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PubMed1990

Beta-adrenergic responses and airway reactivity in healthy adults.

Healthy adults aged 18-90 years were tested for lymphocyte and granulocyte cyclic AMP responses to isoproterenol and prostaglandin E1 (PGE1), beta-adrenergic receptor density and antagonist binding properties, and for airway reactivity to methacholine. Our hypothesis was that reduced beta-adrenergic responses occur with aging and are associated with increased airway reactivity. This hypothesis was not supported by the data. Lymphocyte stimulation ratios (cyclic AMP level with stimulation/baseline cyclic AMP level) at higher concentrations of isoproterenol and PGE1 increased significantly with age. There were no significant age trends for any of the other variables. None of the beta-adrenergic responses or receptor properties correlated with airway reactivity to methacholine. beta-Adrenergic responses in lymphocytes and granulocytes from the same subject were weakly correlated at high concentrations. Prior studies which suggest that reduced beta-adrenergic responses and increased airway reactivity are concomitants of normal aging may differ from the present study in subject selection. In healthy older subjects, there appears to be no reduction in leukocyte beta-adrenergic responses or receptor properties and no change in airway reactivity.

Adolescent↗
PubMed1976

Innervation of trigonal area of canine urinary bladder.

Adrenergic and cholinergic histochemical staining techniques and in vitro muscle strip responses to adrenergic and cholinergic stimulation and blockade have failed to demonstrate any neuromorphologic or neuropharmacologic differences between the musculature of the canine trigone and that of the underlying detrusor. There is no evidence to suggest that a functional potential could be attributed to the trigone separate from that of the related bladder base.

Acetylcholine↗
PubMed1976

Cystometry. VI. Interpretation.

Cystometry should be performed under direct supervision of a physician, and interpretation must be supplemented by additional test procedures.

Female↗
PubMed1983

Effects of leukotrienes C4 and D4 on glycoprotein and lysozyme secretion by human bronchial mucosa.

The effects of leukotrienes C4 (LTC4) and D4 (LTD4) on the secretion by human bronchial mucosa of [14C]glucosamine-labeled, trichloro-acetic acid/phosphotungstic acid-precipitable glycoprotein and lysozyme were evaluated in vitro. LTC4 and LTD4, in the concentration range of 0.16 to 1600 nM, induced a dose-related increase in the release of radiolabeled glycoprotein, but not of lysozyme. This secretagogue effect was selective for high molecular weight glycoproteins of about 2-5 x 10(6) daltons, and the median effective concentrations (EC50) of LTC4 of 9.4 x 10(-9) M and of LTD4 of 2.44 x 10(-8) M, indicate that these leukotrienes are approximately 100-fold more potent than the cholinergic agonist methacholine. Incubation of [14C]glucosamine-labeled bronchial mucosal explants with LTC4 or LTD4 for six sequential 15-min periods revealed a rapid, progressive decrement in glycoprotein release, compatible with stimulatory action on secretion rather than augmentation of the rate of glycoprotein synthesis. This interpretation is also consistent with the finding that the specific activity (ratio of bound radiolabel: protein content) of the macromolecular glycoprotein secreted by the explants is not changed with stimulation of release by the leukotrienes. Based upon the activity of synthetic leukotriene analogs, the specific C-6 chirality of the sulfidopeptide of LTD4, the presence of a hydroxyl at C-5 and the presence of eicosanoid carbons 9-20 were of no importance for secretagogue activity. These findings contrast with the stereochemical requirements for the spasmogenic response to sulfidopeptide leukotrienes and suggest that leukotriene-induced secretion is not likely to be mediated via a specific receptor.

Bronchi↗
PubMed1983

The effect of synthetic leukotrienes on tracheal microvascular permeability.

