Influence of hyperpnea on airway surface fluid volume and osmolarity in normal humans.

To determine the effect of hyperpnea on the characteristics of periciliary liquid, we collected airway surface fluid (ASF) and measured its osmolarity in 11 normal people while they breathed dry, frigid air (-17 +/- 1.2 degrees C) at minute ventilations (VE) of 10, 40, and 80 l/min through a heat exchanger. The ASF was collected at the fifth tracheal ring by absorption onto filter paper pledgets inserted via fiber-optic bronchoscopy. Hyperpnea had no influence on the amount of ASF recovered (ASF volume at a VE of 10 l/min = 12.0 +/- 2.0 microl; at 80 l/min = 8.8 +/- 1.5 microl; P = 0.28) or its osmolarity (at a VE of 10, 40, and 80 l/min = 326 +/- 15, 323 +/- 11, and 337 +/- 12 mosM, respectively; P = 0.65). These findings demonstrate that the tracheal mucosa of normal subjects does not dessicate during hyperpnea and that hypertonicity of the periciliary fluid does not develop even at high levels of ventilation.

Inhibition of nitric oxide synthesis attenuates thermally induced asthma.

To determine whether the inhibition of nitric oxide (NO) synthesis attenuates thermally induced obstruction, we had 10 asthmatic volunteers perform isocapnic hyperventilation with frigid air after inhaling 1 mg of N(G)-monomethyl-L-arginine (L-NMMA) or isotonic saline in a blinded fashion. The challenges were identical in all respects, and there were no differences in baseline lung function [1-s forced expiratory volume (FEV(1)); saline 2.8 +/- 0.3 liters, L-NMMA 2.9 +/- 0.3 liters; P = 0.41] or prechallenge fractional concentration of nitric oxide in the exhaled air (FENO) [saline 23 +/- 6 parts/billion (ppb), L-NMMA 18 +/- 4 ppb; P = 0.51]. Neither treatment had any impact on the FEV(1), pulse, or blood pressure. After L-NMMA, FENO fell significantly (P < 0.0001), the stimulus-response curves shifted to the right, and the minute ventilation required to reduce the FEV(1) 20% rose 53.5% over control (P = 0.02). The results of this study demonstrate that NO generated from the airways of asthmatic individuals may play an important role in the pathogenesis of thermally induced asthma.

Exhaled nitric oxide and thermally induced asthma.

The purpose of the present study was to determine if nitric oxide (NO) is involved in the pathogenesis of thermally induced asthma. To provide data on this issue, 10 normal and 13 asthmatic subjects performed isocapnic hyperventilation with frigid air while the fractional concentration of NO in the expirate air (FENO) was serially monitored with a chemiluminescence analyzer. FEV1 was measured before and after hyperpnea. Prior to and throughout the challenge, the asthmatics had significantly larger values for FENO (baseline FENO normal, 11 +/- 2 ppb; asthma, 16 +/- 1; p = 0.03). Posthyperpnea, the normal subjects had little change in bronchial caliber (deltaFEV1 baseline to 5 min posthyperpnea, -3.5 +/- 1.5%; p = 0.06), whereas the patients with asthma developed significant airway obstruction (deltaFEV1, -27.7 +/- 2.9%; p = 0.0001). During hyperventilation, the volume of NO rose in both groups. The asthmatic subjects, however, generated approximately 55% more NO/min than did the normal control subjects even though their level of ventilation was approximately 66% less. In contrast to the normal subjects, NO production in the asthmatics continued into the recovery period after the challenge stopped and FENO rose temporally as the airflow limitation developed. These results suggest that NO plays an intimate role in the development of airway obstruction that follows hyperpnea.

Comparative effects of long-acting beta2-agonists, leukotriene receptor antagonists, and a 5-lipoxygenase inhibitor on exercise-induced asthma.

BACKGROUND: Exercise-induced asthma (EIA) is a common problem that can be controlled with long-acting beta-agonists and leukotriene-modifying compounds. There is, however, limited information on the comparative effectiveness of the two classes of drugs, as well as the relative potencies of the antileukotriene agents. OBJECTIVE: The purpose of the present study was to provide data on the above issues. METHODS: We performed a random-order, blinded, double-dummy, placebo-controlled trial in 10 patients with EIA. Each subject received standard single doses of salmeterol, montelukast, zafirlukast, zileuton, and placebo on separate days. The participants performed 4 minutes of cycle ergometry while breathing frigid air 1, 4, 8, and 12 hours after administration of the test agents. The primary endpoint was the extent of the decrement in the FEV(1) 10 minutes after exertion. RESULTS: With placebo, symptomatic airway narrowing developed at all times (mean +/- SE decrease in FEV(1) ranged between 21% +/- 5% and 26% +/- 5%). Salmeterol acted quickly and significantly blunted the obstructive response for 12 hours (DeltaFEV(1) first hour: 8% +/- 3%; DeltaFEV(1) twelfth hour: 8% +/- 3%; P <.0001 vs placebo and P =.72 vs time). The leukotriene-modifying agents produced effects within 1 hour of ingestion. Like salmeterol, montelukast and zafirlukast also offered long-lasting protection, and there were no significant differences between them (montelukast DeltaFEV(1) twelfth hour: 9% +/- 4%; zafirlukast DeltaFEV(1) twelfth hour: 11% +/- 2%; P =.75) or the beta(2)-agonist (montelukast vs salmeterol: P =.72; zafirlukast vs salmeterol: P =.48). Zileuton provided equivalent prophylaxis for the first 4 hours (DeltaFEV(1) fourth hour: 11% +/- 2%); however, by 8 hours, it was less efficacious than all of the other active compounds, and by 12 hours it did not differ from placebo (DeltaFEV(1) twelfth hour: 19% +/- 4%; P =.33). CONCLUSIONS: Single doses of the currently available leukotriene receptor antagonists provide prompt effective and persistent defense against EIA that equals that seen with a long-acting beta(2)-agonist. The synthesis inhibitor zileuton affords a comparable magnitude of prophylaxis but has a considerably shorter duration of action.

Integrated response of the upper and lower respiratory tract of asthmatic subjects to frigid air.

To evaluate the influence of cold air hyperpnea on integrated upper and lower airway behavior, 22 asthmatic volunteers hyperventilated through their mouths (OHV) and noses (NHV) while pulmonary and nasal function were determined individually and in combination. In the isolated studies, OHV at a minute ventilation of 65 +/- 3 l/min lowered the 1-s forced expiratory volume (FEV(1)) 24 +/- 2% (P < 0. 001) and NHV (40 l/min) induced a 31 +/- 9% (P < 0.001) increase in nasal resistance (NR). In the combined studies, oral hyperpnea reduced the FEV(1) (DeltaFEV(1) 26 +/- 2%, P < 0.001) and evoked a significant rise in NR (DeltaNR 26 +/- 9%, P = 0.01). In contrast, NHV only affected the upper airway. NR rose 33 +/- 9% (P = 0.01), but airway caliber did not change (DeltaFEV(1) 2%, P = 0.27). The results of this investigation demonstrate that increasing the transfer of heat and water in the lower respiratory tract alters bronchial and nasal function in a linked fashion. Forcing the nose to augment its heat-exchanging activity, however, reduces nasal caliber but has no effect on the intrathoracic airways.