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Comparison of respiratory and cardiovascular effects of isoproterenol, propranolol, and practolol in asthmatic and normal subjects
Comparison of respiratory and cardiovascular effects of isoproterenol, propranolol, and practolol in asthmatic and normal subjects U. Y. Ryo, Ph.D., M.D., and R. G. Townley,
M.D. Omaha, Nebr.
Pulmonary functions, by means of FEV,, FVC, and aircay resistance, and car&ovasonlar responses, i.e., ECG, blood pressure, and pulse contour, acre measured in 10 control and 15 symptom-free asthmatic subjects during and after the infusions of isoproterenol, with or without previous administration of propranoIo1 or practolol. Bronchial sensitivity to methacholine and response to isoproterenol after methacholine were also measured. Bronchial sensitivity to methacholine challenge was markedly enhanced by propranolol and the effect of isoproterenol infusion on the pulmonary function u-as also significantly diminished, whereas practolol did not reuenl any Qect on bronchial sensitivi.ty to methacholine or isoprotevenol. The above changes were much more profound in symptom-free asthmatic subjects than in control affect the beta-l subjects. The results suggest that practolol does not significantly bronchial receptors, is safe to use in asthmatic subjects, and is consistent with an abnormality of these receptors in bronchial asthma.
Recently, Szentivanyi and others L 2 have suggested that a phenomenon common to all patients with asthma is a. partial blockade of the beta adrenergic receptors regardless of what the precipitating factors may be clinically. The beta adrenergic theory regards asthma as a bronchial hpperreactivity to a broad spectrum of immunologic, psychic, infectious, chemical, and physical stimuli. Indeed, beta adrenergic blockade has been shown to enhance bronchial reactivity to inhaled allergens,? or to methacholinc’ in patients with seasonal allergic rhinitis without a previous history of bronchial asthma. By progressively increasing doses of the beta blocker, an acute airway obstruction could be produced which seemed to reach an intensity that may be found in patients with bronchial asthma.& Administration of beta blockers has also been rcported;‘~ (i to aggravate already existent asthmatic conditions and to cause precipitous and prolonged falls in forced 1 see expiratory volume (FEY,). Blockade of beta receptors was found to increase significantly the bronchial sensitivity of asthmatic subjects to methacholine, whereas no such effect was detectable in From thP Department of Medicine, Creighton University School of Medicine. Supported in part by the Ayerst Pharmaceutical Company. Received for publication Aug. 12, 1974. Accepted for publication Dec. 16, 1974. Reprint requests to: Robert G. Totvnley, M.D., Department of Medicine and Microbiology, Criss I, Room 408, Creightou University School of Medicine, 2500 California St., Omaha, Nebr. 68178. Vol. 57, No. 1, pp. 16-84
Comparison
VOLUME 57 NUMBER 1
of respiratory
10 NmNAL AsFNMAFlos oammo ---* ~rnAclvLoL---A 0-PmPNAN0r0L-4
+ '
""NN;k
OF W%C"oLlNi~Tl8S
effects
13
Ii ,’
IS
t
1 + AFTEK ,MLOCKER
and cardiovascular
,
oISOP~:%NOL 3o INFUSION-MINUTES
FIG. 1. Effect of practolol and propranolol on FEV, and its response isoproterenol in normal subjects and asthmatic subiects.
to methacholine
and
normal human subjects as judged by the change in FEV,.? By using a more specific and sensitive measurement of airway resistance, however, the whole body plethysmograph method, a 50% to 100% increase in airway resistance has been observed also in normal subjects in the first 30 min after the administration of a beta blocker.R On the basis of differences in potency of the same sympathomimetic amine, or of different effects of beta adrenergic blocking agents on the beta receptors of various tissues, different subclassifications of beta receptors have been proposed by various investigators.9-‘” Lands and associateslo proposed a differentiation of beta adrenergic receptors as beta-l for cardiac stimulation and lipolysis and beta-2 for bronchodilatation and vasodepression. This new theory of beta adrenergic receptor classification has been applied extensively to promote the understanding of the mechanisms of beta receptor responses in various tissues to adrenergic stimuli. Practolol, 4- (2-hydroxy-3-isopropylaminopropoxy) acetanilide, has been introduced by Dunlop and Shanks’” as a selective beta adrenergic blocking agent which has a potent inhibitory effect on cardiac beta receptors (beta-l) but has minor or no effect on beta receptors of bronchial smooth muscle (beta-g). This agent has been used extensively in Europe. It has been withdrawn from clinical trials in the United States as a result of animal toxicology studies and recent reports of dry eyes and drug-induced systemic lupus erythematosus. Currently, the only agent available in this country that inhibits cardiac beta receptors is propranolol. It is contraindicated in patients with asthma or chronic obstructive lung disease because of the bronchoconstriction that occurs.“’ Ifi. Ii Cardiac arrhythmias are a common problem encountered in the care of patients
14
J. ALLERGY CLIN. IMMUNOL. JANUARY 197.4
Ryo and Townley
TABLE I. Effects of practolol isoproterenol in 10 normal
and propranolol subjects
on bronchial
sensitivity
to methacholine
Min No. of methacholine Baseline Mean
FEV, (%)* Control Practolol Propranolol FVC (%) Control Practolol Propranolol Airway resistance (cm H,O/L/sec) Control Practolol Propranolol
10 SE
Mean
3.48 0.13 92.09t 100.00 0.00 98.64 1.05 95.06 96.88t 0.83 93.56 3.92 100.00 97.78 96.40
0.20 96.27s 0.00 0.78 97.48 1.81 95.51
0.88 0.08 0.95 0.11 1.06t 0.10
I SE
inhalations
20 Mean
40 SE
Mean
of isoproterenol infusion
15 SE
Mean
and
I SE
30 Mean
SE
1.81 85.83$ 2.67 85.26$ 2.96 94.417
1.52 97.213
1.14
1.33 88.83 1.47 88.96
2.43 87.64 2.07 85.24
1.52 97.78 2.32 94.26
1.33 2.30
1.27 92.20t
2.26 92.477 2.35 96.965
1.25 98.81
1.41
1.12 93.57 2.00 93.26
2.30 93.38 2.19 89.75
1.43 98.97 1.62 96.32
1.23 1.50
1.259 0.18 1.26 0.19 1.39 0.16
1.70t 0.22 1.58 0.22 1.66 0.20
2.85 95.73 2.87 91.58
2.53 97.43 2.22 95.75
1.82$ 0.22 1.73 0.21 2.02 0.30
l.lOg 0.11 1.22 0.11 1.547 0.18
p values after practolol or propranolol are vs saline control (vertical comparisons). p values after saline control are vs baseline (horizontal comparisons). “FEV, and FVC are expressed as % to baseline except values in parentheses, absolute values in liters. tp < 0.01. tp < 0.001. $p < 0.05.
1.04 0.11 1.08 0.11 1.21$ 0.14
which
are
with severe asthma or chronic obstructive lung disease, A beta adrenergic blocking agent with a highly selective action on cardiac beta receptors would be very useful for suppression of cardiac beta receptor excitability without augmentation of airway obstruction in asthmatic patients. The present stud! attempts to elucidate the effect of practolol and propranolol on cardiopulmonary response of asthmatic and normal subjects to metacholine challenge and isoproterenol infusion. METHODS The control group consisted of 10 normal persons without any allergic history and negative skin tests with 20 common allergens. The 15 asthmatic subjects, who were currently free of symptoms, had a documented history of allergy and bronchial asthma episodes, and showed positive skin tests to common allergens. None of these subjects was on any medication for asthma for at least 3 mo. Medical history, pertinent physical examinations, allergy skin tests, and tests for bronchial sensitivity to methacholino inhalntionls were carried out prior to this study on all of these subjects. The average age of the normal subjects was 23 yr (range, 17 to 35) ; 5 of 10 were femalr. The average age of the asthmatic subjects was 22 yr (range, 12 to 42) ; 6 were female and 9 were male. An intrav.enous catheter was plared into the antecubital vein. Throughout the experimental procedures, the subject was sitting in the whole boty plethysmogrnph. The electrocardiogram (ECG) and radial pulse curves (E & M Instrument Co.) were monitored. The body plethysmograph was open except during airway resistance measurements. After :\bout 10 min of rest
VOLUME 57 NUMBER 1
TABLE Il. Effects and isoproterenol
Comparison
of respiratory
of practolol and propranolol in 15 symptom-free asthmatic
on bronchial subjects
No. of methacholine Baseline Mean
FEV, (%)* Control Practolol Propranolol FVC (%) Control Practolol Propranolol
measured
3
Mean
SE
Mean
effects
15
to methacholine
Min of isoproterenol infusion 15
30
4.66 69.92$ 3.61
80.85
8.35 90.20s
3.59 102.14
2.58
3.98 71.14 3.70 5.42 57.399 5.71
77.10 12.1092.55 62.60 14.00 76.74t
2.75 101.72 3.45 89.84t
2.11 3.23
87.65
6.15 94.154 2.59 100.10
0.81
86.10 72.50
6.50 95.66 1.89 100.56 7.60 82.76$ 2.79 93.03t
1.62 2.18
2.32$ 0.24 2.706 0.21 3.73t 0.53
2.70$ 0.27 2.79 0.17 3.365 0.24
15
10
3.11 2.92 3.66 2
0.08 0.52 0.40
SE
SE
SE
0.28 85.52§ 4.43 82.12$ 3.36 0.00 1.37 85.23 3.28 79.36 4.30 1.11 72.33 5.53 67.184 6.88
Mean
Mean
Mean
3.66 100.00 97.29 95.854
15
sensitivity
6 SE
0.20 78.97t 0.00 1.85 74.95 1.42 64.99t
0.11 0.12 0.18
cardiovascular
inhalations
3.06 100.00 96.45 92.45t
Airway resistance (cm H%O/L/sec) Control 1.32 Practolol 1.44 Propranolol 1.77t
NO. of subjects
1 SE
and
1.757 0.13 1.76 0.14 3.15$ 0.34
1.36 0.10 1.28 0.09 2.243 0.23
15
14
p values after practolol or propranolol are vs saline control (vertical comparisons). p values after saline control are vs baseline (horizontal comparisons). “FEV, and FVC are expressed as c/o to baseline except values in parentheses, absolute values in liters. tp < 0.01. :p < 0.001. $p < 0.05.
