Effect of bedtime alcohol on inspiratory resistance and respiratory drive in snoring and nonsnoring men.

We measured inspiratory resistance (R1), inspiratory occlusion pressure (P0.1), and the ventilatory responses to hypercapnia and isocapnic hypoxia during waking and during stage 2 non-rapid eye movement sleep in nine young men who were habitual snorers. They were studied on 2 nights during the 3 hours after receiving a bedtime drink containing either a placebo or 100-proof vodka (1.5 ml/kg) in orange juice. We compared the results with those we reported previously in 10 nonsnoring but otherwise similar men. Waking R1 was the same in nonsnorers and snorers, and it was not affected by ethanol. During sleep on the control night, R1 increased by 70% in nonsnorers and by 280% in snorers. On the ethanol night, the increase from waking to sleeping was more than doubled in both nonsnorers and snorers. P0.1 and the responses to hypercapnia and hypoxia showed no differences between nonsnorers and snorers, therefore the results from the two groups were pooled. Minute ventilation and the hypercapnic response decreased from waking to sleeping and P0.1 was more negative during sleep, but there was no significant effect of ethanol. There was a significant correlation between the changes from waking to sleeping in R1 and P0.1 on the ethanol night suggesting that inspiratory effort increased in response to the increased resistance. The response to isocapnic hypoxia showed no effect of either sleep state or drink. Inspiratory time did not change but mean inspiratory flow (VT/T1) was significantly reduced during sleep on both control and ethanol nights. The duty cycle ratio (T1/Ttot) was significantly increased during sleep on the ethanol night. Despite its great effect on inspiratory resistance, especially in snorers, ethanol, in the dose used in our study, does not augment the depression of minute ventilation or of the hypercapnic response that occur normally in stage 2 non-rapid eye movement sleep. After ethanol, our subjects showed the decreased VT/T1 and the increased T1/Ttot that occur normally during sleep in response to an inspiratory resistive load. However, they also showed increased inspiratory effort. The combination of increased inspiratory resistance and greater inspiratory effort would increase the tendency of an unstable upper airway to collapse and could account for the aggravation of obstructive sleep apnea by ethanol.

Effect of bedtime ethanol on total inspiratory resistance and respiratory drive in normal nonsnoring men.

We have previously reported that bedtime ethanol (2.0 ml/kg of 100 proof vodka) increases upper airway closing pressure in males who habitually snored but were otherwise healthy. We also observed that some of these snorers developed obstructive apneas. To explore this phenomenon in more detail, we measured the inspiratory resistance (RI) and respiratory drive after bedtime ethanol in 10 nonobese men (ages 23 to 33) with no history of snoring. Subjects went to bed wearing a tightly fitting valved mask over the nose and mouth that allowed measurement of inspiratory and expiratory flow, pressure in the mask, and endtidal CO2. We measured RI by calculating the pressure difference between the mouth and a balloon positioned in the midesophagus. Respiratory drive was quantified by the inspiratory occlusion pressure (P0.1), the ventilatory response to hyperoxic hypercapnia (delta VE/delta PETCO2), and the ventilatory response to isocapnic hypoxia (delta VE/delta SaO2). Measurements were made during waking and during stage 2 NREM sleep on two nights: (1) when the subjects drank 1.5 ml/kg of 100 proof vodka in orange juice over a 30-min period 15-45 min before lights out and (2) when the orange juice contained less than 0.1 ml of vodka floating on the top. Eight of the nine men in whom we had technically adequate measurements showed a rise in RI during NREM sleep above the waking level on both control and ethanol nights and the sleeping RI was greater on the ethanol than on the control night.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of 0.60 PPM nitrogen dioxide on circulating and bronchoalveolar lavage lymphocyte phenotypes in healthy subjects.

