Lung (1981) 159:81-89

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Airway Responsiveness of Chronic Smokers to Increased Lung Volume and to a Bronchodilator* E. H. Schlenker** and M. J. Jaeger Department of Physiology, College of Medicine, University of Florida. Gainesville, FL 32160, USA

Abstract. Airways responsiveness of chronic smokers to an aerosolized bronchodilator and to breathing at increased lung volume (one liter above Functional Residual Capacity) was compared using a modified flow body plethysmograph to measure large airway resistance (Raw) and distribution of the evenness of the ventilation (PD) of smaller airways simultaneously during normal breathing. The magnitude of the decrease of Raw after bronchodilator administration (M) was significantly correlated with the decrease of Raw after breathing at increased lung volume (r=0.61, P < 0.01), Similarly. the magnitude of the decrease of PD after M was significantly correlated with the decrease noted after breathing at increased lung volume (r=0.65, P<0.01). The responsiveness of the individual subject was related to smoking and respiratory disease (RD) history. The heaviest smokers (pack-year history = 37.8 years) had more responsive large airways and apparently less responsive small airways than did lighter smokers (pack-year history = 14.3 years). Subjects with a past history of RD were more responsive to bronchodilator than subjects without a history of RD even though the smoking history of the two groups was not significantly different. Key words: Airway responsiveness - S m o k i n g - Lung volume - Bronchodilator - Phase difference (PD) Introduction Bronchoconstriction due to reflex and structural changes in both small and large airways is well documented in chronic smokers [22, 20, 19]. Administration of a bronchodilator or cessation of smoking can either partially or totally reverse this constriction [14, 16, 3]. In the present study we compared the effect o f a fl-adrenergic * Supported by grants from the Parker B. Francis Foundation and NIH Training Grant TO1HL0579 ** To whom requests for offprints should be sent at: Division of Biochemistry, Physiology and Pharmacology. The School of Medicine, The University of South Dakota, Vermillion, SD 57069, USA

0341-2040/81/0159/0081/$ 01.80

82

E. H. Schlenker and M. J. Jaeger

bronchodilator to that o f mechanical lung distention on both large and small airways in 43 chronic smokers. Mechanical distention was achieved by having the subject breathe one liter above functional residual capacity. Each procedure was found to increase the caliber of both large and small airways in the same individual by the same magnitude. W e also investigated individual variability by studying its relation to the subject's history.

Methods

Subjects Smokers with a smoking history o f at least 10 years were solicited by' advertisement in our Medical Center. Applicants with a b a c k g r o u n d o f chronic c a r d i o p u l m o n a r y disease or recent acute respiratory disease were not considered. The screening included a brief testing with a modified body p l e t h y s m o g r a p h [1] to insure that the a p p l i cants had at least one sign of bronchial involvement. Twenty-two adult males ranging in age from 2 2 - 6 0 years (mean age 32.5+8.8 years) and 21 femates also r a n g ing in age 22-60 years (mean age 37.5+ 11.3 years) were selected. Mean age o f the entire group was 34.9+ 10.2 years and m e a n pack year history ( n u m b e r o f packs smoked per day x y e a r s smoked) 26.5+ 17.3 years. There was no significant difference in the pack year history between the two groups. Table 1 lists the results o f lung function tests in these subjects.

Techniques Functional Residual Capacity (FRC), and airway resistance (Raw) were m e a s u r e d by the technique o f D u B o i s et al. [I0, 11]. T h e phase difference (PD) between m e a n alveolar pressure and flow rate at the mouth was m e a s u r e d during normal b r e a t h i n g according to the method of Banergee, et al. [1]. The PD, which is an i n d e x o f unevenness o f ventilation, correlates significantly with other tests indicative o f small Table 1. Effect of Metaprel on lung mechanics (mean and SD)

Raw SGaw FRC MMFR AN2 CV CV/VC CC/TL C TLC RV FEV1 / FVC PD

Control

Metapret

P value

2.02 ± 0.50 cm H20/l/s 0.13 - 0.19 - 0.26 cm H20-ls< 3.21 ±0.77 1 3.52± 1.48 1/s 2.22+ 1.35% 0.76 ± 0.041 ! 18.2± 8.46% 0.40 ± 0.072 5.78± 1.36 1 1.55±0.51 1 77.5 ± 7.8% 12.5 ± 6.2 °