which
are
for equilibration in the plethysmograph, basal FEV,, forced vital capacity (FVC), airway resistance, blood pressure, and ECG were measured. The FEV, and FVC were measured with a Collins 13-L spirometer at least 3 times at the given conditions and the highest of the 3 determinations was recorded. Airway resistance (AWR) was measured by means of DuBois body plethysmograph,l9 the measurements were repeated 5 times on each occasion, and the average value was calculated. Measurements of FEV,, FVC, AWR, blood pressure, heart rate with EGG, and radial pulse contour were obtained after intravenous infusion of 30 C.C. of normal saline. These measurements were repeated after methacholine challenge and 15 min and 30 min during infusion of intravenous isoproterenol administered with a Harvard infusion pump. The dose of isoproterenol varied from 1.5 to 4.5 mcg/min, depending upon the sensitivity of the individual subject to the drug. The dose did not vary between experiments in the same subject. There was no significant difference between the normal and asthmatic groups in the dose of isoproterenol administered. Inhalation challenges were performed with methacholine (5 mg/ml) with a vaponephrine nebulizer activated at 6 L/min of compressed air. The numbers of methacholine inhalations were increased sequentially in the order of 10, 20, and 40 in all normal subjects, and 1, 3, and 6 in asthmatic subjects, or until the FEV, decreased more than 20% of control value. Either propranolol, practolol, or normal saline was administered intravenously and the bronchial response to methacholine inhalation challenge was repeated. Also, measurements of FEV,, FVC, AWR, blood pressure, and heart rate before and after intravenous isoproterenol were carried out the same as during the control phase. The total dosage of propranolol was 3
16
J. ALLERGY CLIN. IMMUNOL. JANUARY 1976
Ryo and Townley
I\ST”hlAT,CS CONTROL----.
j
+ AFTER O-BLOCKER
, I
j +TiijiEt:;
4. o
NUMBER OF METHACHOLINE INHALATIONS
FIG. 2. Effects of practolol and propranolol on airway methacholine and isoproterenol in normal and symptom-free
,5
;.
lSOPROTERENOLINFUSION MINUTES
resistance asthmatic
and its response subjects.
to
mg in all normal subjects which was divided into 1 mg plus 2 mg in 6 subjects, and only 1 mg in all asthmatic subjects. Practolol was infused in a dose of 15 mg in 5 normal and 7 asthmatic subjects, and in a dose of 30 mg in 5 normal and 8 asthmatic subjects. The order of these studies with saline, propranolol, or practolol was randomized and, after a study with one of the beta blockers, no further study was done in the same day on the subject.
RESULTS
Resting pulmonary functions in terms of FEV, and FVC in asthmatic subjects in this study were all in the normal range and all of them were more than 80% of their predicted value, even though the values were smaller than those of the control group (Tables I and II). Average airway resistance of the asthmatic group was 150% of the value in the control subjects but still was not out of normal range, 1.5 + 0.49 cm H,O/L/sec.lg The data show that these asthmatic subjects are not only free from subjective symptoms but also do not have any significant objective sign of impairment of airway function at resting states. As shown in Fig. 1, even though none of the asthmatic group had active symptoms or signs of asthma, the average FEV, dropped 21% (p < 0.01) folIowing a single inhalation of methacholine chloride (5 mg/ml) whereas FEV, decreased less than 15% after 70 inhalations of methacholine in the control group. Changes in airway resistance following methacholine inhalations were more striking (Fig. 2) and increased to 190% of baseline after a single inhalation of methacholine after saline in symptom-free asthmatics (p < O.OOl), whereas the increase became significant after a total of 30 inhalations of methacholine in the normal group. All normal subjects received a total of 70
Comparison
VOLUME 57 NUMBER 1
of respiratory
and
cardiovascular
effects
17
I
a'- BLOCKER
FIG. 3. Effects of proctolol,
0
propronolol,
30 ISOPROTERENOL :iF”SION,
ond
isoproterenol
MINUTES
on the heort
rate
and
pulse
pressure.
inhalations of methacholine, whereas only 10 of the 15 asthmatic subjects received more than one inhalation. The AWR after 70 inhalations in the normal group was still less than after one inhalation following saline in the symptom-free asthma group (1.82 vs 2.32). In both groups, the FEV, and FVC increased and the AWR decreased toward baseline values following isoproterenol infusion. Effects of beta blockade on respiratory functions were as follows. Propranolol suppressed baseline FEV, and FVC and raised AWR in both groups but the changes were more profound in symptom-free asthmatic patients (Tables I and II and Figs. 1 and 2). In asthmatic patients, propranolol markedly augmented bronchial sensitivity to methacholine with wheezing and a decrease in FEV, and FVC and an increase in AWR following methacholine inhalations. Propranolol also depressed the isoproterenol reversal of FEV,, FVC, and AWR significantly. The bronchial sensitivity to methacholine was not affected by propranolol in the control group. Infusion of practolol failed to induce any significant change of baseline FEV,, FVC, and AWR in the control group, and did not alter the bronchial sensitivity to methacholine challenge and isoproterenol infusion in either group. Wheezing did not occur in the normal group at any time. Both beta blockers, propranolol and practolol, only slightly slowed the resting heart rate at the dosage used, but blocked isoproterenol-induced tachycardia in both groups (Tables III and IV and Fig. 3) (p < 0.001). The degree of
18
I. ALLERGY CLIN. IMMUNOL. JANUARY 1976
Ryo and Townley
TABLE III. Effects of practolol those responses to isoproterenol Beta
and propranolol in 10 normal
blockade
administration
Before Mean
Heart rate (min) Control (saline) Practolol Propranolol Pulse pressure (mm b-1 Control Practolol Propranolol
15.2 15.3 73.3
41.5 36.6 31.9
on the subiects
heart
::: 2.8
Mean
15.2 10.2 67.5
z 2.2
41.5 34.7
4.2 ::;
112.1 110.1 108.0
:4 3:4
73.1 14.1 73.5
35.9
blood
looproterenol
After SE
rate,
pressure,
infusion
(min)
15 SE
and
30
Mean
SE
Mean
SE
119.4* 3"2 I:9
98.5* 70.3*
6.9 5.3 2.5
125.6* 101.7t 84.2*
6.3 6.1 4.1
:.i 2:4
82.3* 68.3t 51.0*
!t: 3:1
83.7* 70.3 58.4-f
::1 2.9
4.2
137.4*
4.2
135.4*
5.5
3.5
127.8$
3.9
126.4
Systolic pressure EGElg) Practolol Propranolol
112.1 110.5 112.3
4.1
123.17
3.4
127.6
::;
3.2
Q.3_* 55.3 6l.F
2.5 3.6 3.4
49.3* gi .
2.7 3.4 2.1
Diastolic pressure Practolol Propranolol
73.1 14.2 13.0
3.1 3.2
p values after practolol or propranolol are vs saline control (vertical comparisons). p values after saline control are vs baseline (horizontal comparisons). “p < 0.001. tp < 0.01. :p < 0.05.
suppressing effect on isoproterenol-induced tachycardia was slightly greater with propranolol. In asthmatic patients, there was no significant difference between the two beta blockers in response to heart rate. Propranolol tended to inhibit the elevation of systolic blood pressure following isoproterenol infusion in both groups (Tables III and IV). The effects of propranolol and practolol became remarkably different in both normal and asthmatic subjects in response of diastolic pressure (p < 0.01) and pulse pressure (p < 0.01) to isoproterenol infusion. Propranolol, to a significant extent (p < 0.01)) blocked the effects of isoproterenol in lowering the diastolic pressure and in widening of the pulse pressure in both normal and asthmatic subjects; practolol did not produce any change in response of those pressures to isoproterenol in either group (Fig. 3 and Tables III and IV). Although the effect of propranolol on inhibiting the increase in heart rate and pulse pressure following isoproterenol was somewhat greater in the normal group than in the asthmatic, the total dose of propranolol was 3 mg in the normal group and only 1 mg in the asthmatic. When the dose of propranolol was 1 mg in both normal and asthmatic groups, there was no significant difference in the effect of isoproterenol on heart rate or pulse pressure (Table V) . The data do not indicate any beta-l or beta-2 receptor abnormality in the cardiovascular system of the asthmatic group in contrast to the bronchial beta-2 receptor abnormality in this group.
