Airway irritation and cough evoked by inhaled cigarette smoke: role of neuronal nicotinic acetylcholine receptors.

In a series of studies carried out in different experimental models, we investigated the type(s) of lung afferents and mechanism(s) underlying the cigarette smoke-induced airway irritation and cough. In healthy non-smokers, the intensity of airway irritation and cough evoked by cigarette smoke was markedly reduced after premedication with hexamethonium. A similar pattern of responses was also triggered by inhalation of nicotine aerosol. These studies in human subjects suggested nicotine as the primary causative agent in cigarette smoke that evokes airway irritation. Indeed, single-fiber recording experiments performed in anesthetized dogs showed that both C-fibers and rapidly adapting receptors in the lungs and airways were stimulated by inhalation of one puff of cigarette smoke, and the intensity of this stimulatory effect was related to the nicotine content in the cigarette and abolished by hexamethonium. To further study the direct effect of nicotine on these sensory nerves, we measured the change in intracellular calcium concentration ([Ca(2+)](i)) of pulmonary sensory neurons isolated from the nodose and jugular ganglia of adult rats. Our results showed that nicotine evoked an abrupt and transient increase in [Ca(2+)](i) in approximately 34% of the 522 neurons tested, and 1,1-dimethyl-4-phenylpiperazinium, a selective agonist of the neuronal nicotinic acetylcholine receptors (NnAChRs), evoked a similar pattern of response as that of nicotine in these neurons. In conclusion, results of these studies show that nicotine exerts a direct stimulatory effect on vagal pulmonary sensory neurons. This stimulatory effect of nicotine is primarily responsible for the airway irritation and cough evoked by inhaled cigarette smoke, and is mediated through an activation of the NnAChRs.

Effects of therapeutic doses of albuterol on beta2-adrenergic receptor density and metabolic changes.

Beta2-agonist drugs at inhaled supratherapeutic doses or when given orally or parenterally alter peripheral lymphocyte beta2-adrenoceptor density (betaAR) and have demonstrable metabolic effects. However, it is not known whether these changes occur at therapeutic inhaled doses. We therefore studied the effects of therapeutic doses of inhaled albuterol in five asthmatic subjects (mean age 23.0+/-2.4 years) and six normal subjects (mean age 28.3+/-3.3 years). Subjects were studied in a randomized, double-blind protocol in which each subject received either inhaled albuterol (270 microg four times daily) for 2 weeks followed by placebo or vice versa in two sequential 2-week periods separated by a 2-week washout period. In the asthmatics, baseline FEV1 increased significantly (p < 0.05) after 2 weeks of inhaled albuterol treatment compared to the initial visit and after 2 weeks of placebo (mean FEV1: 3.2 L+/-0.7 L, 2.9 L+/-0.5 L, and 3.0 L+/-0. 7 L, respectively). Baseline peripheral lymphocyte betaAR was not significantly different (p > 0.05) between the asthmatic (mean: 757+/-176) and normal subjects (mean: 732+/-251). However, in neither group was there any significant change (p > 0.05) in betaAR or plasma potassium, insulin, or glucose, either acutely or after 2 weeks of albuterol therapy. The present study confirms that there is no difference in peripheral lymphocyte betaAR between asthmatic and normal subjects and also shows that at therapeutic doses of inhaled albuterol, there are no significant changes in betaAR or metabolic effects.

Maximal expiratory flow patterns after single-lung transplantation in patients with and without chronic airways obstruction.