1.55 + 0.98 0.15 - 0.28 - 0.42 3.02+0.64 3.86± 1.48 2.01 ± 1.32 0.69 + 0.043 15.9± 8.39 0.37 ± 0.066 5.78± 1.34 1.43±0.48 79.9 + 7.0 4.93 ± 3.8

< 0.01 < 0.01 < 0.05 < 0.05 NS NS < 0.05 < 0.05 NS < 0.05 NS < 0.01

N was equal to 43; in 6 subjects CV and CC could not be determined. A paired t-test was used to determine all means and standard deviations except for statistics for SGaw wich have a skewed distribution. Using a log transformation, these data were normalized and the 95% confidence limits are reported. The P value for SGaw was obtained using a paired Wilcoxon test.

Effect of Lung Volume and Bronchodilators on Airways

83

airway dysfunction in smokers such as closing volume, mid-maximal expiratory flowrate, and the slope of Phase III [I]. Closing volume (CV) and slope of alveolar plateau in the middle third of the vital capacity (ANa) were measured using the single breath N~ washout technique [7]. dNs was expressed in % [1]. Residual volume (RV) was measured from the single breath Ns tracing using the mean fraction of expired alveolar nitrogen (FANs) in the following equation: RV=

FANs - FVC

0.79 - FANs CV and RV were added to obtain closing capacity (CC). A Stead-Wells spirometer was used to determine forced vital capacity (FVC), forced expiratory volume in one second (FEVl), and mid-maximum expiratory flow rate (MMFR).

Procedures The order of testing was as follows. After a subject signed a consent form. approved by the Health Center Human Experimental Committee, Raw, PD, and FRC were measured. The subject was then told to inspire to 1 1 above FRC and breathe normally at that new lung volume for 30 s to 1 min. PD and Raw were again determined. The spirogram was monitored on an oscilloscope by the subject and the investigator. A PD was accepted only if the subject could maintain the same tidal volume and flow rate and the PD retraced itself on the oscilloscope four or more times. Thirty-five subjects met these criteria while they breathed at FRC + 11. Individuals unable to perform these maneuvers felt an inability to maintain a normal breathing pattern without some muscle discomfort. Next, the subject's RV, CV and AN2 were measured using the single breath N2 washout technique. Measurements were repeated until at least two curves showed the same VC. Afterwards, the subject performed three vital capacity maneuvers into a Stead-Wells spirometer to measure FVC, F E V , , and MMFR. All subjects then received two metered aerosol doses of 0.65 mg ofa fi-adrenergic stimulatory drug, Metaprel (metaproternal sulfate). Subjects exhaled to residual volume and then inhaled the aerosol while inspiring to total lung capacity. They were asked to breath-hold briefly and breathe normally for 30 s before receiving a second dose. The total dose equalled 1,3 mg. Subjects subsequently filled out a British Medical Council questionnaire which included questions concerning 1) smoking history (years and packs per day); 2) a record of episodes of severe respiratory diseases such as pneumonia or severe bronchitis during which the subject had been hospitalized or remained in bed under a physician's care; and 3) symptomology including shortness of breath, cough and sputum production. After a 30-min interval, all tests were repeated. Results

Effects of Metaprel A summary of the effects of Metaprel on various lung function tests is presented in Table 1. Raw showed a decrease from a mean control value of 2.02 cm H 2 0 / i / s to

E. H. SchlenkerandM. J. Jaeger

84

1.55 cm H20/1/s or 77% of control. F R C decreased from 3.21 to 3.02 1. A 32% increase of specific conductance (SGaw = Raw -1 + FRC) from a control value of 0.19 to 0.28 cm H~O -1 s -1 was noted, but the response of individual subjects to Metaprel was extremely variable (0-340%). A reduction of PD from 12.5" to 4.93 ° was observed. Of the 35 subjects able to perform this maneuver, the PD become 0 ° in 28. All other tests listed in Table 1 also changed after Metaprel except TLC. Some of the changes, however, were small.

Increased Lung Volume ( t Ix) W h e n subjects were asked to breathe 1 1 above their FRC, the following reductions in Raw and PD were noted (Figs. 1 and 2). Raw dropped from 2.02 to 1.40 cm H 2 0 / 1 / s or to 69% of control ( P < 0.05). PD decreased from 12.5° to 4.7 ° ( P < 0.01). O f the 35 subjects able to perform this procedure, 60% had a PD of 0. The response to Metaprel and to an increase of lung volume were correlated. Subjects with a large decrease of Raw after Metaprel also had a large decrease of Raw at increased lung volume. The correlation coefficient (r) was equal to 0.61 ( P < 0.01). Similarly the magnitude of the decrease of PD after Metaprel was correlated with the decrease at FRC plus 1 1 (r=0.65, P < 0.01).

