. AIMS: To determine the repeatability of lung function and histamine challenge test results using the RTC technique and to compare the results obtained for bronchial challenges using histamine (H) and methacholine (M). METHODS: Twelve infants [7 healthy, 5 with cystic fibrosis (CF) had pairs of H challenges 1 week apart. Eleven infants (7 healthy, 4 CF) had one H and one M challenge a week apart. The provocative concentration of H or M to cause a 40% fall in maximum flow at functional residual capacity (PC40) was determined using the RTC technique. Twenty-three comparisons were possible between maximal expiratory flow at functional residual capacity (VmaxFRC) measurements made 1 week apart. RESULTS: The mean difference between pairs of VmaxFRC measurements was 6.4% of baseline, and the coefficient of repeatability was 31.1% of baseline. The mean difference between PC40(H) measurements was 0.163 doubling concentrations, with a coefficient of repeatability of 1.66 doubling concentrations. The mean difference between PC40(H) and PC40(M) was 0.75 doubling concentrations, with 95% of PC40(H) between -0.18 to 1.69 doubling concentrations of the PC40(M). CONCLUSIONS: Although the repeatability of VmaxFRC using the RTC technique is less than for voluntary forced expiratory flow parameters in older children, similar results were obtained for infants as observed in older subjects for repeatability of H challenges and agreement between measures of bronchial responsiveness using H or M.

Bronchial Provocation Tests↗
PubMed1988

Muscarinic agonists modulate spontaneous and evoked unit discharge in auditory cortex of cat.

The present experiments studied the effects of cholinergic agonists and antagonists on the spontaneous and acoustic-evoked discharge of auditory cortical neurons and examined whether these effects were mediated by muscarinic cholinergic receptors. A primary focus of this report is the analysis of specific effects of these agents on the spontaneous and tone-evoked discharge and on different temporal components of the evoked discharge. Single neurons were recorded in the auditory cortex of chronically prepared, awake cats with multibarrel micropipette electrodes. The responses to acoustic stimuli were obtained before, during, and following continuous ejection of cholinergic agonist or antagonists by micropressure. The mean rate of discharge of the neurons was analyzed quantitatively for spontaneous discharge and for different peaks of the tone-evoked PSTH corresponding to tone "on," "through," and "off" responses. Acetylcholine (ACh) and acetyl-beta-methacholine (MCh) produced significant effects on spontaneous activity in 72% and 68% of neurons tested, respectively. Tone-evoked responses were effected in 92% and 82% of cells tested, respectively. The ability of these agonists to modify spontaneous or evoked activity was dose-dependent. Agonist effects on spontaneous and evoked activity were often different in the same cell; however, effects on spontaneous activity did predict effects on "through" responses. The most common effect of ACh or MCh on evoked activity was facilitation of the tone "on" response. For neurons with multicomponent discharge patterns in response to tones, the agonists had nonuniform effects on different response components. However, the effects of ACh on the "on" and "off" responses covaried. Hence cholinergic agonists produce heterogeneous, selective effects on different components of the responses of auditory cortical neurons rather than simple increases or decreases in discharge level. The effects of cholinergic agonists were modified in the presence of atropine. The effects of MCh were blocked by atropine in a higher proportion of cases than those of ACh.

Acetylcholine↗
PubMed1989

Cholinergic modulation of frequency receptive fields in auditory cortex: I. Frequency-specific effects of muscarinic agonists.