VOLUME 57 NUMBER 1
Comparison
cardiovascular
effects
19
TABLE IV. Effects of practolol those responses to isoproterenol
and propranolol on the heart rate, blood in 15 symptom-free asthmatic subjects
pressure,
and
Beta
blockade
Before Mean
1
and
lsoproterenol
administration I
SE
of respiratory
After Mean
infusion
(min)
30
15 SE
Mean
SE
Mean
SE
Heart rate (min) Control Practolol (saline) Propranolol
78.9 82.1 83.3
2.3 2.2
74.5 82.1 78.7
2.3 :::
103.0s 124.8* 100.3*
4.8 6.3 4.5
137.3* 102.1* 95.7*
::: 3.0
42.5 39.5 40.3
::i
1.:
2.7
42.5 39.3 34.5
215
78.3* 74.3 60.8t
4.7 4.1 3.4
80.3’ 78.5 62.7;
5.1 4.2 3.4
115.6
2.0
115.6
2.0
136.2*
2.9
133.6*
3.8
112.4 114.1
:::
110.9 108.3
2.3 3.1
;;yc.
2.9 2.3
131.5 127.1$
::‘:
74.4 74.9 75.0
2.3 2.0 2.1
74.4 72.3 75.5
Pulse messure
Cm4 Hg)
Control Practolol Propranolol Systolic pressure ?EZlg) Propranolol Practolol Diastolic uressure
2.3 52.5* 51.4* 2.2 54.4 ::: 50.9 1.5 61.9t 2.1 61.9t p values after practolol or propranolol are vs saline control (vertical comparisons). p values after saline control are vs baseline (horizontal comparisons). *p < 0.001. tp < 0.01. tp < 0.05. Practolol Propranolol
3.2 2.7 1.9
Analysis of pulse contours monitored from the radial artery by means of pulse pickup was carried out with particular interest in the interval between the peak of the R wave (ECG) to the onset of pulse, between each peak of pulse notch P, to P,, and number of peak pulses (Table VI). Amplifications of pulse pressures were uncomparable because a slight movement of arm or wrist changed the position of pulse pickup, thus producing significant alteration in sensitivity of the amplification. The results of pulse contour analysis revealed that propranolol completely blocked the effect of isoproterenol in prolongation of the comparative interval between P, to P,, over percentage to R-R on ECG. Propranolol also blocked the effect of isoproterenol on reduction in the number of peak pulse curves (P) whereas practolol did not exert significant influence on those effects of isoproterenol (Table VI). Again there were no significant differences between the asthmatic and the normal groups in the effect of isoproterenol with or without either beta blocker on the pulse wave contours. DISCUSSION
Availability of specific beta-adrenergic receptor blocking agents in the field of clinical pharmacology has resulted in a greater understanding and differentiation of adrenergic receptors. Therapy of various diseases caused or aggravated by increased sympathetic tone has advanced by this knowledge.
20
J. ALLERGY CLIN. IMMUNOL. JANUARY 1976
Ryo and Townley
TABLE V. A comparison pulse pressure
of the effects of isoproterenol in symptom-free asthmatic and normal Beta
blockade
Before Population’
Heart rate/min Control (saline)
Mean
administration I
SE
and propranoiol subjects
lsoproterenol
After Mean
on heart infusion
(min)
30
15
L
rate and
SE
Mean
SE
Mean
SE
6N 15 SFA 6 N 15 SFA
76.0 82.1 76.8 83.3
5.5 2.3 22:;
76.0 82.1 71.0 78.7
5.5 2.3 :::.
129.2 124.8 91.2 100.3
7.4 6.3 4.1 4.5
134.2 137.3 89.3 95.7
6.3 5.5 5.7 3.0
6 N 15 SFA
42.7 42.5
i::
42.7 42.5
3.3 3.0
82.3 78.3
6.1 4.7
84.3 80.3
10.4 5.1
6 N 38.3 3.3 34.5 2.6 59.2 4.5 15 SFA 40.3 2.7 34.5 2.5 60.8 3.4 ‘6 N = 6 normal subjects; 15 SFA = 15 symptom-free asthmatic patients.
65.3 62.7
3.5 3.4
Propranolol, 1 mg Pulse pressure (mm Hg) Control (saline) Propranolol, 1 mg
one of the most specific and potent beta-adrenergic receptor Propranolol, blocking agents, has been used extensively for investigation in the field of pharmacology of adrenergic receptors and for the treatment of certain cardiac arrhythmias, angina pectoris, and thyrotoxicosis. 13,20-22The antiarrhythmic function of propranolol has been demonstrated by many investigators.23-26Beta blockade is also well known to induce bronchoconstriction, however, particularly in patients who have bronchial asthma or bronchitis,5r 7,*, I69=, 28thus suppressing its usefulness in these patients. Development of a new agent which inhibits beta receptors of the heart and does not affect the bronchial muscle is urgently needed for the treatment of cardiac arrhythmia. This is particularly true when cardiac arrhythmia is combined with or sometimes caused secondarily by bronchial asthma or chronic bronchitis and emphysema. Since Dunlop and ShanksI reported a detailed pharmacologic study on a new beta receptor blocking agent-practolol-selective beta-l receptor blocking effect of the drug haa been acknowledged by many investigators.2”-34 Practolol (average dose, 23 mg in this study) revealed definite cardiac beta-l receptor inhibiting effect equal to that of propranolol (1 mg) by blocking isoproterenol-inducing tachycardia in asthmatic subjects, as shown in Table IV and Fig. 3. On the other hand, practolol did not block the response of isoproterenol on diastolic blood pressure, a beta-2 vasodilator response, whereas propranolol significantly blocked those responses, Analysis of pulse contour (as in Table VI) supports the results that suggest practolol does not inhibit isoproterenol-induced relaxation of vascular smooth muscle whereas propranolol does. These results of practolol’s effect on the cardiovascular systems are in agreement with the studies reported by Dunlop and Shanks,15Powles,29Paton, Brick,35 Barrett,36 and their co-workers. The difference between effects of propranolol and practolol on in vitro
Comparison
VOLUME 57 NUMBER 1
of respiratory
TABLE VI. Effect of practolol and propronolol on arterial to isoproterenol in normal and asthmatic subjects R Pl (set)
and cardiovascular
pulse
PI
contour
effects
and
21
its response
P2/R R (%I Isorproterenol
Saline
Isorproterenol
No of P
Saline
Isorproterm01
Saline
Isorproterenol
Normal Asthmatic
0.78 0.74
0.52 0.55
0.19 0.19
0.13 0.13
34.52 35.87
54.35 46.15
3.38 3.30
2.38 2.30
Practolol Normal Asthmatic
0.84 0.80
0.66 0.64
0.20 0.20
0.15 0.14
34.51 33.54
43.75 40.95
3.25 3.20
2.63 2.90
Propranolol Normal Asthmatic
0.85 0.81
0.75 0.70
0.20 0.19
0.16 0.16
35.33 32.64
38.50 33.99
3.13 3.00
3.25 2.90
Saline
Control
Pl
human airway smooth muscle is striking .37 These studies show that practolol is 17,000 times less potent than propranolol in blocking the effect of isoproterenol on human tracheal smooth muscle. Similar results were obtained with guinea pig trachea. In vivo studies of histamine sensitivity in mice using lethality as an end point2 showed that practolol was at least 5,000 times less potent than propranolol.37 The difference between the effects of propranolol and practolol on in vivo airway function was also distinctive. Propranolol administration in this study was followed by a decrease in FEV, and FVC and increase in airway resistance in both control and symptom-free asthmatic groups at resting state. These changes were greater in the asthmatic group than in the control group. McNeill” and McNeil1 and Ingram8 observed similar findings. Furthermore, in our asthmatic group, only 1 mg of propranolol produced a marked increase in bronchial sensitivity to methacholine and revealed striking inhibition on isoproterenol reversal of bronchoconstriction. Obviously, had we used the usual 7 to 10 mg dose of propranolol instead of 1 mg, the effect on methacholine sensitivity would have resulted in a prohibitive and perhaps dangerous bronchoconstrictive response to methacholine. This suggests that the bronchial beta receptor’s ability to respond to adrenergic stimulation is less in asthmatic subjects than in normal subjects’, 2, I7 and asthmatic or allergic rhinitis patients can be more easily blocked by a smaller dose of propranolol.3* 4 Contrary to propranolol, practolol did not affect FEVI, FVC, or airway
22
Ryo and Townley
J. ALLERGY CLIN. IMMUNOL. JANUARY 1976
