Effect of beta adrenergic blockade on bronchial sensitivity to inhakd acetylchotine in normal subjects J. Orehek, M.D., P. Gayrard, M.D., Ch. Grimaud, M.D., and J. Charpin, M.D. X~seille, Frame
Dose-responses cures were established in 10 normal subjects by measurkng, with a body plethysmograph, the chges of speoi& airway conductance (SGaw) protied by aerosolized acetylcholine. Doses of acetylcholine producing a 50 per cent decrease of control SGaw (ED,,) were found to be largely variable among individwlls. a-a&energio bloclcad.5 with intraven0u.s propranolol (03 mg per kilogram) resulted in a mean potent&ion of the aoetyloholine effect (mean ED, after propranolol was significantly lower than mean ED,, before). This potentiating effect of propranolol, however, was also subjected to individual vartitioras, suggesting indkiducsl variability of the sympathetic system. The san.ge of variation in acetyloholine semsit use of the panting technique.9 First measure’ nients wcr(l discarded until ihc nul,jrct beeamc accuatomctl to the maneuver. Initial value of Raw vnluc‘s during testing wvcrc oh iittw \vas derived from the average of fivcb nic:asuremcn:s; taincd l,y averaging only two measurements, if thesc two values wverc’ similar. maw was converted to its reciprocal, airway conductance (Craw) and divided by Vtg to otltain the specific airway condur*tanc~e (SGam). Heart I’d&: was counted at the! radial artery. ‘I’\\o tests, in random ortlcr, \rcr(’ pcrformetl, with more than 2 days and less than 3 \wt\\ (hen, from 2 to .5 PM. one day t.he subjects inhaled the acctyleholine” aerosol done, ant\ the other day the acetplcholint~ inhalation was preceded 11p an intravenous injection of 0.2 mg per kilogram of propranolol. t The effecst of proprannlol on SGam and heart rate was measured after a lo-minute interval, An aerosolizer (Aeroso~dn Gauthier) delivering 0.5 mg. of ;~cctylcholine per liter of air (size of parlielcs ranging from 0.1 to 5~) was used for tilling up a spirometer with fresh aerosol. The11 the subject was put in communication with the spirometer through a two-may valve enabling inspiration from the spirometer only, whereas expired gas went outside. After each inspiration of 500 ml. (measured by the displacement of the spiromc~ter pen) the sul)ject was instructed to hold his ljrlaath for about 4 seconds, in order to ensure a maximal part& retention. Inhalation of 1 mg. of acetyicholine (i.e., f inspirations of 500 ml.) took about 30 seconds. Measurements of KGnw wvere made after each I-mg. in. halation, in order to determine a dose-response curve. The inhalations were stopped when the SGaw decrease was about 50 per cent of the control valuc~. Throughout the test, the subject remained seated in the plethysn~ograph. Each maneuver (refill of the spirometer with fresh aerosol, which was done just [before each inhalation uf 1 mg. of aectylcholine, inhalation procedure, and measurement of SGaw) lasted about 3 minutes. Ifose-response curves obtained with acetylcholine aerosol before and after propranolol treatment were sufficiently close to parallel so that propranolol effect could be expressed as dosr-ratio.10 KD,, (i.e., the doses of aeetyleholinte t,hat derreasit control SGaw by 50 per cent) mere calculated from the curves, and the dose-ratio for each subject was determined using the ratio of El), after propranolol/ED, before propranolol. A dose-ratio lower than one indicates a potentiation of acetyIeholinc! effect by the propranolol treatment. The variability of the ac.et~yl&olinr! inhalation proccdurc wa. 9 tested in 4 subjeet.s on t\vo different occasions. The method was reproducible sincr fairly close KD, were found (14 and 14 mg., Subject 1; 4.5 and 4 mg., Subject 8; 9.5 and X mg., Subject IO; 4 and 9.5 mg., Subject 4). RESULTS
Fig. 1 and Table I show that the bronchial sensitivity to acctylcholine varied among individuals as demonstrated by the range of ED,, before propranolol (from 3.5 to 21 mg., the latter being almost seven times higher), and the variable slope of the &se-response curves. Propranolol produced an average potentiation of acetylcholiue effect (mean dose-ratio of 0.72, with the mean E1)50 after propranolol significantly different from the mean ET),, beforc) , but large individual variations wcrc still prcscnt since dose-ratios ranged from 0.28 (Subject I), indieating considerable potentiation, to 1.28 (Subject 2)) indicating a slight protection. Following propranolol the individual variability of acetylcholine sensitivity was unchanged since ElIIs0 after propranolol ranged from 1.5 to 14 mg., the latter being almost eight times higher. *Chlorhydrate tAvlocardy1,
d’acetyleholine, Laboratoire ICI Pharma France.
