Pulmonary pharmacology最新文献

Eosinophils are known to be present in the airways of allergic asthmatics, and have been suggested to contribute to the pathophysiological changes accompanying this condition, particularly hyperresponsiveness to airway spasmogens. However, a causal relationship between pulmonary eosinophil accumulation and bronchial hyperresponsiveness in asthma is not proven. In the present study, the time course of pulmonary cell influx was investigated in an immunized guinea-pig model. Eosinophil activation status was also determined together with the bronchial responsiveness to histamine. Guinea-pigs were sensitized [20 μg ovalbumin (OVA) per animal in Al(OH)₃(0.5 ml) ip] and subsequently challenged with aerosolized OVA (100 μg/ml) for 1 h 18–21 days later. At different time points (1 h to 72 h) after OVA challenge, bronchial responses to iv histamine were measured and bronchoalveolar lavage (BAL) was performed to assess pulmonary cell influx. Eosinophil peroxidase (EPO) and total protein levels were measured in BAL fluid supernatants. Exposure of sensitized animals to aerosolized OVA produced a significant increase (P<0.05 vs. sham immunized) in eosinophil infiltration 24 h later which was sustained up to 72 h. Despite this, OVA challenge did not cause either eosinophil activation, as measured by EPO release, or bronchial hyperresponsiveness to histamine at any of the time points examined. These data show that allergen challenge of sensitized guinea-pigs can elicit airway eosinophil accumulation without accompanying airways hyperresponsiveness or eosinophil activation.

The effect of chronic glutathione deficiency on lung mitochondrial energy production using buthionine sulphoximine (BSO) as a depletor has been investigated. Prolonged depletion of mitochondrial glutathione produced an imbalance in the antioxidant defence and resulted in lipid peroxidation, which, in turn, damages the membranous structure, leading to the inactivation of inner membrane enzymes, matrix-bound enzymes and mitochondrial cytochrome content. Altered activities of energy-linked enzymes and electron transport resulted in the decreased rate of ADP-stimulated oxygen uptake, respiratory coupling ratio and ATP synthesis.

No abstract.

This study examined the effect of acute changes in oxygen tension on responses evoked by the bronchoconstrictor methacholine and the dilators salbutamol, atrial natriuretic peptide and isosorbide dinitrate in isolated bovine bronchi. Cumulative concentration–response curves to methacholine (10⁻⁹–3×10⁻⁴M) were constructed in three oxygen tensions; hyperoxia (95%), normoxia (20%) and hypoxia (4% O₂). Oxygen tensions of 20% and 4% each significantly enhanced contractions to methacholine compared to those in 95% O₂. There was no significant difference, however, between responses in 20 and 4%. The ability of salbutamol, atrial natriuretic peptide and isosorbide dinitrate to reverse methacholine induced tone was also compared in the three oxygen tensions (95%, 20% and 4%). Lowering the oxygen tension from 95% enhanced the ability of each of the drugs to reverse contraction, however the pattern differed between drugs; salbutamol was more effective in 20% O₂than 4%, atrial natriuretic peptide was more effective in 4% than either 95 or 20% O₂and isosorbide dinitrate was more effective in both 4 and 20% than 95% O₂. In conclusion, both bronchoconstrictor and bronchodilator responses in 95% O₂(hyperoxia) differed from those in 20% O₂(normoxia) and further changes occurred on moving to 4% (hypoxia), although the direction of the changes varied among the dilators. This suggests that the responses evoked by bronchodilators in 95% O₂may not necessarily predict those in the physiological range of oxygen tensions and that the relative effectiveness of bronchodilators may vary between normoxic and hypoxic conditions.

No abstract.

We have assessed the suitability of electrically-stimulated superfused preparations of guinea-pig trachea, cat trachea and human bronchus for investigating the relaxant activity of theβ-adrenoceptor agonist, isoprenaline. Superfused strips of guinea-pig trachea, cat trachea and human bronchus all contracted in response to electrical stimulation. Guinea-pig trachea possesses inherent tone, and in its presence, electrical stimulation caused biphasic responses, comprising a modest, transient contraction, usually followed by a longer lasting relaxation. Human bronchus also possesses inherent tone, but responses were variable, generally monophasic, comprising a transient contraction of variable magnitude, but a longer lasting relaxation was occasionally observed after the transient contraction. Cat trachea possesses no inherent tone, and electrical stimulation of this preparation caused simple monophasic contractile responses. On guinea-pig trachea, addition of indomethacin (2.8 μM) abolished the inherent tone, and under these conditions, electrical stimulation caused monophasic contractile responses similar to those observed in cat trachea. On human bronchus, however, indomethacin enhanced inherent tone, which tended to uncover or exaggerate any relaxant component in the responses to electrical stimulation. The 5-lipoxygenase inhibitor, zileuton (10 μM), reduced, but did not abolish, the tone and converted the electrically-induced response to a monophasic contraction. In all preparations in which inherent tone was low or absent, whether naturally (cat trachea) or through pharmacological intervention (guinea-pig trachea with indomethacin, or human bronchus with zileuton), isoprenaline (1–100 nM) inhibited electrically-stimulated contractions in a concentration-related fashion (EC₅₀s: 9–100 nM). In preparations exhibiting inherent tone (guinea-pig trachea with indomethacin or human bronchus with or without indomethacin), this tone was inhibited by isoprenaline. This relaxant activity, on guinea-pig trachea at least, was concentration-related (EC₅₀: 5.4 nM). Such isoprenaline-induced relaxations complicated the analysis of inhibitory effects against electrically-induced contractions. Thus, in such experiments, only at higher concentrations did isoprenaline reliably inhibit these contractions (EC₅₀: 23–119 nM), lower concentrations of isoprenaline often resulting in an apparent enhancement. The enhancement was probably artefactual, resulting from the fact that the electrically-induced contractions originated from a lower baseline. These data suggest that electrically-stimulated airway preparations are suitable for evaluating the relaxant activity ofβ-adrenoceptor agonists, but the relaxant potency should be assessed in preparations lacking inherent tone, such as cat trachea, guinea-pig trachea in the presence of cyclo-o