resistance of the control group at resting state, nor was bronchial sensitivity to methacholine inhalation changed by practolol in either group. Similarly, isoproterenol reversal of bronchospasm induced by methacholine challenge was not restrained by practolol. On the basis of results obtained in this study, practolol showed fairly distinctive selectivity in blocking the cardiac response to isoproterenol, leaving the bronchodilator and vasodepressor response comparatively unblocked. The results support the proposal of Landslo of beta receptor classification and defining practolol as a beta-l receptor blocking agent. Minimal changes in basal FEV, and FVC following practolol administration in symptom-free asthmatic subjects indicate that the drug has a slight blocking effect on bronchial beta receptors. A slight bronchoconstrictor effect of practolol has been reported also by Powles, Shinebourne, and Hamer,*’ Palmer and assoeiates,30 Beumer, 38 McDonald and McNei11,33 and Bernecker and Roetscher.39 Even though practolol produced slight bronchoconstriction in asthmatic patients, the bronchoconstriction is reversible by isoproterenol. Other investigators31v 34,4o reported that practolol did not produce a noticeable increase in airway resistance in asthmatic patients. Such controversial results might be due to difference in methods of measurement of airway resistance or in severity of asthma of those subjects used in different investigations. In asthmatic subjects compared to normal subjects, smaller doses of propranolol produced more profound bronchospasm; it could therefore be suggested that even the same dose of practolol could induce different degrees of bronchoconstrietor effects in a group which is different in severity of asthma. We have further studied the effect of practolol on cardiopulmonary functions in symptomatic asthmatics in comparison with the asymptomatic asthmatic subjects described above. Investigations of subjects with symptomatic asthma show findings similar to the above in that practolol did not cause significant bronchoconstriction and did not alter methacholine sensitivity or prevent the response of isoproterenol on bronchodilatation. One of the most common causes of cardiac arrhythmia is chronic obstructive lung disease. Patients with asthma, chronic bronchitis, or emphysema have episodes of hypoxia and are receiving catecholamines and theophylline. All of these factors contribute to cause cardiac arrhythmias. Yet it is these very people for whom the antiarrhythmic agent propranolol is contraindicated because of its known effect of increasing airway obstruction. Although available in Europe, a selective beta blocker that will prevent cardiac arrhythmias by suppressing cardiac beta. receptor excitability without augmenting airway obstruction is urgently needed in the treatment of patients with asthma and chronic obstructive pulmonary disease in this country. We would like to thank Kathleen M. Burke for her technical Martin and David Blasczak for their helpful statistical analyses.
assistance
as well
as Jack
VOLUME 57 NUMBER 1
Comparison
of respiratory
and cardiovascular
effects
23
REFERENCES theory of the atopic abnormality in bronchial asthma, 1 Szentivanyi, A.: Beta-adrenergic J. ALLERGY 42: 203,1968. 2 Townley, R. G., Tranpani, I. L., and Szentivanyi, A.: Sensitization to anaphylaxis and to some of its pharmacological mediators by blockade of the beta-adrenergic receptors, J.
ALLERGY 39: 177,1967. 3 Ouellette, J. J., and Reed, C. E.: The effect of partial beta-adrenergic blockade on the bronchial response of hay fever subjects to ragweed aerosol, J. ALLERGY 39: 160, 1967. blockade on 4 McGeady, S., Conboy, K., and Townley, R.: The effect of beta-adrenergic bronchial sensitivity to methacholine in normal and allergic rhinitis subjects, J. ALLERGY 41: 108, 1968. 5 McNeil, R. 8.: Effect of a beta-adrenergic blocking agent, propranolol, on asthmatics, Lancet 2: 1101, 1964. von adrenergen Betarezeptoren6 Meier, J., Lydtin, H., and Zollner, N.: tiber die Wirking blockern auf ventilatorische Funktionen bei obatruktiven Lungenkrankheiten, Dtsch. Med. Wochenschr. 91: 145-147, 1966. 7 Zaid, G., and Beall, G. N.: Bronchial response to beta-adrenergic blockade, N. Engl. J. Med. 275: 580, 1966. on ventilatory function, Am. J. 8 McNeill, R. S., and Ingram, C. G.: Effect of propranolol Cardiol. 18: 473, 1966. 9 Lands, A. M., and Brown, T. G.: A comparison of the cardiac stimulating and bronehodilator actions of selected sympathomimetic amines, Proc. Sot. Exp. Biol. Med. 116: 331, 1964. 10 Lands, A. M., Arnold, A., MeAuliff, J. P., Luduena, F. P., and Brown, T. G.: Differentiation of receptor systems activated by sympathomimetic amines, Nature 214: 597, 1967. 11 Harley, D., Jack, D., Lunts, L. H. C., and Ritchie, A. C.: New class of selective stimulants of beta-adrenergic receptors, Nature 219: 861, 1968. 12 Moran, N. C.: Pharmacological characterization of adrenergic receptors, Pharmacol. Rev. 18: 503, 1966. 13 Furchgott, R. F. : The pharmacological differentiation of adrenergic receptors, Ann. N. Y. Aead. Sci. 139: 553, 1967. 14 Moran, N. C.: The development of beta adrenergic blocking drugs: A retrospective and prospective evaluation, Ann. N. Y. Acad. Sci. 139: 649, 1967. beta-receptor in the 15 Dunlop, D., and Shanks, R. G.: Selective blockade of adrenoceptive heart, Br. J. Pharmacol. Chemother. 32: 201, 1968. 16 Guirgis, H. M., and McNeill, R. S.: The nature of the adrenergic receptors in isolated human bronchi, Thorax 24: 613, 1969. 17 Townley, R. G.: Mechanisms and management of bronchial asthma, in Tiee, F., Editor: Practice of medicine, Hagerstown, Md., 1972, Harper & Row, Publishers. 18 Townley, R. G., Dennis, M., and Itkin, I. H.: Comparative action of acetyl-beta-methylcholine, histamine, and pollen antigens in subjects with hay fever and patients with bronchial asthma, J. ALLERGY 36: 121, 1965. 19 DuBois, A. B., Botelho, S. Y., and Comroe, J. H.: 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, 1956. 20 Nickerson, M.: New developments in adrenergic blocking drugs, Ann. N. Y. Arad. Sci. 139: 571, 1967. 21 Blinks, J. R. : Evaluation of the cardiac eff e&s of several beta adrenergic blocking agents, Ann. N. Y. Acad. Sci. 139: 673, 1967. 22 Dollery, C. T., Paterson, J. W., and Conolly, M. E.: Clinical pharmacology of beta receptor blocking drugs, Clin. Pharmacol. Ther. 10: 765, 1969. 23 Harris, A.: Long term treatment of paroxysmal cardiac arrhythmias with propranolol, Am. J. Cardiol. 18: 431, 1966. 24 Schamroth, L: Immediate effects of intravenous propranolol on various cardiac arrhythmias, Am. J. Cardiol. 18: 438, 1966. 25 Seaton, A. : Quinidine-induced paroxysmal ventricular fibrillation treated with propranolol, Br. Med. J. 1: 1522, 1966. 26 Ryo, U. Y.: Factors affecting ventricular bigeminy induced by intravenous thiopental in dogs, Fed. Proc. 29: 321 (abst.), 1970.
24
Ryo and Townley
J. ALLERGY CLIN. IMMUNOL. JANUARY 1976
action of propranolol aerosol in asthmatic subjects, 27 Langer, I.: The bronchoconstrictor J. Physiol. 190: 41, 1967. 28 Herxheimer, H.: The bronchoconstrictor action of propranolol aerosol in the guinea pig, J. Physiol. 190: 41, 1967. 29 Powles, R.., Shinebourne, E., and Hamer, J.: Selective cardiac sympathetic blockade as an adjunct to bronchodilator therapy, Thorax 24: 616, 1969. W. F. D., and Diament, M. L. : Effect of a 30 Palmer, K. N. V., Legge, J. S., Hamilton, selective beta-adrenergic blocker in preventing falls in arterial oxygen tension following isoprenaline in asthmatic subjects, Lancet 2: 1092, 1969. 31 Grieco, M. H.: Current concepts of the pathogenesis and management of asthma, Bull. N. Y. Acad. Med. 46: 597, 1970. 32 Paton, D. M.: The evidence for different types of beta-adrenergic. receptors, Am. Heart J. 77: 707, 1969. 33 McDonald, A. G., and McNeill, R. S.: A comparison of the effect on airway resistance of a new beta blocking drug, I.C.I. 50172, and propranolol, Br. J. Anaesth. 40: 508, 1968. 34 Jenkins, A. V. : Adrenergic beta-blockade with I.C.I. 50172 (practolol, “Eraldin” j during bronchoscopy, Br. J. Anaesth. 42: 59, 1970. 35 Brick, I., Hutchison, K. J., McDevit, D. G., R.oddie, I. C., and Shanks, R. G.: Comparison of the effects of I.C.I. 50172 and propranolol on the cardiovascular responses to adrenaline, isoprenaline, and exercise, Br. J. Pharmacol. 34: 127, 1968. 36 Barrett, A. M. Crowther, A. F., Dunlop, D., Shanks, R. G., and Smith, L. H.: Cardioselective beta-blockade, Naunyn Schmiedebergs Arch. Pharmacol. Exp. Pathol. 259: 152, 1968. 37 Adolphson, R. L., and Townley, R. C.: A comparison of the activities of practolol, sotalol, and propranolol in human and guinea pig trxcheal smooth muscle. Submitted to .T.
