Adrenergic airway vascular smooth muscle responsiveness in healthy and asthmatic subjects.

The purpose of the present study was to determine the responsiveness of airway vascular smooth muscle (AVSM) as assessed by airway mucosal blood flow (Qaw) to inhaled methoxamine (alpha(1)-agonist; 0.6-2.3 mg) and albuterol (beta(2)-agonist; 0.2-1.2 mg) in healthy [n = 11; forced expiratory volume in 1 s, 92 +/- 4 (SE) % of predicted] and asthmatic (n = 11, mean forced expiratory volume in 1 s, 81 +/- 5%) adults. Mean baseline values for Qaw were 43.8 +/- 0.7 and 54.3 +/- 0.8 microl. min(-1). ml(-1) of anatomic dead space in healthy and asthmatic subjects, respectively (P < 0.05). After methoxamine inhalation, the maximal mean change in Qaw was -13.5 +/- 1.0 microl. min(-1). ml(-1) in asthmatic and -7.1 +/- 2.1 microl. min(-1). ml(-1) in healthy subjects (P < 0.05). After albuterol, the mean maximal change in Qaw was 3.0 +/- 0.8 microl. min(-1). ml(-1) in asthmatic and 14.0 +/- 1.1 microl. min(-1). ml(-1) in healthy subjects (P < 0.05). These results demonstrate that the contractile response of AVSM to alpha(1)-adrenoceptor activation is enhanced and the dilator response of AVSM to beta(2)-adrenoceptor activation is blunted in asthmatic subjects.     

Effects of airway anesthesia on ventilatory responses to graded dead spaces and CO2

Ventilatory response to graded external dead space (0.5, 1.0, 2.0, and 2.5 liters) with hyperoxia and CO2 steady-state inhalation (3, 5, 7, and 8% CO2 in O2) was studied before and after 4% lidocaine aerosol inhalation in nine healthy males. The mean ventilatory response (delta VE/delta PETCO2, where VE is minute ventilation and PETCO2 is end-tidal PCO2) to graded dead space before airway anesthesia was 10.2 +/- 4.6 (SD) l.min-1.Torr-1, which was significantly greater than the steady-state CO2 response (1.4 +/- 0.6 l.min-1.Torr-1, P less than 0.001). Dead-space loading produced greater oscillation in airway PCO2 than did CO2 gas loading. After airway anesthesia, ventilatory response to graded dead space decreased significantly, to 2.1 +/- 0.6 l.min-1.Torr-1 (P less than 0.01) but was still greater than that to CO2. The response to CO2 did not significantly differ (1.3 +/- 0.5 l.min-1.Torr-1). Tidal volume, mean inspiratory flow, respiratory frequency, inspiratory time, and expiratory time during dead-space breathing were also depressed after airway anesthesia, particularly during large dead-space loading. On the other hand, during CO2 inhalation, these respiratory variables did not significantly differ before and after airway anesthesia. These results suggest that in conscious humans vagal airway receptors play a role in the ventilatory response to graded dead space and control of the breathing pattern during dead-space loading by detecting the oscillation in airway PCO2. These receptors do not appear to contribute to the ventilatory response to inhaled CO2.     

Effect of an inhaled glucocorticoid on endothelial function in healthy smokers

Cigarette smoking is associated with attenuated endothelium-dependent vasodilation (endothelial dysfunction) in the systemic circulation, including the airway circulation. We wished to determine whether an inhaled corticosteroid could restore endothelial function in the airway of lung-healthy current smokers, ex-smokers, and nonsmokers. We measured baseline airway blood flow (Qaw) and Qaw reactivity to inhaled albuterol as an index of endothelium-dependent vasodilation and to sublingual nitroglycerin as an index of endothelium-independent vasodilation in lung-healthy current smokers, ex-smokers, and nonsmokers. Current smokers were then treated with inhaled fluticasone for 3 wk, and all measurements were repeated after fluticasone treatment and after a subsequent 3-wk fluticasone washout period. Baseline mean Qaw and endothelium-independent Qaw reactivity were similar in the three groups. Mean endothelium-dependent Qaw reactivity was 49.5% in nonsmokers, 42.7% in ex-smokers, and 10.8% in current smokers (P < 0.05 vs. nonsmokers). In current smokers, mean baseline Qaw was unchanged after fluticasone treatment, but endothelium-dependent Qaw reactivity significantly increased to 34.9%. Qaw reactivity was again blunted after fluticasone washout. Endothelial dysfunction, as assessed by vascular reactivity, can be corrected with an inhaled corticosteroid in the airway of lung-healthy current smokers. This proof of concept can serve as the basis for future clinical investigations on the effect of glucocorticoids on endothelial function in smokers.     