Lematte
et Boineau.
VOLUME 5.5 NUMBER 3
Effect
of beta
adrenergic
TABLE II. Effect of propranolol (0.2 mg. per kilogram, intravenously) on heart rate in 10 normal subjects [mean 2 S.E.)
blockade
and
167
acetylcholine
challenge
Conlrol 77.8 r 3.9 77.0 f 3.6 *Significantly
different
10 min. after propranolal 64.0 f 2.1* (p < 0.001) from
control
value
After acafylcholIn~
challenge
81.2 f 3.9 66.2 + 2.4* (Student’s
paired
t test).
In addition, Table I shows that the decrease of SGaw caused by propranolol is also largely variable among normal subjects (from no effect to 27.7 per cent decrease of control SGaw), as reported in a previous study,ll whereas the deCrease of heart rate is more constant. WC endeavored to correlate the initial sensitivity to acetylcholine and the effect of propranolol treatment on acetylcholine sensitivity by plotting individual ED,, values before propranolol against individual dose-ratio values. No significant correlation was found (r = - 0.075). No significant relationship (r = - 0.10) was found between the effect of propranolol on control Maw and the effect of propranolol on acetylcholine sensitivity expressed as per cent decrease of control SCaw against dose-ratio values. Table II shows the mean effect of the drugs on heart rate. The acetylcholine challenge produced a slight increase in pulse rate, which might have been due to the accompanying bronchoconstriction. The in j&ion of propranolol resulted in a significant decrease of heart rate. After p-adrcnergic blockade, acetylcholine inhalation still caused a slight and nonsignificant increase of heart rate. IIeart rate was still slower than its control value, however, illustrating that the p-adrencrgic blockade was still effective. lYo significant correlation (r = - 0.05) was found between the effect of propranolol treatment on acetylcholine sensitivity (expressed as dose-ratios) and the effect of propranolol on heart rate (expressed as per cent decrease of control values). DISCUSSION
Acetylcholine dose-response curves before and after propranolol administration were sufficiently close to parallel to allow a valid assessment of the effect of this p-blocking drug. In these conciitions, P-adrenergic blockade with propranolol resulted in an average increase of airway sensitivity to inhaled acetylcholine. However, large individual variations in this potentiating effect of propranolol were observed. The dose of propranolol (0.2 mg per kilogram) that we used was sufficient to block the effects of both circulating catecholamines and sympathetic nerve stimulation,‘z but individual variations in the drug metabolism could result in variable amounts of /?-adrenergic blockade. Zacest and Koch-\Vieser13 reported that propranolol orally administered may be metabolized differently by normal people, but such differences are not demonstrated for intravenous propranolol. The lack of correlation between the propranolol effect on control SGaw and the proprano101effect on acctylcholine sensitivity rules out the! possibility that the changes of initial SGaw produced by propranolol would be responsible per se for the increased acetylcholine sensitivity in some subjects. Thus, one can accept as a possible explanation that the individual variations observed are not due to dif-
168
Orehek
et al.
