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Biomedical subjects

A Ullman

Publications and source records attributed to A Ullman.

At least 37 records · Page 2Linked to original sources
PubMed1992

Onset of action and duration of effect of formoterol and salmeterol compared to salbutamol in isolated guinea pig trachea with or without epithelium.

Formoterol and salmeterol are 2 newly developed beta 2-adrenoceptor agonists for inhalation with prolonged duration of effect compared with currently available beta 2-agonists. The clinical duration of effect has been suggested to be correlated to a decreased washability in vitro, i.e. decreased effect due to continuous washing of the organ bath. In this study we compared the washability and the onset of the relaxatory effect of formoterol (0.01 microM), salmeterol (0.05 microM) and salbutamol (0.1 microM) in isolated guinea pig trachea contracted with carbachol (0.1 microM). We also evaluated a possible influence of the epithelium on onset of action and/or duration of effect. A significant relaxatory effect of formoterol and salmeterol remained after washing, whereas no effect of salbutamol remained. We also found a rapid onset of action for both salbutamol and formoterol, but a significantly slower onset for salmeterol. Both the washability and the onset of action were found to be independent of the presence of the epithelium.

Adrenergic beta-Agonists↗
PubMed1992

The non-adrenergic, non-cholinergic response counteracts changes in guinea-pig airway tone with and without sympathetic activation.

1. We examined whether the non-adrenergic, non-cholinergic (NANC) neural response can counteract changes in smooth-muscle tone with and without simultaneous sympathetic activation in guinea-pig airways. 2. Isolated airway preparations were pretreated with indomethacin (10 microM) and incubated with either atropine (1 microM) and guanethidine (10 microM) or atropine (1 microM) alone. The response to electrical field stimulation (EFS: 1200 mA, 0.5 ms, 3 Hz for 240 s) was studied at various levels of tone prior to EFS: first without induced tone, then at a moderate tone induced by histamine (0.3 microM) and finally at a high tone induced by histamine (6 microM). 3. The response to EFS was a contraction when the tone prior to EFS was low and a relaxation when the tone prior to EFS was high. These responses converged towards a similar level of tone, in the distal trachea and in the main bronchus, with and without guanethidine. 4. The mean (s.e. mean) level of tone towards which the responses to EFS converged was lower after incubation with atropine alone compared with incubation with atropine and guanethidine, both in the distal trachea [8 (1)% compared with 30 (6)% of maximum tone] and in the main bronchus [28 (4)% compared with 57 (2)% of maximum tone]. In separate experiments, the guanethidine-induced effect on the responses to EFS was imitated by propranolol (1 microM) but not by prazosin (0.3 microM) and yohimbine (1 microM). 5. These findings indicate that the NANC neural response can counteract changes in airway smooth-muscle tone via a contraction or via a relaxation, depending on the tone prior to activation.This stabilizing effect on tone does not appear to depend upon adrenergic activation per se. The level of tone towards which the NANC responses converge can, however, be reduced by beta-adrenoceptor activation, thus suggesting an interaction which provides protection from severe airway smooth-muscle contraction.

Adrenergic alpha-Agonists↗
PubMed1992

In vitro tachyphylaxis to isoprenaline in guinea-pig trachea: influence of theophylline?

We used frontally opened tracheal rings, contracted with 10 microM of histamine to produce beta-adrenoceptor tachyphylaxis by isoprenaline incubation and to evaluate whether theophylline can prevent this tachyphylaxis. Two concentration-response experiments with isoprenaline were performed in each ring. Between the concentration-response experiments the rings were incubated using four different treatments, isoprenaline (3 microM), theophylline (1 mM), theophylline + isoprenaline or vehicle for 60 min. Tachyphylaxis was evaluated as the difference in pD2 (-log EC50) during the first and second concentration-response experiment. Isoprenaline incubation produced a shift to the right of the concentration-response curve. The shift was small (approximately 0.2 log units) but significantly different from the control group. Theophylline failed to influence the process either alone or in combination with isoprenaline. In conclusion, beta-adrenoceptor tachyphylaxis after isoprenaline incubation in isolated guinea-pig trachea proved to be a very small effect and we observed no influence by theophylline.