Previously we reported that acetylcholine (ACh) and acetyl-beta-methacholine (MCh) modify responses of neurons in auditory cortex to individual frequencies. The purpose of this study was to determine whether muscarinic agonists produce frequency-specific alterations or general changes in cellular responses. Frequency-specific modifications would be evident in alterations of frequency receptive fields (FRF) that differed across frequencies while general effects would be seen as changes that were more or less the same over frequencies. Responses of single neurons to designated sets of tones were recorded in the auditory cortex of chronically prepared awake cats before, during, and following ejection of ACh or MCh by iontophoresis or micropressure using multibarrel micropipettes. Frequency receptive fields were determined by presenting isointensity tones across a range of frequencies including the cell's best frequency (BF) to tone onset. FRF for "off" and "sustained (through)" responses were also determined quantitatively. The effects of ACh and MCh were predominantly frequency-specific (77%, 39/51 cells); general changes (19%, 10/51) and no effects (4%, 2/51) were less likely. Frequency-specific effects involved both facilitation and reduction of the same response component to different frequencies within the same neuron. For responses to tone onset (but not "through" and "off" responses), agonists were more likely to produce a decrease at the BF while simultaneously increasing responses to other frequencies. Agonists could increase or decrease frequency selectivity. Effects of agonists could be blocked by atropine, suggesting involvement of muscarinic receptors.

Acetylcholine↗
PubMed1993

Airway response to inhaled methacholine in normal human subjects.

The individual airway responsiveness to inhaled, nebulized methacholine (MeCh) was estimated in normal volunteers, measuring specific airway conductance (sGAW). The dose of MeCh was increased logarithmically until a 60-65% reduction from baseline sGAW or an asymptotic approach to a maximal response was attained. The concentration of MeCh that caused a 35% reduction in sGAW (PC35), the dose that caused a 62.5% reduction in sGAW, the slope of the straight, central part of the log-dose-response curve (LDRC), the slope of the straight, initial part of the dose-response curve, the maximal response attainable (Emax) and the dose causing a half-maximal response (ED50) were derived. These parameters were transformed as necessary to attain normality of distribution. Relationships between them were examined by measuring the correlations between their transformed values. The ED50 was taken to represent the least biased estimate of the sensitivity to MeCh. The PC35 was the best practical estimate of sensitivity. The Emax was taken to represent the least biased estimate of the reactivity to MeCh. The slope of the LDRC was the best practical estimate of reactivity. The sensitivity and reactivity varied independently in these normal subjects. Each was also independent of the baseline sGAW.

Administration, Inhalation↗
PubMed1977

Regulation of the secretory cycles of mucous and serous cells in the human bronchial gland.

Studies of the human bronchial gland in organ culture have allowed us to elucidate some of the factors controlling the synthesis and secretion of bronchial mucus. The secretory cycles of mucous and serous cells appear to differ, the former alternately accumulating and discharging secretory material, while in the latter synthesis and discharge occur simultaneously. Parasympathomimetic agents increase the secretory rate of mucous and serous cells by stimulating discharge, but have no effect on the rate of precursor incorporation into intracellular glycoproteins. Glycoprotein synthesis inhibitors reduce the incorporation of precursors into intracellular macromolecules but do not reduce the rate of discharge of preformed glycoproteins. The rate of glycoprotein synthesis appears to be greater in mucus-secreting cells of hypertrophied glands than of normals. Ouabain reduces the incorporation of glucose and threonine, but not glucosamine, into mucous and serous cells but has no effect on the rate of discharge. In hypertrophied glands, ouabain--sensitive threonine, but not glucose, transport appears to be increased. Exposure of rats to tobacco smoke causes an increase in the size of tracheal and laryngeal glands and in the secretory rate of mucous cells. The anti-inflammatory agent, phenylmethyloxadiazole, prevents both tobacco smoke-induced effects, presumably by reducing the secretory activity of mucous cells.

Animals↗
PubMed1979

Autoreversal of bradykinin response in the perfused isolated canine hind limb.

The vascular effects of synthetic bradykinin were studied in perfused isolated canine hind limb preparations. Repeated low doses of bradykinin or high doses administered at sufficiently long time intervals elicited dose-related hypotensive responses. In contrast, administration of bradykinin at short time intervals led first to diminishing hypotensive responses followed by frank increases in perfusion pressure. This autoreversal of bradykinin response tentatively was explained on the basis of known effects of bradykinin on prostaglandin synthesis with specific reference to PGF2 alpha.