J. ALLERGY CLIN. IMMUNOL. MARCH 1975
fercnccs in pharmacologic beta blockade but arc related to individual variations in the adrenergic system activity. Such variations may lie at the beta receptor level, as suggested by the work of George and associates,“’ or in the ,8-adrenergic impulses reaching the airways. I)ouglas and associates’” showed that in guinea pigs individual variations of adrenergic activity were partially responsible for individual variations in histamint sensitivity since the pot,entiating effect of propranolol was inversely relatetl to the initial histamine sensitivitv. On the contrary, the parasympathetic inputs wre found to be constant. Such a relationship was not found in our study. Some “insensitive” subjects (e.g., Subject I ) became “sensitive” after propranolol but, others (lit1 not, (c.g., Subject 3). In the same way some “sensitive” subjects b11came more sensitive (e.g., Subject. 4)) whereas in certain initially “sensitive” subjects propranolol had no effect (e.g., Subject 2)) and the range of individual variability in acetplcholinc sensitivity was unchanged. Thus, in man, the padrenergic activit,v that impinges on airways does not seem to be the only facto) in determining the sensitivity of normal subjects to bronchoconstrictor agents, although it appears important in some cases. Another important and variable factor could be the parasympathetic activity. The broIlrhoconstric’t.or effect of propranolol has been attributed to unmasked vagal activity.l’i* Ii In our study propranolol (*aused a variable decrease of control N;aw. Thus this variable 1troItchoconstriction could hc dnc to a variable parasvnipatlrcttic clrive. ‘I’hc~ individual variations encountered in this study could explain the COIItrovcrsial result,s given in the literature since in these studies the number of SUMjccts cxamincd was small alld the results average. One can therefore think that the mean rcxslllt tlepentletl on the number of subjects tested having a strong gotcntiation by ln+opranolol. Differences in methods used for estimating airway obstruction can be important, too, since authors using sensitive measurements (flowhave more often found an volume (:urves,:i airways resistance dctcrminations” effect of beta blockade than authors using other methods.‘-’ From our results it is difficult to endorse Szent,ivanyiV theory as the unique explanation of bronchial hypersensitivit,v of asthmatic patients since : ( 1) Padrenergic blockade was unable to increase the bronchial sensitivity to acetylcholine in all the normal subjects tested and (2) even when the bronchial SPYsitivity was increased it still did not result in hypersensitivity such as the ow spontaneously encountered in most of the ast,hmatic patient.” Iiowevcr, if such a /3-atlrcnergic abnormality occurs spontaneously, it could be, in some people, an additional factor for creating a bronchial hypersensitivity to bronchoconstrictor agents. REFRRENCES
Szcntivanyi, A.: The beta ndrenergir. theory of the atopic abnormality in bronchial asthma, J. ALLERGY 42: 203, 1968. 2 Rye, LT. Y., and Tow&y, R. G.: Comparison of respiratory and cardiovaveular effects of isoproterenol, propranolol, and practolol in asthmatic and normal snbjscts, J. ALLERGY CLIX. TYM~:XOI.. 49: 105, 1972. (Abst.) 3 Houhuys, A., Douglas, J. S., and Guyatt, A. R.: Pharmacological modification of histaminemediated airway responses, J. Clin. Invest. 50: Sa, 1973. 1
VOLUME 55 NUMBER 3 4
5
6 7
8 9 10 11
12 13 14
15
16
17 18
Effect of beta adrenergic
blockade
169