BACKGROUND: A biphasic-plateau pattern in the maximal expiratory flow-volume (MEFV) curve has been described after single-lung transplantation (SLT) in patients with chronic airways obstruction (CAO). It has been theorized that this pattern is either related to stenosis at the anastomotic or subanastomotic site, or the sum of the airflow contribution from the native lung with airways obstruction and transplanted lung. SUBJECTS AND METHODS: We analyzed data in 16 patients with CAO who had undergone transplantations (5 men, 11 women; mean age [+/- SD], 53.8 +/- 4.9 years), and 9 patients with pulmonary vascular disease (PVD) without airways obstruction who had undergone transplantations (2 men, 7 women; mean age, 35.4 +/- 11.4 years). RESULTS: In the patients with PVD, there were no significant changes in static or dynamic lung volumes or in the MEFV curve after SLT. In the patients with CAO, indexes of airways obstruction improved significantly after SLT, and the typical biphasic-plateau pattern developed in the MEFV curve. In one patient with CAO who required pneumonectomy of the native lung after SLT, the biphasic pattern was absent. CONCLUSIONS: These results support the view that this MEFV pattern is a result of airflow from the native and transplanted lungs in patients with CAO. In addition, the results show that in patients with no prior airways obstruction, SLT does not alter static or dynamic lung volumes or maximal expiratory flow rate.

Effects of acute prolonged exposure to high-altitude hypoxia on exercise-induced breathlessness.

The direct effects of hypoxia on exercise-induced breathlessness are unclear. Increased breathlessness on exercise is known to occur at high altitude, but it is not known whether this is related to the hypoxia per se, or to other ventilatory parameters. To examine the role of high-altitude hypoxia in exercise-induced breathlessness, studies were performed in 10 healthy, normal subjects at sea level and after acute exposure to an altitude of 4450 m. Although the perception of hand weights did not alter between sea level and high altitude, the intensity of exercise-induced breathlessness increased significantly at high altitude. This was associated with a higher minute ventilation and respiratory frequency for any given exercise level, whereas tidal volume was not significantly altered from sea level values. The increased intensity of breathlessness with exercise did not change significantly over the 5 days at high altitude. These results suggest that the increased intensity of exercise-induced breathlessness at high altitude is not related to peripheral mechanisms or the pattern of ventilation, or to the level of hypoxia per se, but to the level of reflexly increased ventilation.

Variability of peripheral blood lymphocyte beta-2-adrenergic receptor density in humans.

Beta2-adrenergic receptor (betaAR) density on peripheral blood lymphocytes has been used as an index to reflect the betaAR state of the body. Lymphocytes betaARs are unequally distributed among lymphocyte subpopulations, with the highest density on CD8+ cells and the lowest on CD4+ cells. Thus, the measurement of peripheral blood lymphocyte betaAR density could vary with changes in CD4+ and CD8+ cell concentrations. We examined the individual and intersubject variance of betaAR density and lymphocyte subpopulations over time in 10 normal subjects, studied on 3 to 5 different d always at approximately 9:00 A.M. over a 4- to 12-wk period. Peripheral blood lymphocytes were isolated and beta2-adrenergic receptor density was determined by specific binding of [125I]-(-)iodopindolol, and lymphocyte subpopulations were measured by flow cytometry. Average receptors per lymphocyte were 776 +/- 183. Whereas the absolute values of CD4+% and CD8+% cell concentrations varied little in individual subjects (coefficient of variation 9.5% and 11.1%, respectively), the individual betaAR variance was greater (coefficient of variation 22.4%). However there was a significant correlation between betaAR and CD4+% and CD8+% cell concentration (correlation coefficients: -0.58, p < 0.001; +0.51, p < 0.001, respectively). This information is relevant to interpretations of changes in peripheral betaAR in humans.

The effects of the combination of inhaled ipratropium and oral theophylline in asthma.