Animals↗
PubMed1988

Ocular autonomic function in progressive autonomic failure.

Ocular autonomic function was assessed in 4 patients with progressive autonomic failure (PAF) and age-matched control subjects, by measurement of the pupil cycle time, and determination of autonomic denervation hypersensitivity of the iris. Pupil cycle time was abnormal in all patients with PAF; sustained pupil cycling was absent in 5 of the 8 eyes tested of the PAF patients, compared with only 16 eyes from 70 control subjects. Pupil constriction in response to 2.5% methacholine, indicative of parasympathetic denervation hypersensitivity, was significantly increased in patients with PAF (p less than 0.001), whilst pupil dilation in response to 0.5% phenylephrine, indicative of sympathetic denervation hypersensitivity, was also significantly higher in the PAF patients (p less than 0.001). The results suggest that ocular autonomic function may provide a sensitive early indicator of generalised autonomic dysfunction.

Aged↗
PubMed1993

Glycopyrronium bromide blocks differentially responses mediated by muscarinic receptor subtypes.

To analyse the potency of glycopyrronium bromide in blocking responses mediated via subtypes of muscarinic receptors in vitro, we tried to determine its equilibrium dissociation constants at prejunctional muscarinic receptors inhibiting the twitch response of rabbit vas deferens (presumed M1 type), at M2 (paced at left atria), M3 (guinea pig ileum) muscarinic receptor subtypes and at the muscarinic receptor of the rabbit iris sphincter (not M1-M4, not m5). Glycopyrronium bromide shifted to the right the curve for inhibition of the twitch response induced by the agonist McN-A-343, and the methacholine-induced curves for inhibition of rat atrial contraction, and for tonic contraction of guinea pig ileum and rabbit iris sphincter. Glycopyrronium bromide blocked with very high potency (> 11, apparent -log KB) the response in rabbit vas deferens. Its affinity was low (9.09) for the M2 subtype, and intermediate (10.31 or 10.13) for the ileal M3 and the atypical iris muscarinic receptor subtype, respectively. Except at the receptors in rabbit vas deferens, the blockade of agonist effect appeared to be of simple competitive type. In conclusion, glycopyrronium bromide is about 10 or 100 fold more potent in preventing a response to activation of the prejunctional receptor in rabbit vas deferens than in blocking an M3 or M2 muscarinic receptor subtype, respectively, in vitro. The low affinity for M2 receptors may, in part, explain the low incidence of unwanted tachycardia in therapy. The drug failed to discriminate between an M3 receptor and the atypical rabbit iris sphincter receptor.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1988

Inhibition of a peripheral sympathetic-cholinergic system by presynaptic alpha 2-adrenoceptors.

Intravenous administration of catecholamines produced dose-related inhibition of electrodermal responses (EDRs) evoked by electrical stimulation of the post-ganglionic sciatic nerve in anaesthetized rats, with relative potencies being (-)-adrenaline greater than (+/-)-adrenaline greater than (-)-noradrenaline = (+)-adrenaline. The suppression of EDRs by (+/-)-adrenaline and (-)-noradrenaline was blocked by pretreatment with yohimbine (0.75 mg/kg i.v.) but not by prazosin (0.3 mg/kg i.v.). The selective alpha 2-adrenoceptor agonist B-HT 920 also inhibited neurally evoked skin potential responses. This effect of B-HT 920 was antagonized by the selective alpha 2-adrenoceptor antagonist idazoxan (0.1 mg/kg i.v.) but was insensitive to prazosin. Idazoxan was more potent than yohimbine in blocking (+/-)-adrenaline-induced suppression of EDRs. Methacholine administered into the femoral artery evoked EDRs by an atropine-sensitive mechanism. Methacholine-induced EDRs were not suppressed by intravenous administration of (-)-adrenaline (1 microgram/kg or 3 micrograms/kg) whereas EDRs evoked by the sciatic nerve stimulation on the other hindpaw were inhibited. Increase in the endogenous catecholamines by asphyxia strongly inhibited EDRs by a mechanism which was also sensitive to yohimbine but not to prazosin. These results suggest that peripheral presynaptic alpha 2-adrenergic mechanisms are involved in inhibition of transmitter release in this sympathetic-cholinergic system.