Airway closure with methacholine-induced bronchoconstriction

We examined airway closure with methacholine-induced bronchoconstriction in eight normal seated adults at a mean lung volume of 39% total lung capacity. Closure was evaluated in two ways. Regional closure was examined by comparing the regional distributions of 133Xe boluses distributed according to N2O uptake with those distributed by pulmonary perfusion; regions that exhibited less N2O uptake than perfusion were interpreted as having airway closure. In addition, we measured single-breath washouts of the same boluses; differences between the washouts indicated closure that was not necessarily regional. Basal airway closure increased with methacholine inhalation from 21 +/- 3 to 46 +/- 4% (means +/- SE; P less than 0.001). This was due to both decreased basal N2O uptake and a relative increase of basal perfusion. Washout curves of boluses distributed by perfusion did not change with bronchoconstriction. Before bronchoconstriction, washouts of boluses distributed by N2O uptake did not differ significantly from those distributed by perfusion. During bronchoconstriction, single-breath washouts of boluses distributed by N2O uptake showed increased concentration differences (P less than 0.015) that were significantly greater than those resulting from boluses delivered by perfusion. Changes in basal closure did not correlate with washout changes. We conclude that methacholine inhalation induced bronchoconstriction-increased basal airway closure and also increased airway closure in other lung regions in a way that did not relate to basal closure.     

Effects of cold dry air nasal stimulation on airway mucosal blood flow in humans

Several studies have demonstrated that nasal challenges can induce reflex responses in the respiratory system. Some authors have described bronchoconstriction and modification of the pattern of breathing following nasal challenges by irritants and cold air. We propose to determine the effect of nasal stimulation with cold dry air on airway mucosal blood flow (Qaw) in the proximal tracheal bronchial tree of healthy humans. Nine healthy subjects participated in the study. Baseline measurement Qaw, nasal airway resistance (NAR) and airway caliber by specific airways conductance (SGaw) were followed by nasal challenge with cold dry air. Qaw, NAR and Sgaw were determined after the challenge. In those subjects in which a significant decline in Qaw was recorded the protocol was repeated after pretreatment with nasal anesthesia using topical lidocaine. Cold dry air challenge produced a significant decrease in mean Qaw for the nine subjects and this response was abolished by pretreatment with nasal anesthesia using topical lidocaine. There was no significant change in Sgaw and NAR after the challenge and topical lidocaine anesthesia. Our data indicates that nasal stimulation with cold dry air leads to a reduction in Qaw and that this effect may be mediated by a nasal reflex.     

Airway responsiveness to inhaled and intravenous carbachol in sheep: effect of airway mucus