de Marcelle, R., Bottin, R., Juchmes, J., and Lecomte, J.: Reactions bronchomotrices 1,homme sain apres blocage des rbcepteurs fl-adrenergiques, Acta Allergol. 23: 11, 1968. blockade on XcGeady, S., Conboy, K., and Townley, R. G.: The effect of beta-adrenergic bronchial sensitivity to methacholine in normal and allergic rhinitis subjects, J. ALLERGY 41: 108, 1968. (Abst.) response to beta-adrenergic blockade, N. Engl. J. Zaid, G., and Beall, G. N. : Bronchial Med. 275: 203, 1966. Turner, P., Burman, J., Hicks, D. C., Cherrington, N. K., McKinnon, J., Waller, T., and of the effects of propranolol and practolol on forced Woolnough, M. : A comparison expiratory volume and resting heart rate in normal subjects, Arch. Int. Pharmacodyn. Ther. 191: 104, 1971. Cara, M., and Poisvert, M.: Tables de r6ferences pour les examens spirographiques, Luxembourg, 1967, Commission of European Communities, editor and publisher. Dubois, A. B., Botelho, S. Y., and Comroe, J. H., Jr.: A new method for measuring airway resistance in man using a body plethysmograph, J. Clin. Invest. 35: 327, 1956. Schild, H. 0.: Pax and competitive drug antagonism, Br. J. Pharmaool. 4: 277, 1949. Gayrard, P., Orehek, J., and Charpin, J.: Stimulation et blocage des reeepteurs P-ad&nergiques bronchiques. Effet chez le sujet normal et l’asthmatique, Rev. Franc. Allergol. 13: 31, 1973. Anonymous: Avlocardyl, Alderley Park, United Kingdom, 1970, Imperial Chemical Industries, editor and publisher. Zacest, R., and Koch-Weser, J.: Relation of propranolol plasma level to beta-blockade during oral therapy, Pharmacology 7: 178, 1972. George, C. F., Conolly, M. E., Fenyvesi, T., Briant, R., and Dollery, C. T.: Intravenously administered isoproterenol sulfate dose-response curves in man, Arch. Intern. Med. 139: 361, 19i2. Douglas, J. S., Dennis, M. W., Ridgway, P., and Bouhuys, A. Airway constriction in guinea pigs: Interaction of histamine and autonomic drugs, J. Pharmacol. Exp. Ther. 184: 169, 1973. Grieco, M. H., and Pierson, R. N., Jr.: Mechanism of bronchoconstriction due to beta adrenergic blockade. Studies with practolol, propranolol, and atropine, J. ALLERQY CLIX. IMMUNOL. 48: 143. 1971. McDonald, A. G., Ingram, C. G., and McNeill, R. S.: The effect of propranolol on airway resistance, Br. J. Anaesthesiol. 39: 919. 1967. Tiffeneau; R. : Examen pulmonaire de pasthmatique, Paris, 1957, Masson et Cie.
Dose-responses cures were established in 10 normal subjects by measurkng, with a body plethysmograph, the chges of speoi& airway conductance (SGaw) protied by aerosolized acetylcholine. Doses of acetylcholine producing a 50 per cent decrease of control SGaw (ED,,) were found to be largely variable among individwlls. a-a&energio bloclcad.5 with intraven0u.s propranolol (03 mg per kilogram) resulted in a mean potent&ion of the aoetyloholine effect (mean ED, after propranolol was significantly lower than mean ED,, before). This potentiating effect of propranolol, however, was also subjected to individual vartitioras, suggesting indkiducsl variability of the sympathetic system. The san.ge of variation in acetyloholine semsit use of the panting technique.9 First measure’ nients wcr(l discarded until ihc nul,jrct beeamc accuatomctl to the maneuver. Initial value of Raw vnluc‘s during testing wvcrc oh iittw \vas derived from the average of fivcb nic:asuremcn:s; taincd l,y averaging only two measurements, if thesc two values wverc’ similar. maw was converted to its reciprocal, airway conductance (Craw) and divided by Vtg to otltain the specific airway condur*tanc~e (SGam). Heart I’d&: was counted at the! radial artery. ‘I’\\o tests, in random ortlcr, \rcr(’ pcrformetl, with more than 2 days and less than 3 \wt\\ (hen, from 2 to .5 PM. one day t.he subjects inhaled the acctyleholine” aerosol done, ant\ the other day the acetplcholint~ inhalation was preceded 11p an intravenous injection of 0.2 mg per kilogram of propranolol. t The effecst of proprannlol on SGam and heart rate was measured after a lo-minute interval, An aerosolizer (Aeroso~dn Gauthier) delivering 0.5 mg. of ;~cctylcholine per liter of air (size of parlielcs ranging from 0.1 to 5~) was used for tilling up a spirometer with fresh aerosol. The11 the subject was put in communication with the spirometer through a two-may valve enabling inspiration from the spirometer only, whereas expired gas went outside. After each inspiration of 500 ml. (measured by the displacement of the spiromc~ter pen) the sul)ject was instructed to hold his ljrlaath for about 4 seconds, in order to ensure a maximal part& retention. Inhalation of 1 mg. of acetyicholine (i.e., f inspirations of 500 ml.) took about 30 seconds. Measurements of KGnw wvere made after each I-mg. in. halation, in order to determine a dose-response curve. The inhalations were stopped when the SGaw decrease was about 50 per cent of the control valuc~. Throughout the test, the subject remained seated in the plethysn~ograph. Each maneuver (refill of the spirometer with fresh aerosol, which was done just [before each inhalation uf 1 mg. of aectylcholine, inhalation procedure, and measurement of SGaw) lasted about 3 minutes. Ifose-response curves obtained with acetylcholine aerosol before and after propranolol treatment were sufficiently close to parallel so that propranolol effect could be expressed as dosr-ratio.10 KD,, (i.e., the doses of aeetyleholinte t,hat derreasit control SGaw by 50 per cent) mere calculated from the curves, and the dose-ratio for each subject was determined using the ratio of El), after propranolol/ED, before propranolol. A dose-ratio lower than one indicates a potentiation of acetyIeholinc! effect by the propranolol treatment. The variability of the ac.et~yl&olinr! inhalation proccdurc wa. 9 tested in 4 subjeet.s on t\vo different occasions. The method was reproducible sincr fairly close KD, were found (14 and 14 mg., Subject 1; 4.5 and 4 mg., Subject 8; 9.5 and X mg., Subject IO; 4 and 9.5 mg., Subject 4). RESULTS
Fig. 1 and Table I show that the bronchial sensitivity to acctylcholine varied among individuals as demonstrated by the range of ED,, before propranolol (from 3.5 to 21 mg., the latter being almost seven times higher), and the variable slope of the &se-response curves. Propranolol produced an average potentiation of acetylcholiue effect (mean dose-ratio of 0.72, with the mean E1)50 after propranolol significantly different from the mean ET),, beforc) , but large individual variations wcrc still prcscnt since dose-ratios ranged from 0.28 (Subject I), indieating considerable potentiation, to 1.28 (Subject 2)) indicating a slight protection. Following propranolol the individual variability of acetylcholine sensitivity was unchanged since ElIIs0 after propranolol ranged from 1.5 to 14 mg., the latter being almost eight times higher. *Chlorhydrate tAvlocardy1,
d’acetyleholine, Laboratoire ICI Pharma France.
Lematte
et Boineau.
VOLUME 5.5 NUMBER 3
Effect
of beta
adrenergic
TABLE II. Effect of propranolol (0.2 mg. per kilogram, intravenously) on heart rate in 10 normal subjects [mean 2 S.E.)
blockade
and
167
acetylcholine
challenge
Conlrol 77.8 r 3.9 77.0 f 3.6 *Significantly
different
10 min. after propranolal 64.0 f 2.1* (p < 0.001) from
control
value
After acafylcholIn~
challenge
81.2 f 3.9 66.2 + 2.4* (Student’s
paired
t test).