The effect of synthetic leukotrienes (LT) C4, D4 and E4 on the permeability of the airway microvasculature to plasma albumin was quantitatively evaluated using an in situ guinea pig tracheal model. Vascular permeability was measured as extravascular albumin content by employing 125I-bovine serum albumin and, in order to correct for blood volume, 51Cr-erythrocytes were used. Intratracheal injection of synthetic LTC4, LTD4 and LTE4 (0.1-1000 ng) produced dose-dependent increases in tracheal extravascular albumin content. The leukotrienes were approximately 100-1000 fold more potent than histamine, although histamine did produce a greater maximal increase in extravascular albumin than the leukotrienes. Methacholine did not increase extravascular albumin content. The microvascular permeability effect of LTD4 was antagonized by FPL 55712 but not by mepyramine; conversely, the effect of histamine was antagonized by mepyramine and not by FPL 55712. Additionally, indomethacin did not alter the LTD4-induced increases in tracheal vascular permeability. These results suggest that the effect of LTD4 on tracheal microvascular permeability is directly mediated and is not the indirect result of cholinergic stimulation, histamine release or de novo synthesis of cyclooxygenase products.

Animals↗
PubMed1986

Ascorbic acid promotes prostanoid release in human lung parenchyma.

Ascorbic acid reduces airway reactivity to inhaled bronchoconstrictor agents in man and guinea pigs. The precise mechanism(s) responsible for this effect are unknown, but in both species an acute indomethacin treatment reverses the action of the ascorbic acid. To determine if ascorbic acid promotes prostanoid synthesis and/or inhibits degradation, human lung parenchymal slices (100-200 mg) were incubated for 60 minutes in oxygenated Tyrode's solution alone or with sodium ascorbate (0.001 M-1 M) and/or methacholine (1 microM-100 microM) and/or indomethacin (0.17 microM-17 microM). Aliquots of the incubation medium were assayed by radioimmunoassay for PGE2, PGF2 alpha, thromboxane B2 and 6-keto-PGF1 alpha. Ascorbic acid increased the accumulation of all four prostanoids in the incubation medium, especially thromboxane B2 and 6-keto-PGF1 alpha. This stimulatory effect of ascorbic acid was concentration-dependent and was inhibited by indomethacin. We conclude that ascorbic acid can alter prostanoid generation by human lung tissue and this effect may, in part, explain its antibronchoconstrictor activity in man.

Ascorbic Acid↗
PubMed1988

Is the epithelium-derived inhibitory factor in guinea-pig trachea a prostanoid?

To examine further the possible prostanoid involvement in the influence of the epithelium on guinea-pig tracheal smooth muscle responsiveness, we have analyzed the effects of LTD4, methacholine and histamine on the level of airway smooth muscle tone and on the amounts of PGE2, PGF2 alpha and PGI2 (determined by radioimmunoassay) in the presence and absence of the epithelium. Removal of the epithelium increased the sensitivity of guinea-pig trachea to the contractile effects of LTD4, methacholine and histamine. LTD4 (3-100 nM), methacholine (0.1-10 microM) or histamine (0.3-30 microM) did not increase prostanoid release above control values in either the presence or absence of the epithelium. The unstimulated release of PGE2 and PGF2 alpha, but not PGI2, was decreased in tissues lacking epithelium. Indomethacin (1 microM) reduced the baseline tone to a smaller extent in the absence of epithelium. In the presence but not the absence of the epithelium, indomethacin increased the sensitivity of preparations to the contractile effect of methacholine. The results support the postulate of an epithelium-derived inhibitory factor modulating guinea-pig tracheal smooth muscle responsiveness. The identity of this factor is not known but is not PGI2 and is unlikely to be PGF2 alpha or PGE2. However, the possibility remains that the basal release of PGE2 and/or PGF2 alpha derived from the epithelium may markedly affect the responsiveness of guinea-pig tracheal smooth muscle. Furthermore, the epithelium is a significant source of PGE2 and PGF2 alpha which may be involved in the maintenance of baseline tone.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

The modulatory effects of leukotrienes C4 and D4 on methacholine- and substance P-induced salivary secretion in rats.