Excessive airway mucus can alter both the mass and site of aerosol deposition, which, in turn, may affect airway responsiveness to inhaled materials. In six prone sheep, we therefore measured pulmonary airflow resistance (RL) and cumulative aerosol deposition during five standard breaths (AD5) at base line and 3 min after inhalation challenge with 2% carbachol in buffered saline (10 breaths, tidal volume = 500 ml) or after an intravenous loading dose of carbachol (3 micrograms/kg) followed by a constant infusion of 0.3 micrograms.kg-1.min-1 with and without instillation of 20 ml of a mucus simulant (MS) into the distal end of each of the main bronchi or 30 ml of MS into the right main bronchus only by means of a flexible fiber-optic bronchoscope. Before carbachol challenge, RL did not change with MS into either both lungs or one lung only. AD5 increased from 36 +/- 2% (SE) before to 42 +/- 2% after MS instillation into both lungs (P less than 0.05) but remained unchanged after MS into one lung. After carbachol inhalation, RL increased significantly by 154 +/- 20 before and 126 +/- 25% after MS into both lungs and 162 +/- 24 before and 178 +/- 31% after MS into one lung (P less than 0.05). When the percent increase in RL was normalized for total aerosol deposition (% delta RL/AD5), the normalized values were lower after MS (3.0 +/- 0.5) than before MS (4.4 +/- 0.3) into both lungs (P less than 0.05) but were not significantly different before and after MS into the right lung only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aerosol deposition in the lung with asymmetric airways obstruction: in vivo observation

Both the total and regional aerosol deposition were measured in six adult sheep before and after an induction of asymmetric airway obstructions, either by local instillation of carbachol solution (CS, 0.1%) distal to the right main bronchus or inhalation challenge of the right lung with carbachol aerosol (CA, 10 breaths). Total lung deposition was determined by monitoring inert monodisperse aerosols [1.0 micron mass median aerodynamic diam (MMAD)] breath-by-breath, at the mouth, by means of a laser aerosol photometer. Cumulative aerosol deposition over the first five breaths as a percent of the initial aerosol concentration (AD5) was used as a deposition index. Regional deposition pattern was determined by scintigraphic images of sulfur-colloid aerosol (1.5 microns MMAD) tagged with 99mTc. Radioactivity counts in the right (R) and left lung (L) were expressed as a percent of the whole lung count. Half-lung AD5 was then determined by multiplying AD5 by fractional radioaerosol depositions in R or L. Pulmonary airflow resistance (RL mean +/- SE), as determined by an esophageal balloon technique, increased by 111 +/- 28 and 250 +/- 96% after CA and CS, respectively (P less than 0.05). AD5 also increased in all the sheep tested by 29 +/- 3 and 52 +/- 8%, respectively, after CA and CS (P less than 0.05). Radioaerosol deposition pattern was even at base line (R/L = 51:49) but shifted toward the unchallenged L after CS (R/L = 40:60). Deposition pattern after CA was variable: a shift toward L in three, no change in one, and a shift toward the R lung in two sheep.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alae nasi activation and nasal resistance in healthy subjects

To investigate the effect of alae nasi (AN) activation on nasal resistance, we monitored AN electromyographic (EMG) activity in 17 healthy subjects using surface electrodes placed on either side of the external nares and measured inspiratory nasal resistance utilizing the method of posterior rhinometry. With CO2 inhalation (6 subj), AN EMG activity increased as nasal resistance fell 23 +/- 5% (P less than 0.01). In the same subjects, voluntary flaring of the external nares also increased AN EMG and decreased nasal resistance by 29 +/- 5% (P less than 0.01). Nasal resistance was altered by nasal flaring and CO2 inhalation even after administration of a topical nasal vasoconstrictive spray (8 subj). In six subjects, voluntary nasal flaring or inhibition with the mouth closed produced a 21 +/- 12% change (P less than 0.01) in total airway resistance as measured by body plethysmography. We conclude that activation of the alae nasi will decrease nasal and total airway resistance during voluntary nasal flaring and during CO2 inhalation and thus should be considered in any studies of upper airway resistance.     