BACKGROUND: In comparison to beta-agonist drugs, which are the primary bronchodilator drugs in current use in asthma, both oral theophylline and inhaled ipratropium have a weaker bronchodilating action in asthma. Although a number of studies have shown an additive effect of ipratropium in combination with beta-agonist bronchodilator drugs in asthmatics, to our knowledge, the effects of combined treatment with ipratropium and theophylline have not been assessed. STUDY OBJECTIVE: To assess whether the combination of oral theophylline and inhaled ipratropium has an additive bronchodilator effect in asthmatics. DESIGN: Double-blind, placebo-controlled, crossover study. SUBJECTS: Nineteen patients (8 male, 11 female) with mild-to-moderate stable asthma. METHODS: Initially the optimal single oral dose of theophylline required to achieve therapeutic blood levels (10 to 20 microg/mL) was established in each patient. They then returned at varying intervals on 4 subsequent days. On each day, they received, in a random, placebo-controlled, double-blind, crossover design, one of four different therapies: oral and inhaled placebo; oral theophylline at the established optimal dose (range, 300 to 700 mg) plus inhaled placebo; oral placebo plus inhaled (40 microg) ipratropium; and the combination of theophylline and ipratropium. Spirometry was performed at baseline and at 15 min, 30 min, and hourly intervals for 6 h after therapy. RESULTS: Each drug regimen resulted in a significant (p<0.05) increase in FEV1, but the combined regimen resulted in a significantly greater bronchodilation (p<0.05) over either ipratropium or theophylline alone (FEV1=3.00+/-0.75 L vs 2.48+/-0.77 L vs 2.61+/-0.72 L, respectively, at 3 h postdrug). CONCLUSIONS: There was a significant, early, sustained additive bronchodilator effect of the combination therapy; there were no untoward side effects. These findings indicate that the addition of inhaled ipratropium to oral theophylline provides greater bronchodilation than either drug alone and may be a useful therapeutic modality in asthma.

Role of tachykinins in sulfur dioxide-induced bronchoconstriction in anesthetized guinea pigs.

To investigate the role of tachykinin release in mediating the bronchoconstrictive effect of sulfur dioxide (SO2) inhalation, measurements of dynamic lung compliance (Cdyn), total pulmonary resistance (RL), and arterial blood pressure (ABP) were made in anesthetized guinea pigs. Brief exposure (six tidal breaths) to SO2 at concentrations between 500 and 2,000 parts/million resulted in a concentration-dependent increase in RL, decrease in Cdyn, and systemic hypotension. For example, SO2 at 2,000 parts/million induced reversible and reproducible changes in RL, Cdyn, and ABP of 1,041 +/- 234, -60 +/- 6, and -25.8 +/- 4.3% of the baseline values, respectively. Pretreatment with two selective neurokinin- (NK) receptor (NK1 and NK2) antagonists, CP-99994 and SR-48968, resulted in almost complete inhibition of the increase in RL and of the decrease in Cdyn while preserving the decrease in ABP. Antagonism of the NK2 receptor alone resulted in inhibition of the majority of the SO2-induced bronchoconstriction, whereas that of the NK1 and muscarinic receptors did not have a significant effect. We conclude that the release of tachykinins from sensory endings plays a central role in SO2-induced bronchoconstriction in anesthetized guinea pigs, primarily via the activation of the NK2 receptor.

Nicotine is responsible for airway irritation evoked by cigarette smoke inhalation in men.

To determine whether nicotine is involved in evoking the irritant effects of cigarette smoke in airways, we studied the responses to inhalation of a single puff (30 ml) of three types of smoke (high nicotine, low nicotine, and gas phase) in healthy male nonsmokers. After the upper airways were locally anesthetized, the subjects, breathing through a mouthpiece, were instructed to signal the detection and the intensity of airway irritation with a push-button device. Inhalation of high-nicotine smoke consistently triggered an intense airway irritation in the lower neck and upper chest region; the total number of push-button signals generated in the first 5 s was 6.61 +/- 0.87 (mean +/- SE, n = 12), with a detection latency of 0.93 +/- 0.11 s. By contrast, inhalation of low-nicotine and gas phase smoke either was not detected or caused only very mild irritation (0.89 +/- 0.4 and 0.36 +/- 0.22, respectively). In addition, the intensity of smoke-induced airway irritation was markedly reduced after premedication with aerosolized hexamethonium, a nicotinic receptor antagonist (P < 0.01, n = 8). Furthermore, inhalation of nicotine aerosol also immediately evoked intense airway irritation and coughs (n = 5). Thus we conclude that the airway irritation evoked by inhaling cigarette smoke results from an activation of sensory endings located in the central airways and nicotine is the primary agent responsible for this action.

The effects of acetazolamide on the ventilatory response to high altitude hypoxia.