Although certain prostaglandins have been found to be inhibitory to nerve-evoked salivary flow, little is known of the effects the leukotrienes on salivary secretion. It was the purpose of this investigation to examine the effects of leukotrienes C4 (LTC4) and D4 (LTD4) on salivary secretion in the rat, using methacholine or substance P to induce basal secretion, and to test whether or not the observed effects of these eicosanoids were receptor-mediated by using the leukotriene receptor blocker FPL-55712. Methacholine (3 x 10(-4) M), or substance P (1 x 10(-6) M) was infused intra-arterially to stimulate secretion and saliva was collected separately from the parotid gland and the submandibular gland of anesthetized rats. LTC4 and LTD4 (each at 1 x 10(-9) to 1 x 10(-6) M) were found to reduce methacholine- and substance P-induced salivary flow in a dose-related manner. Salivary protein concentration and amylase activity were not significantly altered by the leukotrienes; however, arginine-esterase activity, stimulated by substance P, was increased by both leukotrienes. FPL-55712 (1 x 10(-8) M) was shown to reduce the inhibitory effects of LTC4 and LTD4, suggesting the involvement of leukotriene receptors for these agents in their action.

Amylases↗
PubMed1988

Inhibition of the 5-lipoxygenase pathway with piriprost (U-60,257) protects normal primates from ozone-induced methacholine hyperresponsive small airways.

Weekly exposure to ozone in seven normal Rhesus monkeys led to induction of methacholine hypersensitive airways (RL increases 242 +/- 60% and Cdyn decreases 68 +/- 13% of baseline methacholine responses). It took 19 weeks to establish this hyperresponse that persisted for greater than 15 weeks once ozone was stopped. A second exposure led to similar response peaks in 6 weeks. At the peak of the second response, weekly 1% piriprost exposure before ozone led to a return to baseline that was not different between placebo and piriprost treated animals (9.4 +/- 1.0 and 4.3 +/- 2.9 weeks, placebo and treated, respectively P = 0.09 NS). A statistical difference in the mecholyl response in placebo and piriprost treated groups while on ozone was shown only in the Cdyn measurement (Cdyn% change 68 +/- 13 vs 24 +/- 14, placebo and piriprost, respectively P = 0.03). Off ozone (or return to baseline), a statistical difference could be detected both in RL and Cdyn (RL% changed 151 +/- 41 vs 31.1 +/- 49, P = 0.03, and for Cdyn 62.7 +/- 8 vs 9 +/- 10, P = 0.0006, placebo and piriprost, respectively). We conclude tha the primate provides a chronic model of airways reactivity in which the role of lipoxygenase is implicated because of the beneficial role of piriprost, and further that the ozone lesion is primarily in the smaller airways (possibly and alveolitis).

Airway Resistance↗
PubMed1977

Effects of intrastriatal injections of atropine and methacholine on the apomorphine-induced gnawing in the rabbit.

To find out the anatomical location of the target point of cholinergic-dopaminergic equilibrium, atropine (40 microng) or methacholine (10 microng) were injected through previously implanted cannulas into various places of caudate nucleus and putamen of the rabbit, and the effect of the injections on stereotype gnawing induced by subcutaneously or intravenously administered apomorphine (1--2 mg/kg) was assessed. The intensity of gnawing was measured using a special apparatus, counting each bite. Atropine inhibited the stereotype, while metacholine potentiated it. The effects were evident with the method used, but difficult to reveal with the classical method of assessing the intensity of stereotyped behavior, based on visual observation. The results suggest that the striatum is not a target point for the cholinergic component of the cholinergic-dopaminergic equilibrium in the central nervous system.

Animals↗
PubMed1975

Bronchial sensitivity to methacholine in current and former asthmatic and allergic rhinitis patients and control subjects.

Ninety-eight subjects underwent methacholine (Mecholyl) aerosol challenge at a concentration of 5 mg/ml. All atopic groups differed significantly in their bronchial response to Mecholyl compared to nonatopic control subjects. Nineteen normal subjects had a mean decrease of 11.4% in forced expiratory volume in one second (FEV1) with 128 Mecholyl inhalations and 2 decreased by greater than 20%. Fifteen of 27 allergic rhinitis patients had a positive response to Mecholyl as defined by a decrease in FEV1 greater than 20%. Four of these responders developed greater diminution in FEV1 response with additional Mecholyl inhalations in a manner similar to that seen in the asthmatic patients. Eighteen current asthmatics showed the greatest bronchial sensitivity to Mecholyl with a mean 33% decrease in FEV1 at 4.5 inhalations. One hundred per cent of current asthmatics and 82% (28 of 34) of former asthmatics (free of asthma symptoms for 1 to 20 yr) showed positive response to Mecholyl. A 20% decrease in FEV1 with a total of 20 inhalations or less is consistent with a diagnosis of "current asthma," and even 20 of 34 former asthmatics responded in this manner. The Mecholyl aerosol test can be used to diagnose previous and current asthma and may be of value in predicting asthma in hay fever patients.