PD

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FRC

FRC+10I

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FRC

FRC .,,1.0 1

Fig. 1. The effect of Metaprel (dark rectangles) on Raw at FRC and at FRC+ 1.0 1. N = 4 3 at FRC and N=35 at FRC+ 1.0 1. The lines indicate the standard error (SE) of the mean. The asterisks indicate that the values are significantly different from FRC before Metaprel at P < 0.05 Fig. 2. The effect of Metaprel (dark rectangles) on PD at FRC and at FRC+ 1.0 1. N = 4 3 at FRC and N = 35 at FRC + 1.0 1. The lines indicate the SE of the mean. The asterisks indicate that the values are significantly different tiom FRC before Metaprel at P < 0.01

Effect of Lung Volume and Bronchodilators on Airways

85

Effect of Increased Lung Volume in Subjects Pre- Treated with Metaprel There was a further reduction of Raw from 1.55 to 1.25 cm H20/1/s. but the reduction was less than before Metaprel (Fig. 1). Expressed in percent, breathing at l 1 above FRC decreased Raw by 31%. After Metaprel the additional reduction was only by 19%. Similarly, breathing at FRC + 1 1 resulted in a further decrease of the size of PD, and the reduction was less than before treatment (Fig. 2).

Relationship of Lung Function to Subject's History Three tests~ MMFR, FEV1/FVC, and AN2 are significantly correlated with the smoking history expressed in pack years (r =-0.31, P < 0.05; r =-0.41, P < 0.05; and r = 0.50, P < 0.01 respectively, N = 4 3 ) . Other tests such as CV/VC% (r=0.20, P > 0 . 0 5 ) and PD (r=0.18, P > 0.05) showed similar trends without being significant. By selecting 11 of the heaviest (38 pack year history) and 11 of the lightest smokers (14.3 packyear history), the effect of smoking history o n lung function also became evident (Table 2). The responsiveness to Metaprel and to breathing at the increased lung volume was different in the two groups. The only significant response to Metaprel or breathing at FRC + 1.0 1 in the heavy smokers was a decrease of Raw from 2.63 to 1.82 cm H20/1/s and 1.85 cm H 2 0 respectively. On the other hand light smokers showed a significant decrease of AN2 after Metaprel. whereas PD decrease from t2.8 ° to 1.4 ° after either breathing at FRC + 1.0 1 or Metaprel. The 43 subjects were also sub-divided into two groups according to their respiratory history. One group of 16 subjects had a past histo~' of repeated episodes of severe pneumonia or bronchitis. This group is designated as RD. The remaining 27 subjects without such a past history are designated as the nRD group. It may be seen in Table 3 that the R D group had a lower M M F R and higher Raw than those of the nRD group. Other tests also indicated that the R D group had more functional abnormalities. The RD subjects responded with larger changes in M M F R (from 77.6% to 95.4%) and of Raw (from 2.2 to 1.48 cm H20/1/s) after Meta-

Table 2. Comparison of the effects of Metaprel and of breathing at increased lung volume on the lung functions of 11 light (14.3±3.8 pack years) and 11 heavy smokers (37.8±10 pack years) Light smokers

Heavy smokers

B

A

LV

B

A

Raw (cm H20/1/s)

1.80±0.95

1.53+0.93

1.46±0.68

2.63+0.70

1.82+0.50 a 1.85+0.53 a

PD (degrees)

12.8+5.4

1.4±4.5 a

1.4±4.5 "

12.0+6.1

8.0+7.1

MMFR (% predicted)

106:236.6

112±32.6

50.1+ 14

62.9±21.6

AN2 (%)

1.96:2 1.28 1.42+ 1.28 a

3.4± 1.6

2.9± 1.5

CC/TLC

0.33±0.05

0.44±0.07

0.41:20.06

0.31±0.04

B = before Metaprel; A =after Metaprel; LV = breathing at FRC + 1.0 1 a Indicates that value is significantly different at P < 0.05 level from B value