Animals↗
PubMed1991

Non-adrenergic, non-cholinergic regulation of guinea-pig airway smooth muscle-indomethacin-induced changes and segmental differences.

Several lines of evidence suggest a regulatory role for the non-adrenergic, non-cholinergic (NANC) nervous system in the airways of the guinea-pig and man. We examined NANC frequency-response characteristics (0.2-90 Hz) with respect to segmental differences and effects of cyclooxygenase-inhibition (indomethacin 10 microM). Furthermore, the neurogenic contribution to the contractile and the relaxatory NANC response was quantified with tetrodotoxin (1-10 microM). Frontally opened guinea-pig airway rings (n = 3-7) were used. NANC responses were obtained by electrical field stimulation (0.5 ms; 1200 mA; 240 s). A relaxatory NANC response was demonstrated in the proximal and the distal trachea. A contractile NANC response was demonstrated in the distal trachea and the main bronchus. Indomethacin lowered the baseline tension, decreased the relaxatory and increased the contractile NANC response (p less than 0.05; at 0.8 Hz; n = 4). A relationship between the baseline tension and the NANC response is suggested. The relaxatory NANC response was tetrodotoxin-sensitive at 3 Hz stimulation frequency (p less than 0.05; n = 3). At this frequency, the contractile NANC response was also mainly tetrodotoxin-sensitive (p less than 0.05; n = 6) whereas at 60 Hz a dominant, tetrodotoxin-resistant contraction was demonstrated. The pronounced frequency-response relationship as well as the tetrodotoxin sensitivity at very low frequencies (0.2-1.6 Hz) indicates that tetrodotoxin-sensitive NANC nerves are stimulated optimally at low impulse frequencies.

Animals↗
PubMed1991

Non-adrenergic, non-cholinergic neural activation stabilizes smooth-muscle tone independently of eicosanoid factors in guinea-pig isolated airways.

1. We examined the effect of variations in resting smooth-muscle tone induced eicosanoid inhibitors on the direction and magnitude of the non-adrenergic, non-cholinergic (NANC) nervous response in guinea-pig isolated airways. 2. NANC responses (in the presence of 1 microM atropine, 10 microM guanethidine) to electrical field stimulation (1200 mA; 0.5 ms; 240 s; 3 Hz) were studied in guinea-pig isolated airway preparations (n = 4-7) taken from the proximal trachea, the distal trachea and the main bronchus. Tissues were treated with either the cyclo-oxygenase-blocker, indomethacin (10 microM), or the leukotriene receptor antagonist, FPL 55712 (11.5 microM), to modulate the resting tone. 3. Depending on the level of resting tone prior to electrical field stimulation, NANC activation induced either a contraction or a relaxation converging towards a similar level of tone, a 'tonus equilibrium'. This tonus equilibrium displayed an increasing level towards the periphery (3 +/- 3 (s.e.mean) % for the proximal trachea, 28 +/- 3% for the distal trachea and 54 +/- 4% for the main bronchus, in % of maximum active tension). After NANC activation, the tonus returned to a level similar to the resting tone. 4. We conclude that changes in resting smooth-muscle tone not only affect the magnitude but also the direction of the NANC response. It is suggested that the NANC nervous system is a stabilizing factor in the regulation of airway smooth-muscle tone, independent of eicosanoid factors. An increasing contractile component and a decreasing relaxant component of the NANC system towards the peripheral airways is indicated.

Animals↗
PubMed1991

In vitro characteristics of spontaneous airway tone in the guinea-pig.