Asthma↗
PubMed1975

A comparison of methacholine and histamine inhalations in asthmatics.

Bronchial provocation tests using aerosolized serially diluted histamine and methacholine were given to nearly 200 asthmatics. Results were usually reproducible for a given patient and corticosteroids did not influence the procedures. Those patients who could tolerate high doses of methacholine were statistically the least severe asthmatics as measured by their discharge dose of corticosteroids. Reaginmediated asthmatics could not tolerate the higher doses of histamine. These tests help delineate subgroups of asthmatics and may have clinical usefulness since, when combined with other data, they differentiate pathogenetic mechanisms in some patients and suggest therapeutic approaches in others.

Administration, Intranasal↗
PubMed1976

Metabolic changes in exercise-induced and methacholine-induced bronchoconstriction.

Metabolic and physiological responses to graded exercise and methacholine challenge were investigated in asthmatics with or without exercise-induced bronchoconstriction. The results showed that after methacholine challenge, free fatty acid levels increased only in patients with exercise-induced asthma, while they increased in both groups of asthmatics after treadmill exercise. No significant changes were noted in plasma lactic acid levels, ventilation, or oxygen consumption among the groups studied. These data suggest that asthmatics with exercise-induced bronchoconstriction may differ from other asthmatics in some of their metabolic responses.

Adolescent↗
PubMed1976

The effect of beta adrenergic blockade on bronchial sensitivity to acetyl-beta-methacholine in normal and allergic rhinitis subjects.

The effect of propranolol inhalation on sensitivity to methacholine inhalation was studied in normal and allergic rhinitis subjects to determine whether beta adrenergic blockade alters sensitivity to mediators in nonasthmatic atopic individuals. A partial beta adrenergic blockade is suggested as being instrumental in asthma. Hay fever patients studied showed similar effects and also developed asthma for the first time.

Adolescent↗
PubMed1976

The cholinergic nervous system and immediate hypersensitivity. 1. Eccrine sweat responses in allergic patients.

The cholinergically innervated human eccrine sweat gland is a readily available organ permitting the assessment in allergic patients of cholinergic reactivity with few or no adrenergic influences. The sweat responses of four matched groups (male allergic, female allergic, male control, and female control) to intradermal Mecholyl from 0.1 mug to 100 mug was compared; the 45 male and 45 female allergic patients demonstrated statistically significant increases in sweat responses to essentially all concentrations of Mecholyl examined. No difference in the sweat responses of patients with allergic rhinitis alone was compared with patients with both allergic rhinitis and allergic asthma was noted. Five patients with intrinsic asthma most closely resembled the allergic groups in their responses and 8 patients with vasomotor rhinitis sweated at or below the control groups. The increased sensitivity of allergic patients to cholinergic stimulation as measured by eccrine sweat responses suggest that this hyperresponsiveness may be one of the underlying defects in allergic disease.

Contraceptives, Oral↗
PubMed1977

Methacholine and physostigmine airway reactivity in asthmatic and nonasthmatic subjects.

Inhalation challenges using methacholine and physostigmine were performed in 3 human asthmatic and 3 nonallergic normal subjects. Plethysmographic measurements of specific airways conductance (Gaw/Vtg) were used to monitor the response. The dose required to produce a 17% fall in Gaw/Vtg was significantly lower in asthmatic subjects than in normal subjects for both physostigmine (p less than 0.0125) and methacholine (p less than 0.05). Moreover, in all subjects the relative airway sensitivity to methacholine correlated with the relative airway sensitivity to physostigmine. Both methacholine and physostigmine are cholinergic agents. Whereas methacholine acts directly at the end organ cholinergic receptor, physostigmine acts by increasing release and decreasing destruction of endogenous acetycholine at the vagal distal innervation. This suggests that the cholinergic airway hyperreactivity characteristic of asthma is a manifestation of end organ hypersensitivity.

Acetylcholine↗