LV

10.2+5.5

86

E.H. Schlenker and M. J. Jaeger

Table 3. Comparison of lung function tests of RD and nRD groups before and after Metaprel and at increased LV (means and SD) nRD (N = 27) Control

+ LV

RD (N = 16) Metaprel

Control

MMFR (%predicted)

95.35:6.08

99.8:i: 7.6 " 77.6± 7.6

Raw (cm H20/l/s)

1.95± 1.78 1.41±1.78 N =23

1.59± 1.6

4.4± 10.2 b 12.2+6.7

Metaprel 95.4±6.8

1.38±0.70' 1.48 -+-0.67 b N = 12

PD (degrees)

12.9±5.9

CC/TLC

0.40±0.11

0.37±0.94

AN (%N~)

1.98± 1.25

1.66± 1.06 " 2.64± 1.44

2.55± 1.55

RV (1)

1.47±0.59

1.34±0.38

1.59±0.54

1.48 ± 0,52

IzEV (%Pred)

80.0±6.5

81.7±6.2

74.5±8.2

76.9 ± 7.0

Pack years history (years)

23.5+ 15.2

a b

4.2+7.8 b

2.2±0.81

+ LV

0.39±0.094

7.4± 10.2

5.3+6.2 0.35 ± 0.082

29.7±20.4

designates that the value is significantly different from the control value at the 0.05 level designates that the value is significantly different from the control value at the 0.001 level

prel than did the n R D subjects. When R D subjects breathed at 1 1 above F R C , Raw d r o p p e d 37% from the control value, while n R D subjects showed only a 28% fall. Increases in lung volume and administration o f Metaprel had similar effects on the size of PD in each group. This confirms the observation noted earlier that the effect of Metaprel and increased lung volume are highly correlated. Discussion

Effects of Metaprel In this study, as in previous ones. the responses to a bronchodilator within the s a m e subject and between different subjects were quite variabIe [26]. Factors which m a y influence the response o f smokers to a b r o n c h o d i l a t o r are: 1) The site of d e p o s i t i o n of the bronchodilator; 2) The dosage o f the drug; 3) The reactivity of,the i n d i v i d u a l and 4) The resting bronchomotor tone. Dolovich et al. [9] measured the penetrance of 131 iodine labelled albumin aerosol in non-smokers, in a s y m p t o m a t i c smokers, a n d in patients with chronic obstructive lung disease (COLD). They found that particles with an a e r o d y n a m i c diameter of 3 ~tm reached more peripheral airways in n o n smokers than in smokers or patients with C O L D . In the present study the only significant response to Metaprel in 11 heavy smokers was a decrease o f Raw, a test indicative primarily o f central airway caliber (Table 2). On the contrary, light s m o k e r s showed a significant decrease of AN2 and o f PD after Metaprel, two tests which are indicative o f small airway function. Our results can be explained on the basis o f the deposition o f the aerosols at different locations of the bronchial tree in light a n d heavy smokers. A n o t h e r possible explanation is that the small airways o f h e a v y