Spontaneous airway tone has been demonstrated in the guinea-pig and man in vitro but little data on the magnitude and time-course of this phenomenon is available. Moreover, the literature on possible mediators is conflicting. In the present in vitro study, spontaneous airway tone (measured as spontaneous active tension) was examined in frontally-opened guinea-pig airway rings (n = 4-8). The examination related to magnitude, time-course and segmental differences as well as the role of eicosanoids, acetylcholine and adrenergic mechanisms. Spontaneous active tension of considerable magnitude (approximately 40% of maximum active tension) and stability was recorded during the second hour of the experiments. An initial small segmental difference between the trachea and the main bronchus gradually decreased during the first hour of observation. Cyclooxygenase inhibition by indomethacin completely abolished the spontaneous active tension. The leukotriene antagonist FPL 55712 reduced the active tension, whereas the leukotriene antagonist L-648,051 did not significantly affect it. Muscarinic blockade and adrenergic depletion had no effect. We conclude that the spontaneous active tension is of such a large magnitude and stability that it may play an important role in maintaining normal airway tone and that there are no pronounced segmental differences. The complete inhibition by indomethacin and the lack of effect by L-648,051 indicate that the spontaneous airway tone is primarily maintained by prostanoids and suggest that leukotriene D4 is of minor importance. The effect of FPL 55712 was probably due to inhibition of phosphodiesterase.

Animals↗
PubMed1991

Peptidase modulation of noncholinergic vagal bronchoconstriction and airway microvascular leakage.

We investigated whether inhibition of neutral endopeptidase 24.11 (NEP) and/or angiotensin-converting enzyme (ACE) modifies vagally induced nonadrenergic noncholinergic (NANC) airflow obstruction and airway microvascular leakage as measured by extravasation of Evans blue dye (intravenous) in anesthetized guinea pigs. We gave phosphoramidon to inhibit NEP and enalapril maleate or captopril to inhibit ACE. Animals pretreated with inhaled phosphoramidon (7.5 or 75 nmol), enalapril maleate (87 or 870 nmol), or captopril (350 nmol) reached higher peak lung resistance (RL) values (14.3 +/- 2.7, 15.7 +/- 3.8, 16.7 +/- 3.8, 11.4 +/- 1.6, and 24.6 +/- 3.5 cmH2O.ml-1.s, respectively) than saline-treated animals (5.9 +/- 1.1; P less than 0.05) after bilateral vagus nerve stimulation (5 Hz, 10 V, 10 ms, 150 s). Intravenous phosphoramidon (1 mg/kg), but not intravenous captopril (6 mg/kg), potentiated peak RL (22.9 +/- 6.9 and 7.1 +/- 1.5 cmH2O.ml-1.s, respectively). Vagal nerve stimulation (1 and 5 Hz) increased the extravasation of Evans blue dye in tracheobronchial tissues compared with sham-stimulated animals, but this was not potentiated by inhaled enzyme inhibitors or intravenous captopril. However, intravenous phosphoramidon significantly augmented the extravasation of Evans blue dye in main bronchi and intrapulmonary airways. We conclude that degradative enzymes regulate both NANC-induced airflow obstruction and airway microvascular leakage.

Acetylcholinesterase↗
PubMed1991

Tetrodotoxin does not block the epithelium-dependent release of prostaglandin E2 induced by electrical field stimulation in isolated ferret trachea.