ALLERGY CLIN. IMMUXOL. 38 Beumer, H. M.: Local effects of beta-adrenergic blocking drugs in histamine sensitive asthmatics, Pharm. Clinica 1: 172, 1969. 39 Bernecker, C., and Roetscher, I.: The beta-blocking effect of practolol in asthmatics, Lancet 2: 662, 1970. 40 Frullani, F., Merigo, A., and Novelli, G. P.: Propranolol and practolol (I.C.I. 50172) in asthma patients, Minerva Anestesiol. 35: 1130, 1969.
M.D. Omaha, Nebr.
Pulmonary functions, by means of FEV,, FVC, and aircay resistance, and car&ovasonlar responses, i.e., ECG, blood pressure, and pulse contour, acre measured in 10 control and 15 symptom-free asthmatic subjects during and after the infusions of isoproterenol, with or without previous administration of propranoIo1 or practolol. Bronchial sensitivity to methacholine and response to isoproterenol after methacholine were also measured. Bronchial sensitivity to methacholine challenge was markedly enhanced by propranolol and the effect of isoproterenol infusion on the pulmonary function u-as also significantly diminished, whereas practolol did not reuenl any Qect on bronchial sensitivi.ty to methacholine or isoprotevenol. The above changes were much more profound in symptom-free asthmatic subjects than in control affect the beta-l subjects. The results suggest that practolol does not significantly bronchial receptors, is safe to use in asthmatic subjects, and is consistent with an abnormality of these receptors in bronchial asthma.
Recently, Szentivanyi and others L 2 have suggested that a phenomenon common to all patients with asthma is a. partial blockade of the beta adrenergic receptors regardless of what the precipitating factors may be clinically. The beta adrenergic theory regards asthma as a bronchial hpperreactivity to a broad spectrum of immunologic, psychic, infectious, chemical, and physical stimuli. Indeed, beta adrenergic blockade has been shown to enhance bronchial reactivity to inhaled allergens,? or to methacholinc’ in patients with seasonal allergic rhinitis without a previous history of bronchial asthma. By progressively increasing doses of the beta blocker, an acute airway obstruction could be produced which seemed to reach an intensity that may be found in patients with bronchial asthma.& Administration of beta blockers has also been rcported;‘~ (i to aggravate already existent asthmatic conditions and to cause precipitous and prolonged falls in forced 1 see expiratory volume (FEY,). Blockade of beta receptors was found to increase significantly the bronchial sensitivity of asthmatic subjects to methacholine, whereas no such effect was detectable in From thP Department of Medicine, Creighton University School of Medicine. Supported in part by the Ayerst Pharmaceutical Company. Received for publication Aug. 12, 1974. Accepted for publication Dec. 16, 1974. Reprint requests to: Robert G. Totvnley, M.D., Department of Medicine and Microbiology, Criss I, Room 408, Creightou University School of Medicine, 2500 California St., Omaha, Nebr. 68178. Vol. 57, No. 1, pp. 16-84
Comparison
VOLUME 57 NUMBER 1
of respiratory
10 NmNAL AsFNMAFlos oammo ---* ~rnAclvLoL---A 0-PmPNAN0r0L-4
+ '
""NN;k
OF W%C"oLlNi~Tl8S
effects
13
Ii ,’
IS
t
1 + AFTEK ,MLOCKER
and cardiovascular
,
oISOP~:%NOL 3o INFUSION-MINUTES
FIG. 1. Effect of practolol and propranolol on FEV, and its response isoproterenol in normal subjects and asthmatic subiects.
to methacholine
and
normal human subjects as judged by the change in FEV,.? By using a more specific and sensitive measurement of airway resistance, however, the whole body plethysmograph method, a 50% to 100% increase in airway resistance has been observed also in normal subjects in the first 30 min after the administration of a beta blocker.R On the basis of differences in potency of the same sympathomimetic amine, or of different effects of beta adrenergic blocking agents on the beta receptors of various tissues, different subclassifications of beta receptors have been proposed by various investigators.9-‘” Lands and associateslo proposed a differentiation of beta adrenergic receptors as beta-l for cardiac stimulation and lipolysis and beta-2 for bronchodilatation and vasodepression. This new theory of beta adrenergic receptor classification has been applied extensively to promote the understanding of the mechanisms of beta receptor responses in various tissues to adrenergic stimuli. Practolol, 4- (2-hydroxy-3-isopropylaminopropoxy) acetanilide, has been introduced by Dunlop and Shanks’” as a selective beta adrenergic blocking agent which has a potent inhibitory effect on cardiac beta receptors (beta-l) but has minor or no effect on beta receptors of bronchial smooth muscle (beta-g). This agent has been used extensively in Europe. It has been withdrawn from clinical trials in the United States as a result of animal toxicology studies and recent reports of dry eyes and drug-induced systemic lupus erythematosus. Currently, the only agent available in this country that inhibits cardiac beta receptors is propranolol. It is contraindicated in patients with asthma or chronic obstructive lung disease because of the bronchoconstriction that occurs.“’ Ifi. Ii Cardiac arrhythmias are a common problem encountered in the care of patients
14
J. ALLERGY CLIN. IMMUNOL. JANUARY 197.4
Ryo and Townley
TABLE I. Effects of practolol isoproterenol in 10 normal
and propranolol subjects
on bronchial
sensitivity
to methacholine
Min No. of methacholine Baseline Mean
FEV, (%)* Control Practolol Propranolol FVC (%) Control Practolol Propranolol Airway resistance (cm H,O/L/sec) Control Practolol Propranolol
10 SE
Mean
3.48 0.13 92.09t 100.00 0.00 98.64 1.05 95.06 96.88t 0.83 93.56 3.92 100.00 97.78 96.40
0.20 96.27s 0.00 0.78 97.48 1.81 95.51
0.88 0.08 0.95 0.11 1.06t 0.10
I SE
inhalations
20 Mean
40 SE
Mean
of isoproterenol infusion
15 SE
Mean
and
I SE
30 Mean
SE
1.81 85.83$ 2.67 85.26$ 2.96 94.417
1.52 97.213
1.14
1.33 88.83 1.47 88.96
2.43 87.64 2.07 85.24
1.52 97.78 2.32 94.26
1.33 2.30
1.27 92.20t
2.26 92.477 2.35 96.965
1.25 98.81
1.41
1.12 93.57 2.00 93.26
2.30 93.38 2.19 89.75
1.43 98.97 1.62 96.32
1.23 1.50
1.259 0.18 1.26 0.19 1.39 0.16
1.70t 0.22 1.58 0.22 1.66 0.20
2.85 95.73 2.87 91.58
2.53 97.43 2.22 95.75
1.82$ 0.22 1.73 0.21 2.02 0.30
l.lOg 0.11 1.22 0.11 1.547 0.18
p values after practolol or propranolol are vs saline control (vertical comparisons). p values after saline control are vs baseline (horizontal comparisons). “FEV, and FVC are expressed as % to baseline except values in parentheses, absolute values in liters. tp < 0.01. tp < 0.001. $p < 0.05.