Acetazolamide treatment ameliorates the symptoms of AMS; however, the mechanism by which this occurs is unclear. To examine the effects of acetazolamide on oxygenation, CO2 responsiveness and ventilatory pattern during acute exposure to HA, we studied two groups of subjects at SL and following rapid (less than 8 h) transport to HA. Acetazolamide or placebo tablets were given to groups 1 and 2, respectively, in a double-blind manner after baseline SL measurements; treatment was continued during HA exposure. There was no difference in the ventilatory pattern at HA, between the two groups. While the Ve achieved in response to CO2 at HA vs SL was much greater in each group the percent change from baseline at HA versus that at SL was not significantly different. The beneficial effects of acetazolamide in AMS are associated with a higher level of ventilation at HA and better oxygenation: CO2 chemosensitivity is not affected by acetazolamide at HA.

The relationship of resting ventilation to mouth occlusion pressure. An index of resting respiratory function.

In order to examine the relationship of mouth occlusion pressure (MOP), an index of central inspiratory neuromuscular drive, to age and sex and to resting ventilation (VE), measurements were made in the seated posture in 84 healthy, normal subjects (38 men, 46 women; ages 18-72 years, mean +/- SD = 39.8 +/- 14.5 years) and in 79 patients with either airways obstruction (n = 63) or restrictive lung disease (n = 16). In the normal subjects, there was no significant relationship between age or sex and MOP (expressed as P0.1), which is the mouth pressure developed against a complete occlusion at 0.1 s after the beginning of inspiration, and dP/dtmax, the maximal rate of rise of this pressure; mean +/- SD for P0.1 = 0.75 +/- 0.32 cmH2O, and dP/dtmax = 19.41 +/- 10.10 cmH2O/s. Similarly, there was no significant relationship between age or sex and VE/P0.1 or VE/dP/dtmax. In 99 percent of normal subjects (83 of 84), VE/P0.1 was greater than 8.0 L/min/cmH2O, whereas in only 1 of the 79 patients was the value greater than 7.9 L/min/cmH2O. While the mean values of P0.1 and dP/dtmax were significantly different between normal subjects and patients, there was considerable overlap, whereas the ratio VE/P0.1 or VE/dP/dtmax provided excellent differentiation between normal subjects and patients with lung disease. This index, which is easily measured and requires minimal patient cooperation, provides valuable information in the clinical assessment of ventilatory drive and lung mechanics.

Pulmonary function in the elderly: response to theophylline bronchodilation.

This clinical investigation was designed to characterize the pharmacologic response to theophylline in elderly individuals. Incremental theophylline plasma concentrations (0, 5, 10, 15, and 20 mcg/mL), achieved through dose escalation of intravenous aminophylline, were correlated with pulmonary airway responses in ten young and ten elderly male asthmatic volunteers. The older group had lower baseline pulmonary function values, suggestive of a greater degree of baseline airways obstruction. Despite wide intersubject variability, the elderly subjects demonstrated a lower absolute change in bronchodilator response to equal concentrations of theophylline than did their younger counterparts (P less than .05). A progressive increase in heart rate was noted with increasing theophylline concentrations, but no significant difference in heart rate change between groups was detected (P greater than .05). Whether the difference in theophylline induced bronchodilator response observed in the young and elderly groups is due to a difference in age or in severity of airway obstruction is yet unknown.

Effects of sequential doses of parenteral terbutaline on plasma levels of potassium and related cardiopulmonary responses.

beta-agonist bronchodilator drugs are known to cause hypokalemia; nevertheless, successive parenteral doses are recommended for the treatment of status asthmaticus. The metabolic and cardiopulmonary effects of sequential, subcutaneous doses of terbutaline were studied in eight stable adult asthmatic patients. Each subject received terbutaline, 0.25 mg subcutaneously, followed 30 min later either by a second subcutaneous dose of terbutaline (sequential) or normal saline (single) in a randomized, double-blind, crossover fashion. Maximum reductions in plasma potassium from baseline were significantly greater (p less than 0.05) following sequential treatment compared to single treatment (-1.1 versus -0.6 mEq/L, respectively). Improvements in forced expiratory volume in 1 s were temporally related to changes in serum potassium and were significantly greater (p less than 0.01) following sequential terbutaline treatment. Prolongation of the QTc interval occurred following both treatment regimens. The change in QTc was statistically significant only following sequential treatment, increasing from 377 +/- 21 to 441 +/- 39 ms (p less than 0.05). Sequential doses of parenterally administered terbutaline result in clinically significant reductions in plasma potassium that are temporally related to changes in pulmonary function and associated with important electrocardiographic alterations.