Effect of Lung Volume and Bronchodilators on Airways

87

smokers had become rigid so that no change in caliber could occur after Metaprel or after breathing at increased lung volume. Dose is a second factor which may affect the response of a smoker to a bronchodilator. MacFadden, Newton-Howes and Pride [18] gave 17 mg isoproterenol to normal subjects. They noted improvements in Raw, FEV~. MMFR, and an increase in compliance which returned to control values after 30 rain. Stature et al. [25] and Bofiht~ys et al. [5] gave 0.8 to 1.6 mg ofisoproterenol to normal subjects and found significant increases in conductance, but no change in lung compliance, The dose given in the present study was 1.3 mg of Metaprel. Although this relatively small dose was given 30 min before testing, the small but significant decreases in CV/ VC%, FRC, MMFR, and RV could be interpreted as decreases in lung compliance which would be in disagreement with previous investigators' findings on normal non-smokers [5]. The difference in response to a bronchodilator between smokers and non-smokers may be the result of differences in resting bronchomotor and parenchymal tone. However, the variables which changed most profundly after Metaprel were the resistance of large airways and the distribution of small airways resistance, as indicated by the decrease of Raw from 2.02 to 1.58 cm H 2 0 / l / s and decrease of PD from 12.5 to 4.93". A decrease of both resistance and compliance (and the resulting decrease in time constants) may explain the decrease in PD noted [15]. The third factor which may influence the response of smokers to a bronchodilatot is individual reactivity. A number of investigators have shown that some smokers have an increased sensitivity to methacholine, isoproterenol, histamine and propranolol [6, 2, 26, and 28]. The data in Table 3 indicate that smokers with a history of respiratory disease (RD) showed larger changes of MMFR% (from 77.4 to 95.4%) and of Raw with either Metapre[ or increased LV than subjects without such a history (nRD, from 95.3 to 99.8%). The greater reactivity demonstrated by our RD group may be analogous to the findings of Burrows and co-workers [7] who showed that smokers with a history of childhood respiratory trouble and a low FEVa have a greater skin reactivity as measured by standard skin tests than smokers without such a history. Although skin reactivity and bronchial reactivity do not always correlate, patients may develop hyperactive airways following respiratory tract infection [12]. Barter and Campbell [2] noted in a 5-year prospective study that smokers with a high reactivity as indicated by changes of FEV1 after methacholine or isoproterenol had a greater annual decline in FEVI.0 than did non-reactors. The age, pack year history, and FEVa/FVC% of both reactors and non-reactors were equivalent at the start of the study. Reactivity as indicated by a skin test or responsiveness to a bronchodilator and smoking have significant added effects which may result in a more rapid decline in lung function with age and smoking history (as we have found) than otherwise expected. In addition, increasing lung volume 1 1 above FRC and administration.of Metaprel had similar effects on Raw and PD as seen in Table 1 and in Figs. 1 and 2. The effect of increasing lung volume to levels above 1 1 may, however, result in larger decreases of Raw and PD than found in the present study.

Effect of Variation of Lung Volume Increasing lung volume mechanically stretches the airways but may also stimulate stretch receptors which results in reflex bronchodilation [23, 27].

88

E. H. Schtenker and M. J. Jaeger

We found, in our subjects, that Raw decreased from 2.02 cm H 2 0 / l / s to 1.40 cm H20/1/s when lung volume was increased by 1 1 above FRC (Fig. 1). This 31% decrease in Raw may reflect both an increase in large and small airways caliber [18, 13]. Since the relative contribution of peripheral airways to the measurement of Raw is small [17] the 31% change of Raw presumably reflects mostly an increase of large airway caliber. The data on changes of PD, obtained at the same time, give information about the status of small airways (Fig. 2). PD decreased from 12.5 ° to 4.72 ° when the subjects breathed at FRC plus 1 1. According to the theory behind the PD measurement [1] this reflects a more even distribution of ventilation presumably because of the selective dilation of constricted peripheral airways. Mills, Cumming and Harris [21] found that by changing lung volume in normal subjects frequency dependence of compliance varied. The decrease of compliance at 80 bpm was greatest at low lung volumes (near RV), less at high lung volumes (near vital capacity), and least at midlung volumes (near functional residual capacity). Their study, like ours, indicates that increasing lung volume affects both large and small airway caliber and improves the distribution of ventilation.

Effects of Metaprel and Increased Lung Volume When subjects breathed at FRC plus 1 I after receiving Metaprel, only a smafl further decrease in both Raw and PD (Figs. 1 and 2). These data suggest that the limit of distensibility of airways had been reached. Support for this interpretation comes from work by Macklem and co-workers [17] in vagotomized dogs and Olsen et al. [24] in isolated bronchi treated with bronchodilators. We have presented a technique from which one can simultaneously evaluate the central and the peripheral airways function of chronic smokers during normal breathing. The magnitude of the response of smokers to breathing at increased lung volume and a bronchodilator is highly correlated in individual subjects. Increasing lung volume 1 1 above FRC may be an alternative, simple method of testing reactivity in subjects. Factors which may play a role in this responsiveness may include 1) the length of smoking history' and 2) past insults to the lung from diseases such as bronchitis and pneumonia.

