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Increased responsiveness to histamine after propranolol in subjects with asthma nonresponsive to the bronchoconstrictive effect of propranolol
Increased responsiveness to histamine proprandol in subjects with asthma nonresponsive to the bronchoconstrictive effect of propranolol Giuseppe Salvatore
Carpentiere, MD, Francesco Marino, MD Palermo, Italy
Castello,
after
MD, and
Eight nonsmoking subjects with asthma, nonresponsive to the bronchoconstrictive effect of oral propranolol, were studied. The airway response to increasing concentrations of histamine aerosol was assessed by measuring FEV,. The threshold provocative dose of histamine needed to cause a 20% fall in starting FEV, (PD,,) was measured by log dose-response curve. Histamine challenge was performed in duplicate after premeditation with placebo or 40 mg of propranolol on separate days. The mean starting FEV, did not change significantly after placebo and after propranolol administration. The mean PD,, values after propranolol(O.37 mglml and 0.32 mglml, respectively, for the first and the second challenge) were signl$cantly lower (p < 0.01) than mean control PD,, values (I .36 mglml and 1.48 mglml, respectively, for the first and the second challenge). These results indicate that propranolol increases airway responsiveness to histamine, even in those subjects with asthma in whom propranolol has little bronchoconstrictive @ect. (.I ALLERGY CLIN IMMLJNOL 1988;82:595-8.)
Beta-adrenoceptor-blocking drugs are known to carry the risk of inducing bronchoconstriction in subjects with asthma.lm3 In addition to the initial bronchoconstriction, these drugs have been found to enhance responsiveness of the airways to other bronchoconstrictive agents, such as histamine and acetylcholine.“. ’ _ However, it is not well-known whether, in the absence of a significant bronchoconstrictive effect, padrenoceptor-blocking drugs can equally potentiate the nonspecific airway responsiveness in subjects with asthma. This is an important clinical problem because until now we have tried to assessthe risk of using padrenoceptor-blocking drugs in subjects with asthma on the basis of bronchoconstriction induced by test doses. If no bronchoconstriction was observed, we believed we could begin regular therapy with this drug under careful observation.
the Medical Clinical Institute of University of Palermo, Palermo, Italy. Received for publication Sept. 16, 1987. Accepted for publication April 2, 1988. Reprint requests: G. Carpentiere, MD, Medical Clinic Institute, University of Palenno, Piazza delle Cliniche 2, 90127 Palenno, Italy. Fmm
Abbreviations used PD,,: Provocative dose of histamine causing a 20%
drop in FEV, SBP:,~ Systolic blood pressure
This study was therefore designed to investigate whether propranolol, a nonselective P-adrenoceptorblocking drug, enhances airway responsiveness to histamine in subjects with asthma nonresponsive to the bronchoconstrictive effect of propranolol. METHODS Subjects Eight nonsmoking subjectswith asthma (five male subjects) of mean age 25.7 years (range 21 to 32 years) were selected on the basis of a reduction of FEV, <15% from the pretreatment value after oral dose of 40 mg of propran0101.All subjects had mild atopic asthma, as defined by American Thoracic Societycriteria. At the time of the study, all subjects were in stable condition, requiring only occasional inhalation of P-adrenergic agents. None was receiving oral corticosteroids and cromoglycate treatments. None had suffered an exacerbation of wheeze or a respiratory infection in the preceeding 3 months. All subjectsgave their informed consent.
J.ALLERGYCLIN.IMMUNOL. OCTOBER 1988
595 Carpentiere et al.
TABLE
I. Effect of propranolol
on pulse
rate and SBP in eight
subjects
Comparison between two tests
asthma
After propranololt
Baselink*
1st test 2nd test
with
Pulse rate (beatslmin)
SBP (mm Hg)
Pulse rate (beats/min)
84 (9.5) 82 (8.6) NS
122 (10.2) 123 (9.2) NS
73 (7.1) 75 (8.4) NS
SBP (mm Hg)
(p < 0.01) (p < 0.01)
116 (12.3) 118 (11.4)
(p < 0.05) (p < 0.05)
NS
NS = not significant. *Mean (SD) values before propranolol administration. ‘IMean (SD) values 2 hours after propranolol administration; p values refer to comparison with baseline values.