Electrical field stimulation (EFS) has previously been shown to induce the release of prostaglandin (PG) E2 from ferret tracheal epithelium. We have now conducted a study to see whether this effect of EFS is due to the activation of nerves or whether it is a non-neural effect. The release of PGE2 and 6-keto-PGF1 alpha into the bath fluid was assayed in isolated ferret tracheas with (E+) or without (E-) epithelium, stimulated by either EFS or direct vagal nerve stimulation (DNS) repeatedly for 120 min. EFS-stimulated E+ preparations showed a gradual decline in the contractile responses (30 +/- 1% of baseline) and an increase in PGE2 to 296 +/- 38 pg/ml. In EFS-stimulated, epithelium-denuded (E-) preparations, the decline was significantly lower (11 +/- 5%), as well as the final concentration of PGE2 (107 +/- 21 pg/ml). In DNS-stimulated E+ preparations, the contraction decline was 8 +/- 1% and the final concentration of PGE2 was less than 6 pg/ml. Although tetrodotoxin (TTX) abolished the contractile response in EFS-stimulated E+ preparations, it did not significantly reduce the release of PGE2 (260 +/- 6 pg/ml), whereas atropine partly counteracted the release. The bath concentration of 6-keto-PGF1 alpha increased, independently of the electrical stimulation, contractile response, or presence of the epithelium. We conclude that EFS activates the epithelium-dependent release of PGE2 by a TTX-resistant mechanism. This may be due to an activation of TTX-resistant nerves, or possibly to a non-neural effect, such as a direct effect on the epithelial cells. The results indicate that the airway epithelium has the ability to respond to certain stimuli with a pronounced release of PGE2, thereby counteracting bronchoconstriction.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Epithelium-derived PGE2 inhibits the contractile response to cholinergic stimulation in isolated ferret trachea.

We have previously reported that epithelium-dependent inhibitory factors, both prostanoids and non-prostanoids, can be activated by electrical field stimulation (EFS) and direct nerve stimulation (DNS) in an in vitro nerve-muscle preparation of ferret trachea. In this study we set out to compare the release of the inhibitory prostanoids, PGE2 and PGI2, in preparations with intact and with removed epithelium. Ferret tracheae were mounted in organ baths and phasic contractions were induced by EFS and DNS. The bath concentrations of PGE2 and the PGI2-metabolite 6-keto-PGF1 alpha were measured using radioimmuno assays. The gradual decrease in contractile response to DNS, 2 Hz for 120 min, was 95 +/- 2% of baseline (mean +/- SEM) in preparations with intact epithelium compared with 29 +/- 8% in epithelium-denuded preparations (p less than 0.001). The bath-levels of PGE2 showed a slight but significant (p less than 0.01) increase in denuded preparations with a final bath-concentration at 120 min of 13 +/- 3 pg/ml. The release of PGE2 was more pronounced in preparations with intact epithelium which resulted in a final bath-concentrations of PGE2 of 84 +/- 38 pg/ml which was significantly higher compared with epithelium-denuded preparations and also compared with time-matched controls with the same pattern of contraction induced by DNS alone. The concentrations of 6-keto-PGF1 alpha showed a slight increase which was of comparable magnitude (ns) in intact and denuded preparations. In conclusion this study demonstrates that the cyclooxygenase-dependent component of the epithelium-dependent inhibition of the contractile response to cholinergic nerve stimulation in ferret trachea is mediated by PGE2 but not by PGI2.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Effects of growth hormone on muscle regeneration and IGF-I concentration in old rats.

A study was made of regeneration of skeletal muscle in young adult and old rats and of the effects of administration of growth hormone to old rats. Regeneration was achieved by subjecting the right extensor digitorum longus muscle to ischaemic necrosis. The level of insulin-like growth factor I in serum was markedly decreased in old rats of 27 months of age compared with young adult rats aged 6 months. Daily injections of 4 IE recombinant human growth hormone during the 10 weeks of regeneration increased the level of insulin like growth factor I to almost the same levels as in rats aged 6 months. The body weight increased by 13% in the old rats treated with recombinant human growth hormone, while the weight of the untreated old rats was constant. The regenerating right and the normal left extensor digitorum longus muscles were studied 10 weeks after the ischaemic necrosis. The absolute and relative weights of regenerating muscle were decreased in 27-month-old rats compared with the rats aged 6 months. No significant difference between normal old rats and old rats treated with recombinant human growth hormone was observed either in muscle weight or in maximum contraction force. The results show that old rats have reduced levels of circulating insulin-like growth factor I. Administration of recombinant human growth hormone raises the level of insulin-like growth factor I to that of young adult rats, and causes an increased body weight. Muscle regeneration after ischaemic necrosis is impaired in old rats apparently by the formation of large amounts of connective tissue. Supplementation with growth hormone does not reverse this impairment.