Marked stem cell factor expression in the airways of lung transplant recipients

Spherical monodisperse ferromagnetic iron oxide particles of 1.9 μm geometric and 4.2 μm aerodynamic diameter were inhaled by seven patients with primary ciliary dyskinesia (PCD) using the shallow bolus technique, and compared to 13 healthy non-smokers (NS) from a previous study. The bolus penetration front depth was limiting to the phase1 dead space volume. In PCD patients deposition was 58+/-8 % after 8 s breath holding time. Particle retention was measured by the magnetopneumographic method over a period of nine months. Particle clearance from the airways showed a fast and a slow phase. In PCD patients airway clearance was retarded and prolonged, 42+/-12 % followed the fast phase with a mean half time of 16.8+/-8.6 hours. The remaining fraction was cleared slowly with a half time of 121+/-25 days. In healthy NS 49+/-9 % of particles were cleared in the fast phase with a mean half time of 3.0+/-1.6 hours, characteristic of an intact mucociliary clearance. There was no difference in the slow clearance phase between PCD patients and healthy NS. Despite non-functioning cilia the effectiveness of airway clearance in PCD patients is comparable to healthy NS, with a prolonged kinetics of one week, which may primarily reflect the effectiveness of cough clearance. This prolonged airway clearance allows longer residence times of bacteria and viruses in the airways and may be one reason for increased frequency of infections in PCD patients.     

Radioprotective effectiveness of gas hypoxic mixture GHM-10 in experiments on dogs

In experiments on 128 dogs (males and females) weighing 7-24 kg it was demonstrated that inhalation of gas hypoxic mixture containing O2 (10%) and N2 (90%) decreased significantly the level of PO2 in radiosensitive tissues and exerted a radioprotective effect on the exposed animals (60Co, doses of 2.8, 3.5-3.8 and 4.2 Gy, DMF = 1.3). At a dose of 8 Gy the average life of animals increased from 6.2 +/- 0.8 days (control) up to 9.3 +/- 1.1 days after the application of GHM -10.     

PAF responsiveness in Japanese subjects with plasma PAF acetylhydrolase deficiency

Approximately 4% of the Japanese population genetically lack plasma platelet activating factor acetylhydrolase (PAF-AH) and show a higher prevalence of thromboembolic disease, but whether they are susceptible to another PAF-related disease, asthma, remains controversial. To determine the role of plasma PAF-AH in airway physiology, we performed PAF bronchoprovocation tests in 8 plasma PAF-AH-deficient subjects and 16 control subjects. Serial inhalation of PAF (1-1000 microg/ml) concentration-dependently induced acute bronchoconstriction, but there was no significant difference between PAF-AH-deficient and control subjects (11.7 +/- 4.6% vs. 9.6 +/- 2.8% decrease in forced expiratory volume in 1 s). Transient neutropenia after single inhalation of PAF (1000 microg/ml) showed no significant difference between the groups either in its magnitude (72 +/- 11% vs. 65 +/- 9% decrease) or duration (4.1 +/- 1.0 vs. 3.3 +/- 0.8 min). In conclusion, a lack of plasma PAF-AH activity alone does not augment physiological responses to PAF in the airway.     

Effects of induced bronchoconstriction on pulmonary blood flow

Allergic bronchoconstriction may be associated with hemodynamic alterations due to changes in respiratory mechanics (or the associated changes in arterial blood gas composition) or the cardiovascular effects of chemical mediators. In an attempt to differentiate between these two possible mechanisms, we obtained measurements of hemodynamics, respiratory mechanics, and O2 consumption (VO2) in nine asymptomatic adult ragweed asthmatics before and after inhalation challenge with either ragweed extract or methacholine. We measured specific airway conductance (sGaw) by body plethysmography, pleural pressure with an esophageal balloon catheter, pulmonary blood flow (Q) and VO2 by a rebreathing technique, and heart rate. For a similar degree of bronchoconstriction after the two types of challenge (mean +/- SD sGaw 0.06 +/- 0.03 and 0.05 +/- 0.02 cmH2O-1 . s-1, P = NS), mean Q increased by 29 and 29%, and mean VO2 by 33 and 37% 15-20 min after ragweed and methacholine, respectively. Since heart rate did not change, there was a concomitant increase in mean stroke volume by 25 and 35%, respectively (P less than 0.05). The respiratory pleural pressure swings during quiet breathing and the rebreathing maneuver and the work of breathing during rebreathing also increased to a similar degree after the two types of challenge. These observations suggest that, if chemical mediators are released into the circulation during antigen-induced bronchoconstriction, their blood concentrations are too low for appreciable cardiovascular effects. The increase in rebreathing cardiac output during allergic and nonallergic bronchoconstriction is probably due to increases in intrathoracic pressure swings and in the work of breathing.     

Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation

The effect of a bronchodilator in asthmatics is only partially described by changes in spirometric values since no information on regional differences can be obtained. Imaging techniques like high-resolution computed tomography (HRCT) provide further information but lack detailed information on specific airway responses. The aim of the present study was to improve the actual imaging techniques by subsequent analysis of the imaging data using computational fluid dynamics (CFD). We studied 14 mild to moderately severe asthmatics. Ten patients underwent HRCT before and 4h after inhalation of a novel long acting beta(2) agonist (LABA) that acts shortly after inhalation. Four patients were studied for chronic effects and underwent CT scans twice after adequate wash-out of bronchodilators. In the active group, a significant bronchodilator response was seen with a forced expiratory volume in 1s (FEV1) increase of 8.78 +/- -6.27% pred vs -3.38 +/- 6.87% pred in the control group. The changes in FEV1 correlated significantly with the changes in distal airway volume (r = 0.69, p = 0.007), total airway resistance (r = -0.73, p = 0.003) and distal airway resistance (r = -0.76, p = 0.002) as calculated with the CFD method. The changes in distal R(aw) were not fully homogeneous. In some patients with normal FEV1 at baseline, CFD-based changes in R(aw) were still detectable. We conclude that CFD calculations, based on airway geometries of asthmatic patients, provide additional information about changes in regional R(aw). All changes in the CFD-based calculated R(aw) significantly correlate with the observed changes in spirometric values therefore validating the CFD method for the studied application.     

Airway diffusing capacity of nitric oxide and steroid therapy in asthma.

Exhaled nitric oxide (NO) concentration is a noninvasive index for monitoring lung inflammation in diseases such as asthma. The plateau concentration at constant flow is highly dependent on the exhalation flow rate and the use of corticosteroids and cannot distinguish airway and alveolar sources. In subjects with steroid-naive asthma (n = 8) or steroid-treated asthma (n = 12) and in healthy controls (n = 24), we measured flow-independent NO exchange parameters that partition exhaled NO into airway and alveolar regions and correlated these with symptoms and lung function. The mean (+/-SD) maximum airway flux (pl/s) and airway tissue concentration [parts/billion (ppb)] of NO were lower in steroid-treated asthmatic subjects compared with steroid-naive asthmatic subjects (1,195 +/- 836 pl/s and 143 +/- 66 ppb compared with 2,693 +/- 1,687 pl/s and 438 +/- 312 ppb, respectively). In contrast, the airway diffusing capacity for NO (pl.s-1.ppb-1) was elevated in both asthmatic groups compared with healthy controls, independent of steroid therapy (11.8 +/- 11.7, 8.71 +/- 5.74, and 3.13 +/- 1.57 pl.s-1.ppb-1 for steroid treated, steroid naive, and healthy controls, respectively). In addition, the airway diffusing capacity was inversely correlated with both forced expired volume in 1 s and forced vital capacity (%predicted), whereas the airway tissue concentration was positively correlated with forced vital capacity. Consistent with previously reported results from Silkoff et al. (Silkoff PE, Sylvester JT, Zamel N, and Permutt S, Am J Respir Crit Med 161: 1218-1228, 2000) that used an alternate technique, we conclude that the airway diffusing capacity for NO is elevated in asthma independent of steroid therapy and may reflect clinically relevant changes in airways.     

