The influence of aerosol retention and pattern of deposition on bronchial responsiveness to atropine and methacholine in humans.

We have examined the influence of total intrapulmonary deposition and its pattern on the bronchial response to aerosolized methacholine and atropine in 10 normal and 12 asthmatic subjects. On Day 1 we performed a dose-response challenge to methacholine and defined responsiveness as the provocative dose (PD35) needed to cause a 35% decrease in specific airway conductance (SGaw). On Day 2 we repeated methacholine challenge after premedication with aerosolized atropine, and we defined the response to atropine as dose ratio-1 (DR-1) where DR = PD35 after atropine/PD35 without atropine. On Day 3 we imaged intrapulmonary aerosol deposition by mixing 99mtechnetium with methacholine aerosol and scanning the thorax with a gamma camera during the development of bronchoconstriction. Total pulmonary aerosol deposition varied considerably between individuals (1.2 to 23.6% of nebulized dose) but there was no difference between normal and asthmatic subjects, and no correlation between deposition and baseline SGaw or PD35; there was a significant positive correlation between deposition and DR-1. Deposition of aerosol in central lung zones was inversely related to SGaw and correlated positively with DR-1; there was no significant relationship with PD35. Total intrapulmonary aerosol deposition and its pattern partially determine bronchial responsiveness to atropine, but we have not demonstrated any significant effect on responsiveness to methacholine.

Morning-evening changes in airway responsiveness to methacholine in normal and asthmatic subjects: analysis using partial flow-volume curves.

In eight normal and eight asthmatic subjects airway responsiveness to methacholine was measured by means of partial flow-volume loops at 0800 and 1800 hours on the same day. Airway responsiveness was lower in the evening in both normal and asthmatic subjects.

Abolition of methacholine induced bronchoconstriction by the hyperventilation of exercise or volition.

Total pulmonary resistance was measured from continuous records of flow and oesophageal pressure in five normal subjects on three separate days before and after inhalation of methacholine. The dose of methacholine produced, on average, a fivefold increase in airway resistance. Immediately after methacholine inhalation the subjects underwent a progressive exercise test on a cycle ergometer (day 1) or voluntary hyperventilation (day 2) or remained resting (day 3). On the first day during exercise pulmonary resistance fell rapidly to baseline levels within two to three minutes and remained there for the 10 minute duration of the exercise. On day 2 voluntary reproduction of the same level and pattern of ventilation as during exercise resulted in a similar fall of resistance. On the third day, when the subjects remained at rest, pulmonary resistance remained raised for 10 minutes. It is concluded that the bronchodilator effects of exercise can be explained by the increased ventilation rather than the exercise itself, but with much smaller tidal volumes than have previously been thought necessary to reduce drug induced bronchoconstriction.

Measurement of pharmacological antagonism produced by atropine in bronchi of normal and asthmatic subjects.

The bronchial response of six normal and six asthmatic subjects to increasing concentrations of methacholine aerosol was measured by serial measurements of specific airways conductance (sGaw) in a body plethysmograph. On separate days, the subjects were premedicated with 0.9% NaCl, inhaled atropine at four different doses, or intravenous atropine at two different doses. Cumulative log dose-response curves were constructed. The provocative dose of methacholine needed to cause a 35% fall in sGaw was measured from each curve (PD35). The antagonism produced by a given atropine dose was quantified as the dose ratio, which was defined as the ratio of PD35 after atropine to PD35 after saline. In normal subjects, approximately equal amounts of atropine given by the inhaled or intravenous routes produced mean dose ratios of almost identical value. However, in asthmatic subjects inhaled atropine (1.28 mg, 4.4 mumol) produced a mean dose ratio 7.5 times greater than the mean value seen with intravenous atropine (1.0 mg, 3.46 mumol). Intravenous atropine (1.0 mg, 3.46 mumol) produced a mean dose ratio of 18.3 for all subjects, compared to a value of 26 predicted from in vitro experiments. The slope of the regression line for the relationship of log (dose ratio -1) vs -log atropine dose (Schild plot) for all subjects was -0.99. The actions we have observed are compatible with the main actions of atropine being that of a competitive antagonist at the muscarinic receptor. The greater blocking effect of inhaled atropine in some asthmatics suggests that a higher concentration of atropine is achieved at the muscarinic receptor by the inhaled route in these subjects.

Measurement of lung tissue mass, thoracic blood and interstitial volumes by transmission/emission scanning using [99mTc]pertechnetate.

1. We have developed a method for non-invasive measurement of lung tissue mass, thoracic blood and interstitial volumes by a combination of transmission and emission scanning with technetium isotope (99mTc). 2. In a lung model we demonstrated that emission counts could be successfully corrected for attenuation with data obtained by transmission scanning, despite an uneven distribution of radioactivity and attenuation in the model. 3. In dogs we compared regional transthoracic tissue thickness, measured by transmission scanning, and regional 'thickness' of blood measured by transmission/emission scanning with direct gravimetric measurements made post mortem. Scanning and direct measurements correlated significantly. 4. In man we used a [99mTc]pertechnetate (99mTcO4) flood source to obtain antero-posterior transmission scans with a gamma-camera. The thickness of attenuating tissue was estimated in each pixel. Scans were obtained of thoracic blood (by labelling erythrocytes with 99mTcO4) and of interstitium (with 99mTc-labelled diethylenetriaminepenta-acetic acid and subtraction of the blood image). We used a computer program to correct the emission scans for attenuation using the transmission scan derived tissue thickness, pixel by pixel. Finally we took a lateral chest radiograph to estimate chest wall thickness. 5. In normal man lung tissue thickness at hilar level was 3.1 +/- 0.5 cm (n = 8). Thoracic blood thickness increased from the apex downwards in the upright lung, being 1.2 +/- 0.1 cm at the hilar level and 2.0 +/- 0.3 cm at the lung base. Interstitial thickness was 0.8 +/- 0.3 cm at the hilum and 0.85 +/- 0.2 at the base. These values compare well with data in the literature.(ABSTRACT TRUNCATED AT 250 WORDS)