In addition, Table I shows that the decrease of SGaw caused by propranolol is also largely variable among normal subjects (from no effect to 27.7 per cent decrease of control SGaw), as reported in a previous study,ll whereas the deCrease of heart rate is more constant. WC endeavored to correlate the initial sensitivity to acetylcholine and the effect of propranolol treatment on acetylcholine sensitivity by plotting individual ED,, values before propranolol against individual dose-ratio values. No significant correlation was found (r = - 0.075). No significant relationship (r = - 0.10) was found between the effect of propranolol on control Maw and the effect of propranolol on acetylcholine sensitivity expressed as per cent decrease of control SCaw against dose-ratio values. Table II shows the mean effect of the drugs on heart rate. The acetylcholine challenge produced a slight increase in pulse rate, which might have been due to the accompanying bronchoconstriction. The in j&ion of propranolol resulted in a significant decrease of heart rate. After p-adrcnergic blockade, acetylcholine inhalation still caused a slight and nonsignificant increase of heart rate. IIeart rate was still slower than its control value, however, illustrating that the p-adrencrgic blockade was still effective. lYo significant correlation (r = - 0.05) was found between the effect of propranolol treatment on acetylcholine sensitivity (expressed as dose-ratios) and the effect of propranolol on heart rate (expressed as per cent decrease of control values). DISCUSSION
Acetylcholine dose-response curves before and after propranolol administration were sufficiently close to parallel to allow a valid assessment of the effect of this p-blocking drug. In these conciitions, P-adrenergic blockade with propranolol resulted in an average increase of airway sensitivity to inhaled acetylcholine. However, large individual variations in this potentiating effect of propranolol were observed. The dose of propranolol (0.2 mg per kilogram) that we used was sufficient to block the effects of both circulating catecholamines and sympathetic nerve stimulation,‘z but individual variations in the drug metabolism could result in variable amounts of /?-adrenergic blockade. Zacest and Koch-\Vieser13 reported that propranolol orally administered may be metabolized differently by normal people, but such differences are not demonstrated for intravenous propranolol. The lack of correlation between the propranolol effect on control SGaw and the proprano101effect on acctylcholine sensitivity rules out the! possibility that the changes of initial SGaw produced by propranolol would be responsible per se for the increased acetylcholine sensitivity in some subjects. Thus, one can accept as a possible explanation that the individual variations observed are not due to dif-
168
Orehek
et al.
J. ALLERGY CLIN. IMMUNOL. MARCH 1975
fercnccs in pharmacologic beta blockade but arc related to individual variations in the adrenergic system activity. Such variations may lie at the beta receptor level, as suggested by the work of George and associates,“’ or in the ,8-adrenergic impulses reaching the airways. I)ouglas and associates’” showed that in guinea pigs individual variations of adrenergic activity were partially responsible for individual variations in histamint sensitivity since the pot,entiating effect of propranolol was inversely relatetl to the initial histamine sensitivitv. On the contrary, the parasympathetic inputs wre found to be constant. Such a relationship was not found in our study. Some “insensitive” subjects (e.g., Subject I ) became “sensitive” after propranolol but, others (lit1 not, (c.g., Subject 3). In the same way some “sensitive” subjects b11came more sensitive (e.g., Subject. 