Adrenergic alpha-Antagonists↗
PubMed1988

Methoctramine selectively blocks cardiac muscarinic M2 receptors in vivo.

The antimuscarinic effects of methoctramine (N, N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, 8-octanediamine tetrahydrochloride), a polymethylene tetraamine endowed with high cardioselectivity in vitro, were assessed in two in vivo preparations. Methoctramine (300 micrograms/kg i.v.) strongly inhibited the methacholine- and muscarine-induced bradycardia in the anaesthetized an pithed rat, respectively. The same dose of methoctramine did not significantly affect the depressor action of methacholine in the anaesthetized rat mediated by vascular M2 receptors. Furthermore, even high doses of methoctramine (up to 1 mg/kg i.v.) did not reduce the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarine or McN-A-343 in the pithed rat. These data suggest that methoctramine while showing high affinity for cardiac M2 alpha receptors has rather low affinity for ganglionic M1 and vascular M2 receptors. This in vivo study thus provides further evidence to support the view that methoctramine is a potent and highly selective antagonist of cardiac M2 alpha receptors.

Animals↗
PubMed1988

Effect of muscarinic receptor stimulation on release of cysteinyl-leukotrienes and thromboxane B2 from anaphylactic guinea-pig hearts.

The effects of muscarinic receptor stimulation by infusions of methacholine (6.25 x 10(-8) mol/min or 1.9 x 10(-7) mol/min) into isolated perfused, spontaneously beating sensitized guinea-pig hearts on the anaphylactic release of cysteinyl-leukotrienes (LT) and thromboxane (TX) B2 were investigated. Methacholine increased coronary flow and decreased heart rate under basal conditions. Furthermore, infusions of methacholine (1.9 x 10(-7) mol/min) significantly increased the anaphylactic release of TXB2 as well as of immunoreactive cysteinyl-LT, which were demonstrated by reversed phase high pressure liquid chromatography to consist of a mixture of LTC4, LTD4 and LTE4. Infusions of atropine (1.3 x 10(-7) mol/min) alone did not significantly affect coronary flow and heart rate prior to ovalbumin injection nor anaphylactic release of cysteinyl-LT. The anaphylactic release of TXB2 was, however, significantly decreased in the presence of atropine. Atropine (1.3 x 10(-7) mol/min) infused in addition to methacholine (1.9 x 10(-7) mol/min) abolished the effects of the muscarinic receptor agonist on spontaneous heart rate and significantly antagonized the increase in coronary flow prior to ovalbumin injection. Similarly, the simultaneous infusion of atropine abolished the effects of methacholine on the anaphylactic release of TXB2 and cysteinyl-LT. After antigen challenge hearts infused with methacholine, atropine or the combination of both drugs did not exhibit any differences with respect to anaphylactic changes of heart rate or the time course of anaphylactic coronary flow reduction. Thus, in the isolated perfused anaphylactic guinea-pig heart, muscarinic receptor stimulation significantly enhanced the release of the arachidonic acid-derived mediators TXB2 and cysteinyl-LT.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylaxis↗
PubMedDate not supplied

Muscarine receptor types mediating autoinhibition of acetylcholine release and sphincter contraction in the guinea-pig iris.