Aging↗
PubMed1990

Nerve stimulation releases mucosa-derived inhibitory factors, both prostanoids and nonprostanoids, in isolated ferret trachea.

The influence of an intact mucosa layer in isolated ferret trachea on the contractile responses to repeated, short-lasting (20 s, every 2 min) nerve stimulations was studied in a nerve-muscle preparation stimulated to cholinergic-evoked contractions by either direct vagal nerve stimulation (DNS) or transmural electrical field stimulation (EFS). The contractile responses were monitored by three strain gauges connected to the proximal, middle, and distal segments of the trachea. The mucosa was either left intact (M+) or removed from the membranous part by dissection (M-). The successive decrease in contractile responses was studied for 60 min using repeated DNS and for a further 60 min using alternating EFS and DNS. During the first period, in which DNS alone was used, there was a significantly more pronounced decrease in the M+ preparation compared with the M-. This effect was most prominent in the proximal part of the trachea and was not blocked by indomethacin. During the subsequent stimulation period in which alternating EFS and DNS were used, the rate of decrease was significantly greater in all segments. In this phase, however, the inhibitory mucosa-dependent effect was significantly attenuated by indomethacin treatment. In conclusion, this study demonstrates that the mucosa-dependent inhibition or relaxation in ferret trachea is mediated by both a prostanoid and a nonprostanoid factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Inhaled salmeterol and salbutamol in asthmatic patients. An evaluation of asthma symptoms and the possible development of tachyphylaxis.

Salmeterol (SM) is a new beta 2-adrenoceptor agonist for inhaled use that has been shown to produce long-lasting bronchodilation in asthmatic patients. In the present study, evaluating efficacy and possible development of tachyphylaxis after SM, 12 patients with stable asthma were included after the demonstration of reversibility in FEV1 of at least 15% to 200 micrograms salbutamol (SB) or 20% to 500 micrograms SB. At inclusion all patients were receiving treatment with inhaled beta 2-agonists, and 11 of the 12 patients were also receiving inhaled corticosteroids. The patients were treated for two 2-wk periods with either inhaled SM 50 micrograms twice a day or SB 200 micrograms four times a day, following a double-blind, double-dummy, randomized design. The treatment periods were separated by a washout period of 1 wk. Dose-response curves to inhaled SB were obtained the day before and the day after each treatment period. On each of these days, basal FEV1, tremor, heart rate, and blood pressure were recorded and were then followed after the inhalation of 100 + 300 + 900 micrograms SB to obtain a cumulative dose-response curve. During the treatment periods, as well as during the washout week after each treatment, the patients recorded their morning and evening peak expiratory flow (PEF) each day before the inhalation of the study drug. Subjective asthma symptoms were monitored by a visual analog scale after each treatment period. The dose-response curves to SB revealed no signs of a reduced response to SB after any of the treatments, but significant increases in basal FEV1 and FVC were seen after the SM period (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1989

Effects of dilevalol, a beta-adrenoceptor antagonist with intrinsic sympathetic activity in asthmatic patients.

The effects on baseline ventilation as well as beta 2-receptor stimulant-induced bronchodilation and tremor of atenolol and dilevalol, a beta-blocking agent with non-selective beta-antagonistic properties and intrinsic activity on the beta 2-receptor were evaluated in 8 patients with stable asthma. Both atenolol and dilevalol were found to significantly decrease both forced expiratory volume during 1 s (FEV1) and forced vital capacity (FVC). This decrease was significantly more pronounced after atenolol. Both agents decreased systolic and diastolic blood pressure as well as heart rate to a similar degree. Increased activation of beta 2-adrenoceptors by terbutaline infusion resulted in increased FEV1 and FVC as well as beta 2-adrenoceptor mediated reflex tachycardia and skeletal muscle tremor. The dose response curves for all these parameters were significantly shifted to the right and a decrease of the maximum relative response was seen after atenolol pretreatment. This effect was more pronounced after treatment with dilevalol with a further shift to the right of the response curve and a decrease of the maximum relative response. The haemodynamic and ventilatory effects of dilevalol are consistent with a non-selective beta-adrenoceptor blockade combined with intrinsic activity on the beta 2-receptors.