Nitrogen dioxide (NO2) is a common oxidant air pollutant. Animal studies have suggested that NO2 exposure causes a decrease in the numbers of some splenic lymphocyte subtypes and impairs lymphocyte-dependent immune responses. To investigate whether ambient levels of NO2 alter circulating and bronchoalveolar lavage fluid (BALF) human lymphocytes, we studied five healthy nonsmoking adult volunteers. In each subject, blood and bronchoalveolar lavage fluid was obtained and then, more than 2 weeks later, volunteers were exposured to 0.60 ppm NO2 for 2 hr with intermittent light to moderate exercise on 4 separate days within a 6-day period. We measured standard tests of pulmonary function (airway resistance, thoracic gas volume, maximal expiratory flow) and had the subjects rate the severity of respiratory symptoms before and after each NO2 exposure. Circulating and BALF lymphocytes were labeled with fluorochrome-conjugated monoclonal antibodies to human lymphocyte antigens and a flow cytometer was used to count lymphocyte subtypes. Neither any single day's exposure nor all four exposures caused a change in symptoms or in the results of tests of pulmonary function. The total number of circulating lymphocytes obtained after NO2 exposure was slightly greater than at baseline (1792 +/- 544 vs 1598 +/- 549 cells/mm3 at baseline; P = not significant) but the proportions of lymphocyte subtypes did not differ. In the BALF obtained after NO2 exposure and in the baseline state, the total number of lymphocytes and the percentages of T cells (CD 3), B cells (CD 20), T cytotoxic-suppressor cells (CD 8), T helper-inducer cells (CD 4), and large granular lymphocytes (CD 57) also did not differ after NO2 exposure. A slightly but significantly greater proportion of natural killer cells (CD 16) was found in the BALF obtained after NO2 exposure (7.2 +/- 3.1 vs 4.2 +/- 2.4% of total lymphocytes). We conclude that repeated exposures of healthy nonsmoking adults to 0.60 ppm NO2 are not associated with clinically significant symptoms, changes in airway caliber, or alterations in circulating and BALF lymphocyte subtypes. We suggest that brief, daily exposures to NO2 at levels higher than those achieved in urban atmosphere are unlikely to provoke acute respiratory impairment in healthy, nonsmoking adults.

Short-term exposure to 0.3 ppm nitrogen dioxide does not potentiate airway responsiveness to sulfur dioxide in asthmatic subjects.

Whether short-term exposure to low levels of nitrogen dioxide (NO2) enhances airway responsiveness in asthmatic subjects is controversial. Because it is well established that asthma is associated with increased airway responsiveness to another common air pollutant, sulfur dioxide (SO2), we examined whether short-term exposure of asthmatic subjects to 0.3 ppm NO2 potentiates airway responsiveness to inhaled SO2. We exposed nine subjects with clinically stable asthma to 0.3 ppm NO2 or filtered air in an environmental room for 30 min on 2 separate days at least 1 wk apart in a double-blind, randomized fashion. A questionnaire about common symptoms related to inhaled irritants was completed before and immediately after each exposure. Each subject exercised (60 to 80 W) on a cycloergometer during the first 20 min of each exposure. We measured specific airway resistance (SRaw) and FEV1/FVC before, 5 min after, and 1 h after completion of the air or NO2 exposure. The single-breath nitrogen test (SBN2) was also performed before and 1 h after completion of the air or NO2 exposures and closing volume was determined; subsequently, SO2 dose-response curves (0.25 to 4.0 ppm) were performed via a mouthpiece. Each dose of SO2 was inhaled at a minute ventilation of 20 L/min for 4 min and was doubled until SRaw increased by at least 8 U above baseline. The dose of SO2 required to provoke an increase in SRaw of 8 U above baseline was determined by linear interpolation from the dose-response curve (PD8Uso2).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of exercise, hyperpnea, and bronchoconstriction on plasma atrial natriuretic peptide.

To examine whether endogenous secretion of atrial natriuretic peptide (ANP) modifies the bronchomotor response to moderately strenuous exercise and, conversely, whether hyperpnea of exercise or bronchoconstriction alone modulates the release of ANP, we compared the rise in specific airway resistance and the rise in circulating immunoreactive ANP (IR-ANP) induced by a 5-min submaximal exercise and by eucapnic hyperpnea with cold dry air and exercise-matched minute ventilation in six healthy individuals and in five subjects with clinically stable asthma. As expected, the increase in specific airway resistance from base line provoked by exercise was greater in the asthmatic subjects (from 11.8 +/- 7.1 to 34.0 +/- 18.6 l.cmH2O.l-1.s-1) than in the healthy subjects (from 3.7 +/- 1.2 to 4.5 +/- 1.9 l.cmH2O.l-1.s-1). In both groups, exercise was associated with a similar and significant rise in plasma IR-ANP levels, ranging from 222 to 550% from base-line value in the healthy group and from 176 to 1,120% from base-line value in the asthmatic group. Peak plasma IR-ANP levels occurred from 3 to 15 min after completion of exercise with a return to base-line values within 60 min. Although eucapnic hyperpnea was associated with a similar increase in specific airway resistance as was exercise, it provoked an increase in circulating IR-ANP in only one subject.(ABSTRACT TRUNCATED AT 250 WORDS)