The potencies of several muscarine receptor antagonists in blocking either the autoinhibition of acetylcholine release or the muscarinic contraction of the sphincter muscle upon acetylcholine release were investigated in the guinea-pig iris. The agonist at pre- or postjunctional muscarine receptors was acetylcholine released upon field stimulation (5.5 Hz, 2 min) of the irides preloaded with 14C-choline. The stimulation-evoked 14C-overflow was doubled in the presence of atropine 0.1 mumol/l but unaffected by the agonist (+/-)-methacholine (50 mumol/l). Thus, under the present stimulation conditions, the autoinhibition of acetylcholine release on the guinea-pig iris cholinergic nerves was nearly maximally activated. Isotonic contractions of the irides upon field stimulation consisted of a rapid, atropine (0.1 mumol/l)-sensitive peak phase followed by a sustained contraction which involved a cholinergic and a non-cholinergic stimulation of the sphincter muscle. The M2-selective antagonists methoctramine (10 mumol/l) and gallamine (100 mumol/l) increased both the 14C-overflow and the peak contractions evoked by field stimulation. In contrast, the M3-selective antagonist hexahydrosiladifenidol (0.1-10 mumol/l) failed to affect the evoked 14C-release but concentration-dependently (1-10 mumol/l) reduced the iris contractions. Pirenzepine (10 mumol/l) enhanced the evoked 14C-overflow and inhibited the peak contractions (0.1-10 mumol/l; maximal effect at 10 mumol/l). The low potency of the antagonist at both receptor sites indicates that an M1 muscarine receptor is not involved. The results are consistent with the idea of M2 muscarine receptors mediating autoinhibition of acetylcholine release in the guinea-pig iris and M3-like receptors inducing the contraction of the sphincter muscle.

Acetylcholine↗
PubMed1981

Tracheal submucosal gland serous cells stimulated in vitro with adrenergic and cholinergic agonists. A morphometric study.

A morphometric analysis was made of alterations in serous cell structure induced by adrenergic and cholinergic agonists. Ferret tracheal rings were exposed for 30 min in vitro to one of the following agonists: phenylephrine, terbutaline, or methacholine (all at 10(-5) M). Controls were incubated similarly in medium containing no drugs or medium containing both the agonist and an excess of the appropriate antagonist (phentolamine, propranolol or atropine, all at 10(-4) M). Electron microscopic observation and stereological analysis of the incubated samples revealed that the volume density of serous cell granules in controls (0.30 +/- 0.02, mean +/- SE, n = 4) was significantly reduced by phenylephrine (0.19 +/- 0.03, n = 4) and methacholine (0.17 +/- 0.01, n = 4), but not by terbutaline (0.27 +/- 0.04, n = 4). The presence of antagonists in the medium prevented the observed changes (phenylephrine/phentolamine: 0.29 +/- 0.03, n = 3 and methacholine/atropine: 0.33 +/- 0.06, n = 3). In addition, the volume density of intracellular vacuoles in controls (0.02 +/- 0.05, n = 4) was increased in response to methacholine stimulation (0.12 +/- 0.05, n = 4), but not in response to the other agonists. This effect was blocked by atropine (0.01 +/- 0.00, n = 3). We conclude that serous-cell granules are discharged by both alpha-adrenergic and cholinergic, but not beta-adrenergic stimulation. In addition, cholinergic stimulation evokes the formation of intracellular vacuoles, a possible indication of active ion and water transport.

Animals↗
PubMed1987

Epidemiological diagnosis of asthma: methodological considerations of prevalence evaluation.

Within an epidemiological survey on Chronic Obstructive Pulmonary Disease, before reporting data on the prevalence of bronchial asthma we checked the group of subjects defined as "pathological" by means of a suitable questionnaire and a group of "normals" as a control. We evaluated the sensitivity and specificity of the questionnaire, in comparison with a clinical evaluation made by two physicians and controlled the relationship among their results, non-specific bronchial hyperreactivity and skin tests. In particular the correspondence between diagnosis made by physicians from a clinical evaluation and that obtained by questionnaire was not satisfactory. We suggest the importance of employing physicians for an epidemiological approach to asthma, in absence of a valid objective criterion.

Adolescent↗