1.04 0.11 1.08 0.11 1.21$ 0.14
which
are
with severe asthma or chronic obstructive lung disease, A beta adrenergic blocking agent with a highly selective action on cardiac beta receptors would be very useful for suppression of cardiac beta receptor excitability without augmentation of airway obstruction in asthmatic patients. The present stud! attempts to elucidate the effect of practolol and propranolol on cardiopulmonary response of asthmatic and normal subjects to metacholine challenge and isoproterenol infusion. METHODS The control group consisted of 10 normal persons without any allergic history and negative skin tests with 20 common allergens. The 15 asthmatic subjects, who were currently free of symptoms, had a documented history of allergy and bronchial asthma episodes, and showed positive skin tests to common allergens. None of these subjects was on any medication for asthma for at least 3 mo. Medical history, pertinent physical examinations, allergy skin tests, and tests for bronchial sensitivity to methacholino inhalntionls were carried out prior to this study on all of these subjects. The average age of the normal subjects was 23 yr (range, 17 to 35) ; 5 of 10 were femalr. The average age of the asthmatic subjects was 22 yr (range, 12 to 42) ; 6 were female and 9 were male. An intrav.enous catheter was plared into the antecubital vein. Throughout the experimental procedures, the subject was sitting in the whole boty plethysmogrnph. The electrocardiogram (ECG) and radial pulse curves (E & M Instrument Co.) were monitored. The body plethysmograph was open except during airway resistance measurements. After :\bout 10 min of rest
VOLUME 57 NUMBER 1
TABLE Il. Effects and isoproterenol
Comparison
of respiratory
of practolol and propranolol in 15 symptom-free asthmatic
on bronchial subjects
No. of methacholine Baseline Mean
FEV, (%)* Control Practolol Propranolol FVC (%) Control Practolol Propranolol
measured
3
Mean
SE
Mean
effects
15
to methacholine
Min of isoproterenol infusion 15
30
4.66 69.92$ 3.61
80.85
8.35 90.20s
3.59 102.14
2.58
3.98 71.14 3.70 5.42 57.399 5.71
77.10 12.1092.55 62.60 14.00 76.74t
2.75 101.72 3.45 89.84t
2.11 3.23
87.65
6.15 94.154 2.59 100.10
0.81
86.10 72.50
6.50 95.66 1.89 100.56 7.60 82.76$ 2.79 93.03t
1.62 2.18
2.32$ 0.24 2.706 0.21 3.73t 0.53
2.70$ 0.27 2.79 0.17 3.365 0.24
15
10
3.11 2.92 3.66 2
0.08 0.52 0.40
SE
SE
SE
0.28 85.52§ 4.43 82.12$ 3.36 0.00 1.37 85.23 3.28 79.36 4.30 1.11 72.33 5.53 67.184 6.88
Mean
Mean
Mean
3.66 100.00 97.29 95.854
15
sensitivity
6 SE
0.20 78.97t 0.00 1.85 74.95 1.42 64.99t
0.11 0.12 0.18
cardiovascular
inhalations
3.06 100.00 96.45 92.45t
Airway resistance (cm H%O/L/sec) Control 1.32 Practolol 1.44 Propranolol 1.77t
NO. of subjects
1 SE
and
1.757 0.13 1.76 0.14 3.15$ 0.34
1.36 0.10 1.28 0.09 2.243 0.23
15
14
p values after practolol or propranolol are vs saline control (vertical comparisons). p values after saline control are vs baseline (horizontal comparisons). “FEV, and FVC are expressed as c/o to baseline except values in parentheses, absolute values in liters. tp < 0.01. :p < 0.001. $p < 0.05.
which
are
for equilibration in the plethysmograph, basal FEV,, forced vital capacity (FVC), airway resistance, blood pressure, and ECG were measured. The FEV, and FVC were measured with a Collins 13-L spirometer at least 3 times at the given conditions and the highest of the 3 determinations was recorded. Airway resistance (AWR) was measured by means of DuBois body plethysmograph,l9 the measurements were repeated 5 times on each occasion, and the average value was calculated. Measurements of FEV,, FVC, AWR, blood pressure, heart rate with EGG, and radial pulse contour were obtained after intravenous infusion of 30 C.C. of normal saline. These measurements were repeated after methacholine challenge and 15 min and 30 min during infusion of intravenous isoproterenol administered with a Harvard infusion pump. The dose of isoproterenol varied from 1.5 to 4.5 mcg/min, depending upon the sensitivity of the individual subject to the drug. The dose did not vary between experiments in the same subject. There was no significant difference between the normal and asthmatic groups in the dose of isoproterenol administered. Inhalation challenges were performed with methacholine (5 mg/ml) with a vaponephrine nebulizer activated at 6 L/min of compressed air. The numbers of methacholine inhalations were increased sequentially in the order of 10, 20, and 40 in all normal subjects, and 1, 3, and 6 in asthmatic subjects, or until the FEV, decreased more than 20% of control value. Either propranolol, practolol, or normal saline was administered intravenously and the bronchial response to methacholine inhalation challenge was repeated. Also, measurements of FEV,, FVC, AWR, blood pressure, and heart rate before and after intravenous isoproterenol were carried out the same as during the control phase. The total dosage of propranolol was 3
16
J. ALLERGY CLIN. IMMUNOL. JANUARY 1976
Ryo and Townley
I\ST”hlAT,CS CONTROL----.
j
+ AFTER O-BLOCKER
, I
j +TiijiEt:;
4. o
NUMBER OF METHACHOLINE INHALATIONS
FIG. 2. Effects of practolol and propranolol on airway methacholine and isoproterenol in normal and symptom-free
,5
;.
lSOPROTERENOLINFUSION MINUTES
resistance asthmatic
and its response subjects.
to
mg in all normal subjects which was divided into 1 mg plus 2 mg in 6 subjects, and only 1 mg in all asthmatic subjects. Practolol was infused in a dose of 15 mg in 5 normal and 7 asthmatic subjects, and in a dose of 30 mg in 5 normal and 8 asthmatic subjects. The order of these studies with saline, propranolol, or practolol was randomized and, after a study with one of the beta blockers, no further study was done in the same day on the subject.
RESULTS
Resting pulmonary functions in terms of FEV, and FVC in asthmatic subjects in this study were all in the normal range and all of them were more than 80% of their predicted value, even though the values were smaller than those of the control group (Tables I and II). Average airway resistance of the asthmatic group was 150% of the value in the control subjects but still was not out of normal range, 1.5 + 0.49 cm H,O/L/sec.lg The data show that these asthmatic subjects are not only free from subjective symptoms but also do not have any significant objective sign of impairment of airway function at resting states. As shown in Fig. 1, even though none of the asthmatic group had active symptoms or signs of asthma, the average FEV, dropped 21% (p < 0.01) folIowing a single inhalation of methacholine chloride (5 mg/ml) whereas FEV, decreased less than 15% after 70 inhalations of methacholine in the control group. Changes in airway resistance following methacholine inhalations were more striking (Fig. 2) and increased to 190% of baseline after a single inhalation of methacholine after saline in symptom-free asthmatics (p < O.OOl), whereas the increase became significant after a total of 30 inhalations of methacholine in the normal group. All normal subjects received a total of 70
Comparison
VOLUME 57 NUMBER 1
of respiratory
and
cardiovascular
effects
17
I
a'- BLOCKER
FIG. 3. Effects of proctolol,
0
propronolol,
30 ISOPROTERENOL :iF”SION,
ond
isoproterenol
MINUTES
on the heort
rate
and
pulse
pressure.
inhalations of methacholine, whereas only 10 of the 15 asthmatic subjects received more than one inhalation. The AWR after 70 inhalations in the normal group was still less than after one inhalation following saline in the symptom-free asthma group (1.82 vs 2.32). In both groups, the FEV, and FVC increased and the AWR decreased toward baseline values following isoproterenol infusion. Effects of beta blockade on respiratory functions were as follows. Propranolol suppressed baseline FEV, and FVC and raised AWR in both groups but the changes were more profound in symptom-free asthmatic patients (Tables I and II and Figs. 1 and 2). In asthmatic patients, propranolol markedly augmented bronchial sensitivity to methacholine with wheezing and a decrease in FEV, and FVC and an increase in AWR following methacholine inhalations. Propranolol also depressed the isoproterenol reversal of FEV,, FVC, and AWR significantly. The bronchial sensitivity to methacholine was not affected by propranolol in the control group. Infusion of practolol failed to induce any significant change of baseline FEV,, FVC, and AWR in the control group, and did not alter the bronchial sensitivity to methacholine challenge and isoproterenol infusion in either group. Wheezing did not occur in the normal group at any time. Both beta blockers, propranolol and practolol, only slightly slowed the resting heart rate at the dosage used, but blocked isoproterenol-induced tachycardia in both groups (Tables III and IV and Fig. 3) (p < 0.001). The degree of
18
I. ALLERGY CLIN. IMMUNOL. JANUARY 1976
Ryo and Townley
TABLE III. Effects of practolol those responses to isoproterenol Beta
and propranolol in 10 normal
blockade
administration
Before Mean
Heart rate (min) Control (saline) Practolol Propranolol Pulse pressure (mm b-1 Control Practolol Propranolol
15.2 15.3 73.3
41.5 36.6 31.9
on the subiects
heart
::: 2.8
Mean
15.2 10.2 67.5
z 2.2
41.5 34.7
4.2 ::;
112.1 110.1 108.0
:4 3:4
73.1 14.1 73.5
35.9
blood
looproterenol
After SE
rate,
pressure,
infusion
(min)
15 SE
and
30
Mean
SE
Mean
SE
119.4* 3"2 I:9
98.5* 70.3*
6.9 5.3 2.5
125.6* 101.7t 84.2*
6.3 6.1 4.1
:.i 2:4
82.3* 68.3t 51.0*
!t: 3:1
83.7* 70.3 58.4-f
::1 2.9
4.2
137.4*
4.2
135.4*
5.5
3.5
127.8$
3.9
126.4
Systolic pressure EGElg) Practolol Propranolol
112.1 110.5 112.3
4.1
123.17
3.4
127.6
::;
3.2
Q.3_* 55.3 6l.F
2.5 3.6 3.4
49.3* gi .