Airways responsiveness determined by consecutive histamine challenges in asymptomatic asthmatics.

The effect of two consecutive histamine inhalation challenges on airways responsiveness was assessed in a group of eight nonsmoking nonmedicated asthmatics aged 19-27 yr. All subjects had a base-line forced expiratory volume in 1 s (FEV1) of greater than 80% of their predicted normal value before the initial challenge and were allowed to recover to greater than 95% of the initial base-line FEV1 value before the second challenge was initiated. The average airways recovery time after the first challenge was 44 min but ranged between 30 and 90 min. The mean +/- SD values of cumulative histamine dose units provoking a 20% decrease of the FEV1 from the buffer control value (PD20FEV1) were 10.79 +/- 5.95 determined with the first and 30.50 +/- 46.36 with the second challenge (P greater than 0.05). We conclude that sequential histamine challenges performed in mild asthmatics with closely controlled prechallenge airways function are well tolerated. Although some variance does exist in intersubject airways recovery time and in intra-subject histamine airways responsiveness determined by sequential challenges, our data do not support recent observations (J. Appl. Physiol. 63: 1572-1577, 1987) that histamine tolerance is a characteristic finding associated with bronchial asthma.

Pulmonary gas exchange during histamine-induced bronchoconstriction in asthmatic subjects.

Bronchial provocation for testing airway hyperreactivity is now well-established. However, the effects of histamine-induced bronchoconstriction on pulmonary gas exchange in man have not been systematically studied. We empirically noted marked decreases in PaO2 in some asthmatic subjects following induced bronchoconstriction. Nine subjects with mild, stable asthma were studied, each on two separate days. The first determined the dose of inhaled histamine necessary to decrease FEV1 by 20 percent and the relationship to lung volume and to pulmonary resistance by the interrupter technique (Rint). On the second day arterial blood gases, ventilation, Rint, and the anatomic (VDan) and physiologic (VDphys) dead spaces were measured simultaneously. There was a significant (p less than 0.05), profound fall in PaO2 (mean, -21.8 mm Hg) and in P(A-a)O2 (mean +14.7 mm Hg) within 5 min after bronchoconstriction, associated with a significant (p less than 0.05) increase in respiratory frequency (mean +5.1 min-1); and decrease in tidal volume (mean, -0.3 L). The ratio VDphys/VT increased significantly (p less than 0.05; mean change, +0.08) even though VDan and VDphys did not. Bronchoconstriction induced the broadening of ventilation (V)/perfusion (Q) ratios, with, most likely, an increase in areas of high V/Q. Histamine-induced bronchoconstriction in mild asthma results in a marked fall in PaO2 due to induced V/Q inequality. Therefore, histamine airway challenge should be used with caution in patients with any preexisting hypoxemia.

Measurements of ventilatory regulation.

The ventilatory control system, although not yet fully understood, is a complex interaction of volitional and reflex mechanisms extending from the cerebral cortex to receptors in the lungs and chest wall. Measurements of ventilatory control mechanisms can be made at rest, during exercise, during sleep, and during hypercapnic or hypoxic stimuli. Measurements of ventilation, ventilatory pattern, and mouth occlusion pressure at rest provide valuable information on ventilatory control mechanisms; these measurements can be extended by measurements of diaphragmatic EMG (indicating central neural output) and measurements of ventilation and mouth occlusion pressure during CO2 or hypoxic stimulation. Clinical assessment of ventilatory control abnormalities requires an understanding of the basic features of the control system and a logical application of the available tests.