Sulfur dioxide does not acutely increase nasal symptoms or nasal resistance in subjects with rhinitis or in subjects with bronchial responsiveness to sulfur dioxide.

We examined whether brief exposures to moderately high concentrations of sulfur dioxide (SO2) causes acute increases in nasal symptoms and nasal resistance in subjects with chronic rhinitis. We studied 19 subjects with allergic rhinitis and 3 subjects with chronic intermittent rhinorrhea, nasal congestion, and sneezing without any other manifestation of allergy. We found that the change in nasal resistance and symptoms caused by nasal inhalation of 4 ppm of SO2 for 10 min was no greater than the changes caused by nasal inhalation of conditioned room air. In a second set of experiments, we examined whether allergic subjects with demonstrable bronchomotor responsiveness to SO2 also had nasal responsiveness to the gas. We studied 8 subjects with a history of both asthma and allergic rhinitis. Each subject developed symptoms of dyspnea or wheezing and an increase in specific airway resistance of at least 8 L x cm H2O/L/s after breathing 1 or 2 ppm of SO2 by mouthpiece at 20 L/min, and did not develop these changes after breathing room air under the same conditions. No subject, however, developed more nasal symptoms or a greater increase in nasal airway resistance after tidally breathing SO2 through the nose than after breathing room air, even when the concentration of SO2 delivered to the nose was double the concentration delivered through the mouthpiece to the lower airways. We conclude that brief exposure to SO2 at a concentration of 4 ppm or less is unlikely to cause significant nasal dysfunction in most subjects with chronic rhinitis, and that in subjects with both allergic rhinitis and asthma, responsiveness to SO2 is not uniform throughout the respiratory tract.

Indomethacin blocks airway tolerance to repetitive exercise but not to eucapnic hyperpnea in asthmatic subjects.

We have examined the effects of indomethacin (I) on tolerance to the bronchomotor effects of repetitive challenge with exercise (EX) and eucapnic hyperpnea (EH) in 7 asthmatic subjects. Each subject was studied on 4 separate days. EH was performed for 4 min at a minute ventilation found previously to increase specific airway resistance (SRaw) by 8 units (cm H2O/L/s). All exercise challenges were performed on a cycle ergometer for 5 min at a constant work load. Subjects breathed room temperature, dry air for both stimuli. SRaw was serially measured before and after each stimulus. Tolerance was examined by giving up to 3 repetitions of EH or EX, allowing a return of SRaw to within 1 unit of baseline between repetitions. Placebo (P) or I (25 mg four times a day for 7 doses) was administered in a single-blind manner. The timing between stimulus repetitions on the P day was matched to that of the I day. After P, the initial rise in SRaw was similar for both EX and EH, with a significant and progressive decrease in this rise after each stimulus repetition (p = 0.032 for EX, p = 0.006 for EH). After I, tolerance was still demonstrated to EH (p = 0.002), but not to EX (p = 0.231). This finding indicates that EH and EX are not identical stimuli, since there is an I-sensitive mechanism (possibly a bronchodilating prostaglandin) associated with the development of tolerance to EX but not to EH. Our data also suggest a possible additional bronchoconstricting mechanism associated with EX and not with EH.

Interaction of cromolyn and a muscarinic antagonist in inhibiting bronchial reactivity to sulfur dioxide and to eucapnic hyperpnea alone.