2.7 3.4 2.1
Diastolic pressure Practolol Propranolol
73.1 14.2 13.0
3.1 3.2
p values after practolol or propranolol are vs saline control (vertical comparisons). p values after saline control are vs baseline (horizontal comparisons). “p < 0.001. tp < 0.01. :p < 0.05.
suppressing effect on isoproterenol-induced tachycardia was slightly greater with propranolol. In asthmatic patients, there was no significant difference between the two beta blockers in response to heart rate. Propranolol tended to inhibit the elevation of systolic blood pressure following isoproterenol infusion in both groups (Tables III and IV). The effects of propranolol and practolol became remarkably different in both normal and asthmatic subjects in response of diastolic pressure (p < 0.01) and pulse pressure (p < 0.01) to isoproterenol infusion. Propranolol, to a significant extent (p < 0.01)) blocked the effects of isoproterenol in lowering the diastolic pressure and in widening of the pulse pressure in both normal and asthmatic subjects; practolol did not produce any change in response of those pressures to isoproterenol in either group (Fig. 3 and Tables III and IV). Although the effect of propranolol on inhibiting the increase in heart rate and pulse pressure following isoproterenol was somewhat greater in the normal group than in the asthmatic, the total dose of propranolol was 3 mg in the normal group and only 1 mg in the asthmatic. When the dose of propranolol was 1 mg in both normal and asthmatic groups, there was no significant difference in the effect of isoproterenol on heart rate or pulse pressure (Table V) . The data do not indicate any beta-l or beta-2 receptor abnormality in the cardiovascular system of the asthmatic group in contrast to the bronchial beta-2 receptor abnormality in this group.
VOLUME 57 NUMBER 1
Comparison
cardiovascular
effects
19
TABLE IV. Effects of practolol those responses to isoproterenol
and propranolol on the heart rate, blood in 15 symptom-free asthmatic subjects
pressure,
and
Beta
blockade
Before Mean
1
and
lsoproterenol
administration I
SE
of respiratory
After Mean
infusion
(min)
30
15 SE
Mean
SE
Mean
SE
Heart rate (min) Control Practolol (saline) Propranolol
78.9 82.1 83.3
2.3 2.2
74.5 82.1 78.7
2.3 :::
103.0s 124.8* 100.3*
4.8 6.3 4.5
137.3* 102.1* 95.7*
::: 3.0
42.5 39.5 40.3
::i
1.:
2.7
42.5 39.3 34.5
215
78.3* 74.3 60.8t
4.7 4.1 3.4
80.3’ 78.5 62.7;
5.1 4.2 3.4
115.6
2.0
115.6
2.0
136.2*
2.9
133.6*
3.8
112.4 114.1
:::
110.9 108.3
2.3 3.1
;;yc.
2.9 2.3
131.5 127.1$
::‘:
74.4 74.9 75.0
2.3 2.0 2.1
74.4 72.3 75.5
Pulse messure
Cm4 Hg)
Control Practolol Propranolol Systolic pressure ?EZlg) Propranolol Practolol Diastolic uressure
2.3 52.5* 51.4* 2.2 54.4 ::: 50.9 1.5 61.9t 2.1 61.9t p values after practolol or propranolol are vs saline control (vertical comparisons). p values after saline control are vs baseline (horizontal comparisons). *p < 0.001. tp < 0.01. tp < 0.05. Practolol Propranolol
3.2 2.7 1.9
Analysis of pulse contours monitored from the radial artery by means of pulse pickup was carried out with particular interest in the interval between the peak of the R wave (ECG) to the onset of pulse, between each peak of pulse notch P, to P,, and number of peak pulses (Table VI). Amplifications of pulse pressures were uncomparable because a slight movement of arm or wrist changed the position of pulse pickup, thus producing significant alteration in sensitivity of the amplification. The results of pulse contour analysis revealed that propranolol completely blocked the effect of isoproterenol in prolongation of the comparative interval between P, to P,, over percentage to R-R on ECG. Propranolol also blocked the effect of isoproterenol on reduction in the number of peak pulse curves (P) whereas practolol did not exert significant influence on those effects of isoproterenol (Table VI). Again there were no significant differences between the asthmatic and the normal groups in the effect of isoproterenol with or without either beta blocker on the pulse wave contours. DISCUSSION
Availability of specific beta-adrenergic receptor blocking agents in the field of clinical pharmacology has resulted in a greater understanding and differentiation of adrenergic receptors. Therapy of various diseases caused or aggravated by increased sympathetic tone has advanced by this knowledge.
20
J. ALLERGY CLIN. IMMUNOL. JANUARY 1976
Ryo and Townley
TABLE V. A comparison pulse pressure
of the effects of isoproterenol in symptom-free asthmatic and normal Beta
blockade
Before Population’
Heart rate/min Control (saline)
Mean
administration I
SE
and propranoiol subjects
lsoproterenol
After Mean
on heart infusion
(min)
30
15
L
rate and
SE
Mean
SE
Mean
SE
6N 15 SFA 6 N 15 SFA
76.0 82.1 76.8 83.3
5.5 2.3 22:;
76.0 82.1 71.0 78.7
5.5 2.3 :::.
129.2 124.8 91.2 100.3
7.4 6.3 4.1 4.5
134.2 137.3 89.3 95.7
6.3 5.5 5.7 3.0
6 N 15 SFA
42.7 42.5
i::
42.7 42.5
3.3 3.0
82.3 78.3
6.1 4.7
84.3 80.3
10.4 5.1
6 N 38.3 3.3 34.5 2.6 59.2 4.5 15 SFA 40.3 2.7 34.5 2.5 60.8 3.4 ‘6 N = 6 normal subjects; 15 SFA = 15 symptom-free asthmatic patients.
65.3 62.7
3.5 3.4
Propranolol, 1 mg Pulse pressure (mm Hg) Control (saline) Propranolol, 1 mg
one of the most specific and potent beta-adrenergic receptor Propranolol, blocking agents, has been used extensively for investigation in the field of pharmacology of adrenergic receptors and for the treatment of certain cardiac arrhythmias, angina pectoris, and thyrotoxicosis. 13,20-22The antiarrhythmic function of propranolol has been demonstrated by many investigators.23-26Beta blockade is also well known to induce bronchoconstriction, however, particularly in patients who have bronchial asthma or bronchitis,5r 7,*, I69=, 28thus suppressing its usefulness in these patients. Development of a new agent which inhibits beta receptors of the heart and does not affect the bronchial muscle is urgently needed for the treatment of cardiac arrhythmia. This is particularly true when cardiac arrhythmia is combined with or sometimes caused secondarily by bronchial asthma or chronic bronchitis and emphysema. Since Dunlop and ShanksI reported a detailed pharmacologic study on a new beta receptor blocking agent-practolol-selective beta-l receptor blocking effect of the drug haa been acknowledged by many investigators.2”-34 Practolol (average dose, 23 mg in this study) revealed definite cardiac beta-l receptor inhibiting effect equal to that of propranolol (1 mg) by blocking isoproterenol-inducing tachycardia in asthmatic subjects, as shown in Table IV and Fig. 3. On the other hand, practolol did not block the response of isoproterenol on diastolic blood pressure, a beta-2 vasodilator response, whereas propranolol significantly blocked those responses, Analysis of pulse contour (as in Table VI) supports the results that suggest practolol does not inhibit isoproterenol-induced relaxation of vascular smooth muscle whereas propranolol does. These results of practolol’s effect on the cardiovascular systems are in agreement with the studies reported by Dunlop and Shanks,15Powles,29Paton, Brick,35 Barrett,36 and their co-workers. The difference between effects of propranolol and practolol on in vitro
Comparison
VOLUME 57 NUMBER 1
of respiratory
TABLE VI. Effect of practolol and propronolol on arterial to isoproterenol in normal and asthmatic subjects R Pl (set)
and cardiovascular
pulse
PI
contour
effects
and
21
its response
P2/R R (%I Isorproterenol
Saline
Isorproterenol
No of P
Saline
Isorproterm01
Saline
Isorproterenol
Normal Asthmatic
0.78 0.74
0.52 0.55
0.19 0.19
0.13 0.13
34.52 35.87
54.35 46.15
3.38 3.30
2.38 2.30
Practolol Normal Asthmatic
0.84 0.80
0.66 0.64
0.20 0.20
0.15 0.14
34.51 33.54
43.75 40.95
3.25 3.20
2.63 2.90
Propranolol Normal Asthmatic
0.85 0.81
0.75 0.70
0.20 0.19
0.16 0.16
35.33 32.64
38.50 33.99
3.13 3.00
3.25 2.90
Saline
Control
Pl