4)) whereas in certain initially “sensitive” subjects propranolol had no effect (e.g., Subject 2)) and the range of individual variability in acetplcholinc sensitivity was unchanged. Thus, in man, the padrenergic activit,v that impinges on airways does not seem to be the only facto) in determining the sensitivity of normal subjects to bronchoconstrictor agents, although it appears important in some cases. Another important and variable factor could be the parasympathetic activity. The broIlrhoconstric’t.or effect of propranolol has been attributed to unmasked vagal activity.l’i* Ii In our study propranolol (*aused a variable decrease of control N;aw. Thus this variable 1troItchoconstriction could hc dnc to a variable parasvnipatlrcttic clrive. ‘I’hc~ individual variations encountered in this study could explain the COIItrovcrsial result,s given in the literature since in these studies the number of SUMjccts cxamincd was small alld the results average. One can therefore think that the mean rcxslllt tlepentletl on the number of subjects tested having a strong gotcntiation by ln+opranolol. Differences in methods used for estimating airway obstruction can be important, too, since authors using sensitive measurements (flowhave more often found an volume (:urves,:i airways resistance dctcrminations” effect of beta blockade than authors using other methods.‘-’ From our results it is difficult to endorse Szent,ivanyiV theory as the unique explanation of bronchial hypersensitivit,v of asthmatic patients since : ( 1) Padrenergic blockade was unable to increase the bronchial sensitivity to acetylcholine in all the normal subjects tested and (2) even when the bronchial SPYsitivity was increased it still did not result in hypersensitivity such as the ow spontaneously encountered in most of the ast,hmatic patient.” Iiowevcr, if such a /3-atlrcnergic abnormality occurs spontaneously, it could be, in some people, an additional factor for creating a bronchial hypersensitivity to bronchoconstrictor agents. REFRRENCES
Szcntivanyi, A.: The beta ndrenergir. theory of the atopic abnormality in bronchial asthma, J. ALLERGY 42: 203, 1968. 2 Rye, LT. Y., and Tow&y, R. G.: Comparison of respiratory and cardiovaveular effects of isoproterenol, propranolol, and practolol in asthmatic and normal snbjscts, J. ALLERGY CLIX. TYM~:XOI.. 49: 105, 1972. (Abst.) 3 Houhuys, A., Douglas, J. S., and Guyatt, A. R.: Pharmacological modification of histaminemediated airway responses, J. Clin. Invest. 50: Sa, 1973. 1
VOLUME 55 NUMBER 3 4
5
6 7
8 9 10 11
12 13 14
15
16
17 18
Effect of beta adrenergic
blockade
169
de Marcelle, R., Bottin, R., Juchmes, J., and Lecomte, J.: Reactions bronchomotrices 1,homme sain apres blocage des rbcepteurs fl-adrenergiques, Acta Allergol. 23: 11, 1968. blockade on XcGeady, S., Conboy, K., and Townley, R. G.: The effect of beta-adrenergic bronchial sensitivity to methacholine in normal and allergic rhinitis subjects, J. ALLERGY 41: 108, 1968. (Abst.) response to beta-adrenergic blockade, N. Engl. J. Zaid, G., and Beall, G. N. : Bronchial Med. 275: 203, 1966. Turner, P., Burman, J., Hicks, D. C., Cherrington, N. K., McKinnon, J., Waller, T., and of the effects of propranolol and practolol on forced Woolnough, M. : A comparison expiratory volume and resting heart rate in normal subjects, Arch. Int. Pharmacodyn. Ther. 191: 104, 1971. Cara, M., and Poisvert, M.: Tables de r6ferences pour les examens spirographiques, Luxembourg, 1967, Commission of European Communities, editor and publisher. Dubois, A. B., Botelho, S. Y., and Comroe, J. H., Jr.: A new method for measuring airway resistance in man using a body plethysmograph, J. Clin. Invest. 35: 327, 1956. Schild, H. 0.: Pax and competitive drug antagonism, Br. J. Pharmaool. 4: 277, 1949. Gayrard, P., Orehek, J., and Charpin, J.: Stimulation et blocage des reeepteurs P-ad&nergiques bronchiques. Effet chez le sujet normal et l’asthmatique, Rev. Franc. Allergol. 13: 31, 1973. Anonymous: Avlocardyl, Alderley Park, United Kingdom, 1970, Imperial Chemical Industries, editor and publisher. Zacest, R., and Koch-Weser, J.: Relation of propranolol plasma level to beta-blockade during oral therapy, Pharmacology 7: 178, 1972. George, C. F., Conolly, M. E., Fenyvesi, T., Briant, R., and Dollery, C. T.: Intravenously administered isoproterenol sulfate dose-response curves in man, Arch. Intern. Med. 139: 361, 19i2. Douglas, J. S., Dennis, M. W., Ridgway, P., and Bouhuys, A. Airway constriction in guinea pigs: Interaction of histamine and autonomic drugs, J. Pharmacol. Exp. Ther. 184: 169, 1973. Grieco, M. H., and Pierson, R. N., Jr.: Mechanism of bronchoconstriction due to beta adrenergic blockade. Studies with practolol, propranolol, and atropine, J. ALLERQY CLIX. IMMUNOL. 48: 143. 1971. McDonald, A. G., Ingram, C. G., and McNeill, R. S.: The effect of propranolol on airway resistance, Br. J. Anaesthesiol. 39: 919. 1967. Tiffeneau; R. : Examen pulmonaire de pasthmatique, Paris, 1957, Masson et Cie.