Effect of substance P on cardiovascular and respiratory function in subjects

The effect of substance P (SP), administered both intravenously and by inhalation, has been studied in normal and asthmatic humans. Intravenous infusion of SP (0.2-3.3 pmol X kg-1 X min-1) achieving a plasma concentration of SP between 5 and 25 pM produced vasodilatation (mean +/- SD), maximal increase in skin temperature (0.9 +/- 0.3 degree C) (P less than 0.05), and fall in diastolic blood pressure (8.5 +/- 2.9 mmHg) (P less than 0.05) associated with an increase in heart rate (15 +/- 10 beats/min) (P less than 0.05). All subjects had a fall in Vp30 (airflow at 70% of forced vital capacity measured from total lung capacity after a forced partial expiratory flow maneuver) at low infusion rate (P less than 0.05) and a significant rise at the highest infusion rate (P less than 0.05). Ventilation at rest and when stimulated by transient hypoxia increased (mean increase in resting ventilation 0.73 +/- 0.4 l/min and mean percent increase in transient ventilatory hypoxic response 41 +/- 27%). There was a small nonsignificant increase in plasma norepinephrine but no change in epinephrine or histamine. Inhaled SP, up to 0.7 mumol, caused a small nonsignificant fall in airway function in asthmatic subjects. SP has demonstrable effects on vascular smooth muscle and control of ventilation but at the doses studied had little effect on airway function.     

Airway hyperresponsiveness to ultrasonically nebulized distilled water in subjects with tetraplegia.

The majority of otherwise healthy subjects with chronic cervical spinal cord injury (SCI) demonstrate airway hyperresponsiveness to aerosolized methacholine or histamine. The present study was performed to determine whether ultrasonically nebulized distilled water (UNDW) induces airway hyperresponsiveness and to further elucidate potential mechanisms in this population. Fifteen subjects with SCI, nine with tetraplegia (C4-7) and six with paraplegia (T9-L1), were initially exposed to UNDW for 30 s; spirometry was performed immediately and again 2 min after exposure. The challenge continued by progressively increasing exposure time until the forced expiratory volume in 1 s decreased 20% or more from baseline (PD20) or the maximal exposure time was reached. Five subjects responding to UNDW returned for a second challenge 30 min after inhalation of aerosolized ipratropium bromide (2.5 ml of a 0.6% solution). Eight of nine subjects with tetraplegia had significant bronchoconstrictor responses to UNDW (geometric mean PD20 = 7.76 +/- 7.67 ml), whereas none with paraplegia demonstrated a response (geometric mean PD20 = 24 ml). Five of the subjects with tetraplegia who initially responded to distilled water (geometric mean PD20 = 5.99 +/- 4.47 ml) were not responsive after pretreatment with ipratropium bromide (geometric mean PD20 = 24 ml). Findings that subjects with tetraplegia are hyperreactive to UNDW, a physicochemical agent, combined with previous observations of hyperreactivity to methacholine and histamine, suggest that overall airway hyperresponsiveness in these individuals is a nonspecific phenomenon similar to that observed in patients with asthma. The ability of ipratropium bromide to completely block UNDW-induced bronchoconstriction suggests that, in part, airway hyperresponsiveness in subjects with tetraplegia represents unopposed parasympathetic activity.     

Human temperature regulation during narcosis induced by inhalation of 30% nitrous oxide.

The study investigated the effect of inhalation of 30% nitrous oxide (N2O) on temperature regulation in humans. Seven male subjects were immersed to the neck in 28 degrees C water on two separate occasions. They exercised at a rate equivalent to 50% of their maximum work rate on an underwater cycle ergometer for 20 min and remained immersed for an additional 100 min after the exercise. In one trial (AIR) the subjects inspired compressed air, and in the other trial (N2O) they inspired a gas mixture containing N2O (20.93% O2-30% N2O-49.07% N2). Sweating, measured at the forehead, and shivering thermogenesis, as reflected by O2 uptake, were monitored throughout the 100-min recovery period. The threshold core temperatures at which sweating was extinguished and shivering was initiated were established relative to resting preexercise levels. Neither the magnitude of the sweating response nor the core threshold at which it was extinguished was significantly affected by the inhalation of N2O. In contrast, shivering thermogenesis was both significantly reduced during the N2O condition and initiated at significantly lower core temperatures [change in esophageal temperature (delta T(es)) = -0.98 +/- 0.33 degrees C and change in rectal temperature (delta T(re)) = -1.26 degrees C] during the N2O than during the AIR condition (delta T(es) = -0.36 +/- 0.31 degrees C and delta T(re) = -0.44 +/- 0.22 degrees C).(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrapulmonary distribution of bronchial blood flow after moderate smoke inhalation

