In vitro bronchial responsiveness in two highly inbred rat strains.

We investigated methacholine (MCh)-induced bronchoconstriction in explanted airways from Fischer and Lewis rats. Lung explants, 0.5- to 1.0-mm thick, were prepared from agarose-inflated lungs of anesthetized 8- to 12-wk-old male rats. After overnight culture, videomicroscopy was used to record baseline images of the individual airways. Dose-response curves to MCh were then constructed by repeated administration of MCh; airways were reimaged 10 min after each MCh administration. Airway internal luminal area (Ai) was measured at successive MCh concentrations from 10(-9) to 10(-1) M. In addition to the effective concentration leading to 50% of the achieved maximal response, we also determined the effective concentration leading to a 40% reduction in Ai. Both the effective concentration leading to 50% of the achieved maximal response and the concentration leading to a 40% reduction in Ai were significantly lower among Fischer rat airways (P < 0.05). Airway closure was more common among Fischer rat airways (17%) than among those of Lewis rats (7.5%). Responsiveness of Fischer rat airways was more heterogeneous than among Lewis airways; a larger number of Fischer rat airways exhibited high sensitivity to MCh. There was no relationship between responsiveness and baseline Ai in either strain. In a second experiment, we measured the rate of contraction of explanted airways from lungs inflated to 50, 75, and 100% of total lung capacity. The average rate of contraction in the first 15 s was higher in Fischer rat airways at each inflation volume. These data indicate that the hyperresponsiveness of the Fischer rat reflects the responsiveness of individual airways throughout the airway tree and are consistent with the notion that in this model hyperresponsiveness is an intrinsic property of airway smooth muscle.

Furosemide-induced bronchodilation in the rat bronchus: evidence of a role for prostaglandins.

Pretreatment with inhaled fuorsemide has been shown to protect against bronchoconstrictive stimuli that indirectly activate airway smooth muscle. However, it is controversial as to whether furosemide acts directly on airway smooth muscle. To investigate this we studied the effect of furosemide on both methacholine (MCh)- and serotonin (5-HT)-induced bronchoconstriction in explanted rat airways. Lungs from 21 Sprague-Dawley rats (269 +/- 15 g) were excised, inflated with agarose solution at 37 degrees C (1% w/v, 48 ml/kg), embedded in 4% agarose, and refrigerated to gel the agarose. Lung slices (0.5-1.0 mm thick) were cultured overnight at 37 degrees C. Explants were placed on a dissecting video microscope, and airway area was measured with an image analysis system. MCh or 5-HT was administered directly to explanted airways (final concentrations 3.8 x 10(-6) M and 3.8 x 10(-5) M, respectively). Five min later furosemide (3.7 x 10(-5) M or 3.7 x 10(-4) M) was added and airway area monitored 5, 10, 15, 30, and 60 min later. Results were expressed as a percentage of the maximal response. Significant bronchodilation was seen after 30 min in airways preconstricted with MCh and after 15 min in those preconstricted with 5-HT following 3.7 x 10(-4) M furosemide (p < 0.05). 3.7 x 10(-5) M furosemide caused bronchodilation only at 60 min in airways constricted with 5-HT. The effect was blocked by a 30-min incubation of explants with 10(-6) M indomethacin. The furosemide-induced bronchodilation effect was not observed in airways strongly constricted with 3.8 x 10(-5) M MCh. These findings indicate that in the rat at least, furosemide induces a weak bronchodilator effect present only at high doses, which seems to be dependent on the production of prostaglandins. This effect may be relevant to the observed therapeutic action of furosemide in asthmatics.

Interpretation of spirometric tests in asthmatic patients with reduced forced vital capacity.

We have studied 175 consecutive asthmatic patients presenting with: 1) a reversible airflow obstruction, demonstrated by an increase in the forced expiratory volume in 1 second (FEV1) or in the forced vital capacity (FVC) by at least 12% along with an absolute increase of 200 ml versus prebronchodilator values after inhalation of salbutamol; 2) FVC below the lower normal limit before administration of the bronchodilator; and 3) normal FVC or slow vital capacity after bronchodilator. Two different criteria for the lower normal limit of the FEV1/FVC ratio were used to determine whether prebronchodilator spirometric patterns could be considered obstructive or not. The use of the predicted FEV1/FVC ratio as the lower normal limit allowed correct identification of obstruction in 94.9% of the patients, whereas taking the estimated fifth percentile as the lower normal limit of the FEV1/FVC correctly identified obstruction in only 78.9% of the asthmatics. Our results suggest that the predicted FEV1/FVC ratio is an adequate estimate of the lower normal limit in asthmatic patients with reduced FVC in order to distinguish obstructive from nonobstructive patterns.

Atrial natriuretic peptide in bronchial asthma.

Regulation of ion transport across the airway mucosa may be involved in the mechanisms producing hyperreactivity and asthma. Atrial Natriuretic Peptide (ANP) has been proposed to participate in the pathogenesis of asthma, and it has been found to have a bronchodilatory effect on asthmatic patients. Experimental evidences suggest that ANP also has some effect on fluid accumulation in the lungs. We hypothesise that ANP may also play a role in the pathogenesis of asthma through changes in the transport of water and ions across the airway epithelium.