To determine whether the combination of an agent thought to inhibit mediator release (cromolyn) and an agent that inhibits parasympathetic pathways inhibits sulfur dioxide-induced bronchoconstriction more than either agent alone, we measured the bronchomotor response of 9 asthmatic subjects to inhalation of sulfur dioxide after treatment with cromolyn sodium (200 mg by spinhaler), with atropine sulfate (2.0 mg by nebulizer), and with the 2 drugs given together. Then, to determine whether the combination of cromolyn and a parasympathetic antagonist would similarly inhibit bronchoconstriction provoked by a different nonallergic stimulus, we measured the bronchomotor response of another group of asthmatic subjects to eucapnic hyperpnea of dry air at room temperature after treatment with cromolyn (200 mg), with ipratropium bromide (100 and 200 micrograms by metered-dose inhaler), and with cromolyn (200 mg) and ipratropium bromide (200 micrograms) given together. In both studies, we found that the combination treatment provided greater protection than that obtained with either agent alone. The concentration of sulfur dioxide required to cause bronchoconstriction was significantly greater after treatment with the combination of cromolyn and atropine (2.58 ppm, geometric mean) than after cromolyn alone (0.84 ppm), after atropine alone (0.78 ppm), or after placebo (0.43 ppm). Similarly, the rate of ventilation with dry air required to cause bronchoconstriction was significantly greater after treatment with the combination of cromolyn and ipratropium (106 +/- 22 L/min, mean +/- SD) than after cromolyn alone (65 +/- 19 L/min), after 200 micrograms of ipratropium alone (64 +/- 13 L/min), or after placebo (43 +/- 10 L/min).(ABSTRACT TRUNCATED AT 250 WORDS)

The inhibition of sulfur dioxide-induced bronchoconstriction in asthmatic subjects by cromolyn is dose dependent.

To determine whether the inhibitory effect of cromolyn on sulfur dioxide-induced bronchoconstriction is dose dependent, we compared the effects of treatment with 200 mg of cromolyn, with 20 mg of cromolyn, and with placebo on the rise in specific airway resistance provoked by inhalation of serially increasing concentrations of sulfur dioxide (0.25 to 8.0 ppm) in 10 asthmatic subjects. The geometric mean concentration of sulfur dioxide needed to cause an increase in SRaw of 8 L X cm H2O/L/s was significantly greater after 200 mg of cromolyn (1.98 ppm) than after 20 mg of cromolyn (0.94 ppm), which was in turn significantly greater than after placebo (0.35 ppm). We then examined whether the greater protection afforded by 200 mg of cromolyn was due to direct inhibition of smooth muscle contraction. We measured the bronchomotor response to the inhalation of serially increasing concentrations of methacholine aerosol (0.06 to 2.0 mg/ml) in 7 asthmatic subjects. Again, each subject was treated on 3 separate days with 200 mg of cromolyn, with 20 mg of cromolyn, and with placebo. We found that methacholine responsiveness was not decreased by either dose of cromolyn. We conclude that cromolyn inhibits sulfur dioxide-induced bronchoconstriction in a dose-dependent manner and that it does not directly inhibit smooth muscle responsiveness.

O3-induced change in bronchial reactivity to methacholine and airway inflammation in humans.

The increase in airway responsiveness induced by O3 exposure in dogs is associated with airway epithelial inflammation, as evidenced by an increase in the number of neutrophils (polymorphonuclear leukocytes) found in epithelial biopsies and in bronchoalveolar lavage fluid. We investigated in 10 healthy, human subjects whether O3-induced hyperresponsiveness was similarly associated with airway inflammation by examining changes in the types of cells recovered in bronchoalveolar lavage fluid obtained after exposure to air or to O3 (0.4 or 0.6 ppm). We also measured the concentrations of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in lavage fluid. We measured airway responsiveness to inhaled methacholine aerosol before and after each exposure and performed bronchoalveolar lavage 3 h later. We found more neutrophils in the lavage fluid from O3-exposed subjects, especially in those in whom O3 exposure produced an increase in airway responsiveness. We also found significant increases in the concentrations of prostaglandins E2, F2 alpha, and thromboxane B2 in lavage fluid from O3-exposed subjects. These results show that in human subjects O3-induced hyperresponsiveness to methacholine is associated with an influx of neutrophils into the airways and with changes in the levels of some cyclooxygenase metabolites of arachidonic acid.