The systemic blood flow to the airways of the left lung was determined by the radioactive microsphere technique before and 17 h after smoke inhalation in six conscious sheep (smoke group) and six sheep insufflated with air alone (sham group). Smoke inhalation caused a sixfold increase in systemic blood flow to the lower trachea (baseline 10.6 +/- 1.7 vs. injury 60.9 +/- 16.1 ml.min-1.100 g-1) and an 11- to 14-fold increase to the intrapulmonary central airways (baseline range 9.5 +/- 1.9 to 13.5 +/- 3.7 ml.min-1.100 g-1 vs. injury 104.6 +/- 32.2 to 187.3 +/- 83.6 ml.min-1.100 g-1). There was a trend for this hyperemic response to be greater as airway diameter decreased from the trachea to 2-mm-diam central airways. In airways smaller than 2 mm, the hyperemic response appeared to diminish. The total systemic blood flow to whole lung is predominantly to small peripheral airways and showed no significant increase from its baseline level of 17.5 +/- 3.7 ml.min-1.100 g-1 in the lung homogenate. Occlusion of the bronchoesophageal artery decreased central airway blood flow 60-80% and peripheral airway blood flow 40-60% in both the sham and the smoke groups.     

Effects of inspired CO2, hyperventilation, and time on VA/Q inequality in the dog.

In a recent study by Tsukimoto et al. (J. Appl. Physiol. 68: 2488-2493, 1990), CO2 inhalation appeared to reduce the size of the high ventilation-perfusion ratio (VA/Q) mode commonly observed in anesthetized mechanically air-ventilated dogs. In that study, large tidal volumes (VT) were used during CO2 inhalation to preserve normocapnia. To separate the influences of CO2 and high VT on the VA/Q distribution in the present study, we examined the effect of inspired CO2 on the high VA/Q mode using eight mechanically ventilated dogs (4 given CO2, 4 controls). The VA/Q distribution was measured first with normal VT and then with increased VT. In the CO2 group at high VT, data were collected before, during, and after CO2 inhalation. With normal VT, there was no difference in the size of the high VA/Q mode between groups [10.5 +/- 3.5% (SE) of ventilation in the CO2 group, 11.8 +/- 5.2% in the control group]. Unexpectedly, the size of the high VA/Q mode decreased similarly in both groups over time, independently of the inspired PCO2, at a rate similar to the fall in cardiac output over time. The reduction in the high VA/Q mode together with a simultaneous increase in alveolar dead space (estimated by the difference between inert gas dead space and Fowler dead space) suggests that poorly perfused high VA/Q areas became unperfused over time. A possible mechanism is that elevated alveolar pressure and decreased cardiac output eliminate blood flow from corner vessels in nondependent high VA/Q regions.     

Systemic pilocarpine increases deposition of and decreases responsiveness to inhaled carbachol in sheep.

The purpose of this study was to determine whether excessive airway secretions could serve as a barrier function against inhaled particulate matter. To increase airway secretions, six conscious sheep were treated with pilocarpine (0.8 mg/kg i.v.). Pilocarpine increased pulmonary resistance (RL) and total aerosol deposition within five breaths (AD5) as determined by the rebreathing of an inert monodisperse aerosol. When RL had returned to baseline, AD5 remained elevated [21 +/- 2% (SE), P < 0.05] and tracheal secretions were increased (237 +/- 77%, P < 0.05) above the values before pilocarpine administration. A carbachol aerosol dose-response curve was carried out at this time and compared with a control carbachol dose-response curve by calculating the dose of carbachol required to increase RL by 400% (PD400). Mean PD400 was increased postpilocarpine by 53 +/- 18 (P < 0.05) and 85 +/- 25% (P < 0.05) when normalized for increased aerosol deposition. Thus, pilocarpine decreased airway responsiveness to inhaled carbachol despite increasing aerosol deposition. The pilocarpine-induced airway hyporesponsiveness to inhaled carbachol is consistent with the hypothesis that excessive secretions have a protective role in the airways.