Adrenergic beta-Antagonists↗
PubMed1988

Salmeterol, a new long acting inhaled beta 2 adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients.

Salmeterol is a new inhaled beta 2 adrenoceptor agonist, which has been shown in animal experiments to produce a more prolonged bronchodilator effect than currently available beta 2 adrenoceptor agonists. It was studied in eight adult asthmatic patients. Each patient received on separate test days salbutamol 200 micrograms and salmeterol 50, 100, and 200 micrograms according to a randomised, double blind, crossover design. FEV1, peak expiratory flow (PEF), heart rate, blood pressure, and tremor were recorded in the clinic for six hours after drug inhalation; PEF was recorded for a further six hours at home. All three doses of salmeterol produced peak increases in FEV1 (mean 0.5-0.8 l) and PEF (71-100 l/min) similar to those produced by salbutamol 200 micrograms (0.5 l and 74 l/min). After salbutamol FEV1 and PEF had returned to baseline within six hours, but after all three doses of salmeterol more than half of the maximum bronchodilator effect remained after 12 hours. The effects of salbutamol and the two lower doses of salmeterol (50 and 100 micrograms) on cardiovascular measurements and on tremor were similar, whereas after salmeterol 200 micrograms there was a small decrease in diastolic blood pressure and an increase in heart rate and tremor. Thus inhaled salmeterol has a long acting bronchodilator action in asthmatic patients. This effect may be of value in the treatment of asthma, particularly in patients with nocturnal symptoms.

Administration, Inhalation↗
PubMed1988

Mucosal inhibition of cholinergic contractions in ferret trachea can be transferred between organ baths.

The influence of the mucosa on the contractile responses to cholinergic nerve stimulation in an in vitro nerve muscle preparation of ferret trachea was studied. Repeated contractions were induced by alternating direct vagal nerve stimulation (DNS) and electrical field stimulation (EFS). With intact mucosa there was a marked successive decrease of the contractile responses. During 60 minutes the responses decreased to 46 +/- 8% of baseline (Mean +/- SEM, n = 6), compared to 86 +/- 2% in preparations, in which the mucosa was initially removed. The mucosa dependent inhibition could be partly blocked by indomethacin (10 microM). The inhibitory effect could be transferred via the bath fluid from a donor preparation with intact mucosa to a recipient preparation with removed mucosa. Fluid transferred from a donor preparation with removed mucosa or from indomethacin treated preparations did not affect the contractile responses in the recipient preparation. We conclude that ferret tracheal mucosa can release a factor which inhibits the contractile responses to cholinergic nerve stimulation. The release of this factor can be blocked to a major part by indomethacin and the factor can be transferred from a donor to a recipient preparation.

Animals↗
PubMed1983

Malignant hemangiopericytoma with admixed glandular structures in breast and lung metastases. A light and electron microscopic and histochemical study of a case.

A 29-year-old woman with a malignant retroperitoneal hemangiopericytoma which metastasized to both breasts and the lung, is reported. The metastases in the breasts and the lung included numerous glandular structures. The light and electron microscopic, and histochemical analysis confirmed the diagnosis of hemangiopericytoma, and indicated that the glandular component was not a true part of the neoplasm but preformed glandular structures were included. The findings are discussed in relation to previous reports on low-grade leiomyosarcoma with glandular formation in lung metastases. The differential diagnosis against synovial sarcoma, which in monophasic forms may show a prominent pericytoma-like pattern, and in biphasic forms includes pseudoglandular structures, is discussed.

Adult↗