References 1. Banerjee M, Evans JM, Jaeger MJ (1976) Uneven ventilation in smokers. Respir Physiol 27:277-291 2. Barter CE, Campbell AH (1976) Relationship of constitutional factors and cigarette smoking to decrease in l-second forced expiratory volume. Am Rev Respir Dis 113:305-314 3. Bode FR, Dosman J, Martin R, Macklem PT (1975) Reversibility of pulmonary function abnormalities in smokers. A prospective study of early diagnostic tests of small airways disease. Am J Med 59:43-52 4. Bouhuys A, Van de Woestijine K P (1971) Mechanical consequences of airway smooth muscle relaxation. J Appl Physio130:670-676 5. Brooks SM, Barber MO (1974) Changes in closing volume measurement after isoproteronol inhalation. Am Rev Respir Dis 109:198-204 6. Brown NE, McFadden ER, Ingram RH Jr (1977) Airway responses to inhaled histamirte in asymptomatic smokers and non-smokers. J Appl Physio142:508-5 l 3

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7. Burrows B, Knudson RJ, Cline MG, Lebowitz MD (1977) Quantitative relationships between cigarette smoking and ventilatory function. Am Rev Respir Dis 115:195-205 8. Buist AS, Ross RB (1977) Predicted values for closing columes using a modified single breath nitrogen test. Am Rev Respir Dis 107:744-752 9. Dolovich MB, Sanchis J, Rossman C (I976) Aerosol penetrance: a sensitive index of peripheral airways obstruction, d Appl Physiol 40:468-471 10. DuBois AB, Bottlho SY, Bedell GN, Marshall R, Comroe JH Jr (1956) A rapid plethysmographic method for measuring thoracic gas volume: a comparison with a nitrogen washout method for measuring function residual capacity in normal subjects. J Clin Invest 35:332-336 11. DuBois AB, Bottlho SY, Comroe JH Jr (1956) A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and in patients with respiratory disease. J Clin Invest 35:327-334 12. Empey DW, Laitiren LA, Jacobs L, Goldand WM, Nade JA (1976) Mechanics of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 113:131-139 13. Hoppin FC Jr, Green M. Morgan MS, (1978) Relationship of central and peripheral airway resistance to lung volume in dogs. J Appl Physiol Respir Environ Exercise Physiol 44:728-73 l 14. Ingrain RH Jr, O'Cain, CG (1971) Frequency dependence of compliance in apparently health smokers versus non-smokers. Bull Physiopathol Respir 7:195-210 15. Jaeger MJ (1968) Die Entstehung yon Schleifen im Druck-FluB-Diagramm der Atemwege mit besonderer Beriicksichtigung der Ergebnisse Ganzk0rperplethysmographie. Kiln Wochenschr 46:1154-1162 16. Krumohotz RZ, Chevalier RB, Ross JC (1956) Changes in cardiopulmonary function related to abstinence from smoking: studies in young cigarette smokers at rest and exercise at 3 and 6 weeks of abstinence. Ann Intern Med 62:197-207 17. Macklem PT, Woolcock AJ, Hogg JC, Nadel JA, Wilson NJ (1969) Partitioning of pulmonary resistance in the dog. J Appl Physiol 26:789-805 18. McFadden ER Jr, Newton-Howes J, Pride NB (1970) Acute effects of inhaled isoproterenol on the mechanical characteristics of the lungs in normal man. J Clin Invest 49:779 19. Mann JS, Woolcock AJ (1975) Influence of smoking on lung function. Aust NZ J Med 5:476 20. Martin RR, Lindsay D, Despas P, Bruce D, Leroux M, Anthonisen NR, Macklem PT (1975) The early detection of airway obstruction. Am Rev Respir Dis 111:119-125 2I. Mills RJ, Cumming G, Harris P (1963) Frequency dependent compliance at different levels of inspiration in normal adults. J Appl Physiol 18:1061-1064 22. Nadel JA, Comroe JH Jr (1961) Acute effects of inhalation of cigarette smoke on airway conductance. J AppI Physiot 16:713-716 23. Nadel JA, Tierney DF (1961) Effect of a previous deep inspiration on airway resistance in man. J Appl Physiol 16:717-719 24. Olson CR, Stevens AE, Mclcroy MB (1967) Rigidity of trachea and bronchi during muscular constriction. J Appl Physiol 23:27-34 25. Stamm AM, Clamsen JL, Tisi GM (1976) Effect of aerosolized isoproterenol on resting myogenic tone in normals. J AppI Physiol 40:525-532 26. Watanabe S, Renzette AD Jr, Begin R, Bigler AH (1974) Airway responsiveness to a bronchodilator aerosol, Am Rev Respir Dis 109:530-537 27. Widdicombe JG, Sterling GM (1970) The autonomic nervous system and breathing. Arch Intern Med 126:311-329 28. Zuskin E, Mitchell CA, Bouhuys A (1974) Interaction between effects of beta blockade and cigarette smoke on airways. J Appt Physiol 36:449-542 Accepted for publication: 21 October 1980