human airway smooth muscle is striking .37 These studies show that practolol is 17,000 times less potent than propranolol in blocking the effect of isoproterenol on human tracheal smooth muscle. Similar results were obtained with guinea pig trachea. In vivo studies of histamine sensitivity in mice using lethality as an end point2 showed that practolol was at least 5,000 times less potent than propranolol.37 The difference between the effects of propranolol and practolol on in vivo airway function was also distinctive. Propranolol administration in this study was followed by a decrease in FEV, and FVC and increase in airway resistance in both control and symptom-free asthmatic groups at resting state. These changes were greater in the asthmatic group than in the control group. McNeill” and McNeil1 and Ingram8 observed similar findings. Furthermore, in our asthmatic group, only 1 mg of propranolol produced a marked increase in bronchial sensitivity to methacholine and revealed striking inhibition on isoproterenol reversal of bronchoconstriction. Obviously, had we used the usual 7 to 10 mg dose of propranolol instead of 1 mg, the effect on methacholine sensitivity would have resulted in a prohibitive and perhaps dangerous bronchoconstrictive response to methacholine. This suggests that the bronchial beta receptor’s ability to respond to adrenergic stimulation is less in asthmatic subjects than in normal subjects’, 2, I7 and asthmatic or allergic rhinitis patients can be more easily blocked by a smaller dose of propranolol.3* 4 Contrary to propranolol, practolol did not affect FEVI, FVC, or airway
22
Ryo and Townley
J. ALLERGY CLIN. IMMUNOL. JANUARY 1976
resistance of the control group at resting state, nor was bronchial sensitivity to methacholine inhalation changed by practolol in either group. Similarly, isoproterenol reversal of bronchospasm induced by methacholine challenge was not restrained by practolol. On the basis of results obtained in this study, practolol showed fairly distinctive selectivity in blocking the cardiac response to isoproterenol, leaving the bronchodilator and vasodepressor response comparatively unblocked. The results support the proposal of Landslo of beta receptor classification and defining practolol as a beta-l receptor blocking agent. Minimal changes in basal FEV, and FVC following practolol administration in symptom-free asthmatic subjects indicate that the drug has a slight blocking effect on bronchial beta receptors. A slight bronchoconstrictor effect of practolol has been reported also by Powles, Shinebourne, and Hamer,*’ Palmer and assoeiates,30 Beumer, 38 McDonald and McNei11,33 and Bernecker and Roetscher.39 Even though practolol produced slight bronchoconstriction in asthmatic patients, the bronchoconstriction is reversible by isoproterenol. Other investigators31v 34,4o reported that practolol did not produce a noticeable increase in airway resistance in asthmatic patients. Such controversial results might be due to difference in methods of measurement of airway resistance or in severity of asthma of those subjects used in different investigations. In asthmatic subjects compared to normal subjects, smaller doses of propranolol produced more profound bronchospasm; it could therefore be suggested that even the same dose of practolol could induce different degrees of bronchoconstrietor effects in a group which is different in severity of asthma. We have further studied the effect of practolol on cardiopulmonary functions in symptomatic asthmatics in comparison with the asymptomatic asthmatic subjects described above. Investigations of subjects with symptomatic asthma show findings similar to the above in that practolol did not cause significant bronchoconstriction and did not alter methacholine sensitivity or prevent the response of isoproterenol on bronchodilatation. One of the most common causes of cardiac arrhythmia is chronic obstructive lung disease. Patients with asthma, chronic bronchitis, or emphysema have episodes of hypoxia and are receiving catecholamines and theophylline. All of these factors contribute to cause cardiac arrhythmias. Yet it is these very people for whom the antiarrhythmic agent propranolol is contraindicated because of its known effect of increasing airway obstruction. Although available in Europe, a selective beta blocker that will prevent cardiac arrhythmias by suppressing cardiac beta. receptor excitability without augmenting airway obstruction is urgently needed in the treatment of patients with asthma and chronic obstructive pulmonary disease in this country. We would like to thank Kathleen M. Burke for her technical Martin and David Blasczak for their helpful statistical analyses.
assistance
as well
as Jack
VOLUME 57 NUMBER 1
Comparison
of respiratory
and cardiovascular
effects
23
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ALLERGY 39: 177,1967. 3 Ouellette, J. J., and Reed, C. E.: The effect of partial beta-adrenergic blockade on the bronchial response of hay fever subjects to ragweed aerosol, J. ALLERGY 39: 160, 1967. blockade on 4 McGeady, S., Conboy, K., and Townley, R.: The effect of beta-adrenergic bronchial sensitivity to methacholine in normal and allergic rhinitis subjects, J. ALLERGY 41: 108, 1968. 5 McNeil, R. 8.: Effect of a beta-adrenergic blocking agent, propranolol, on asthmatics, Lancet 2: 1101, 1964. von adrenergen Betarezeptoren6 Meier, J., Lydtin, H., and Zollner, N.: tiber die Wirking blockern auf ventilatorische Funktionen bei obatruktiven Lungenkrankheiten, Dtsch. Med. Wochenschr. 91: 145-147, 1966. 7 Zaid, G., and Beall, G. N.: Bronchial response to beta-adrenergic blockade, N. Engl. J. Med. 275: 580, 1966. on ventilatory function, Am. J. 8 McNeill, R. S., and Ingram, C. G.: Effect of propranolol Cardiol. 18: 473, 1966. 9 Lands, A. M., and Brown, T. G.: A comparison of the cardiac stimulating and bronehodilator actions of selected sympathomimetic amines, Proc. Sot. Exp. Biol. Med. 116: 331, 1964. 10 Lands, A. M., Arnold, A., MeAuliff, J. P., Luduena, F. P., and Brown, T. G.: Differentiation of receptor systems activated by sympathomimetic amines, Nature 214: 597, 1967. 11 Harley, D., Jack, D., Lunts, L. H. C., and Ritchie, A. C.: New class of selective stimulants of beta-adrenergic receptors, Nature 219: 861, 1968. 12 Moran, N. C.: Pharmacological characterization of adrenergic receptors, Pharmacol. Rev. 18: 503, 1966. 13 Furchgott, R. F. : The pharmacological differentiation of adrenergic receptors, Ann. N. Y. Aead. Sci. 139: 553, 1967. 14 Moran, N. C.: The development of beta adrenergic blocking drugs: A retrospective and prospective evaluation, Ann. N. Y. Acad. Sci. 139: 649, 1967. beta-receptor in the 15 Dunlop, D., and Shanks, R. G.: Selective blockade of adrenoceptive heart, Br. J. Pharmacol. Chemother. 32: 201, 1968. 16 Guirgis, H. M., and McNeill, R. S.: The nature of the adrenergic receptors in isolated human bronchi, Thorax 24: 613, 1969. 17 Townley, R. G.: Mechanisms and management of bronchial asthma, in Tiee, F., Editor: Practice of medicine, Hagerstown, Md., 1972, Harper & Row, Publishers. 18 Townley, R. G., Dennis, M., and Itkin, I. H.: Comparative action of acetyl-beta-methylcholine, histamine, and pollen antigens in subjects with hay fever and patients with bronchial asthma, J. ALLERGY 36: 121, 1965. 19 DuBois, A. B., Botelho, S. Y., and Comroe, J. H.: 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, 1956. 20 Nickerson, M.: New developments in adrenergic blocking drugs, Ann. N. Y. Arad. Sci. 139: 571, 1967. 21 Blinks, J. R. : Evaluation of the cardiac eff e&s of several beta adrenergic blocking agents, Ann. N. Y. Acad. Sci. 139: 673, 1967. 22 Dollery, C. T., Paterson, J. W., and Conolly, M. E.: Clinical pharmacology of beta receptor blocking drugs, Clin. Pharmacol. Ther. 10: 765, 1969. 23 Harris, A.: Long term treatment of paroxysmal cardiac arrhythmias with propranolol, Am. J. Cardiol. 18: 431, 1966. 24 Schamroth, L: Immediate effects of intravenous propranolol on various cardiac arrhythmias, Am. J. Cardiol. 18: 438, 1966. 25 Seaton, A. : Quinidine-induced paroxysmal ventricular fibrillation treated with propranolol, Br. Med. J. 1: 1522, 1966. 26 Ryo, U. Y.: Factors affecting ventricular bigeminy induced by intravenous thiopental in dogs, Fed. Proc. 29: 321 (abst.), 1970.
24
Ryo and Townley
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ALLERGY CLIN. IMMUXOL. 38 Beumer, H. M.: Local effects of beta-adrenergic blocking drugs in histamine sensitive asthmatics, Pharm. Clinica 1: 172, 1969. 39 Bernecker, C., and Roetscher, I.: The beta-blocking effect of practolol in asthmatics, Lancet 2: 662, 1970. 40 Frullani, F., Merigo, A., and Novelli, G. P.: Propranolol and practolol (I.C.I. 50172) in asthma patients, Minerva Anestesiol. 35: 1130, 1969.