Histamine
challenge
Histamine challenge was performed by inhalation of his-
tamine in increasingconcentrations(0.03,0.06,0.125, 1.O, 2.0, 4.0. 8.0, and 16.0 mg/ml) until FEV, fell 20% from the preinhalation baseline. Histamine aerosols were generated by a nebulizer calibratedto deliver an output of 0.130 to 0.135 ml/mm at a flow rate of 8 L/min. Subjectsinhaled five inspiratory capacities of each concentration with a 5minute interval between successivedosage to prevent any cumulative effect of histamine.6 FEV, was measured immediately before challenge and 1 minute after the administration of each histamine dosage. PD, was obtained from the individual dose-responsecurves, and geometric mean values were calculated.
of either propranolol(40 mg) or placebo. At 2 hours, pulse rate, blood pressure,and FEV, were recorded. Immediately after these procedures, the histamine challenge was performed as previously described.
Statistical
analysis
Reproducibility of the values for PD, obtained on the first and secondtests after placebo treatment were examined by calculating the intraclasscorrelation coefficient. Mean values of pulse rate and SBP were compared with Student’s paired t test. The responsesof histamine challenges were compared with analysisof variance followed by Duncan’s multiple range test’ where significant differences were recorded. We accepted a p value of CO.05 as indicating a significant difference.
Study design Each subject performed four histamine challenges at about the same time of day on 4 separatedays. Subjectsin two challengeswere premeditated with placebo tablet (control) to assessreproducibility. Subjects in two challenges were premeditated with a 40 mg propranolol tablet administered 2 hours before the first challenge dose of histamine. This time interval was allowed so that the histamine challengecoincided with postulated peak pharmacologiceffect of propranolol.’ The order by which subjectstook propranolol or placebowas randomized. Subjects were unaware of the nature of the premeditating tablets. At least 3 days elapsed between successivechallenge studies. For each study, subjectswere asked to refrain from coffee, tea, and alcohol for a minimum of 12 hours. All treatment was withdrawn for 24 hours before testing. Two hours after a light breakfast, subjects rested in the 45” semirecumbent position, except when FEV, or the inhaling of histamine was recorded. Arterial blood pressurewas measured by the same investigator throughout the experiment using a mercury sphygmomanometer. Radial pulse rate was taken by palpation. Pulse rate and blood pressurewere recorded until they were steady, and then FEV, was recorded with a computerized spirometer (Compuspir, COSMED, Rome, Italy). The subjectsthen received a single oral dose
RESULTS Effect of propranolol
on pulse rate and SBP
There was no statistically significant difference either in initial pulse rate and SBP between days of propranolol administration (p > 0.05). The mean pulse rate was significantly reduced from 84 to 73 beats/min for the first test (p < 0.01) and from 82 to 75 for the second test (p < 0.01). The mean SBP was significantly reduced from 122 to 116 mm Hg for the first test (p < 0.05) and from 122 to 115 for the second test (p < 0.05). Variability of FEV, and reproducibility PC& values
of
There was no >lO% difference in the FEV, measured on the 4 study days in individual subjects. On the first and second control test, the response to inhaled histamine was reproducible, being within one doubling concentration.’ The correlation for repeated PD, determinations was 0.798 (p < 0.05), and the mean percentage difference between two control tests was 16 + 12%.
Responsiveness
VOLUME 82 NUMBER 4
to histamine
after
~ro~)l-~rl~lo~
TABLE II. individual starting values of FEV, and PD, for histamine challenges 1St control
2nd control
2nd propranolol -_I--
PDzo (mglml)
Starting FEV, (L)
PDa (m&ml)
Baseline FEV, (L)”
Starting FEV, (L)
PD, (mg/ml)
2 3 4 5
3.08 3.82 2.57 3.32 2.84
1.13 2.10 1.70 0.70 2.30
3.16 3.88 2.64 3.27 2.88
1.11 2.08 2.44 0.50 3.10
3.18 3.84 2.65 3.32 2.97
2.97 3.69 2.45 3.24 2.87
6 7 8 Mean
3.25 2.76 3.78 3.17
0.45 4.00 0.90 I .36t
3.32 2.73 3.88 3.22
0.78 3.10 1.10 I .48t
3.25 2.75 3.86 3.22
SD
(0.52)
3.08 2.64 3.75 3.08 (0.47)
I
*Measured t Geometric
(0.47)
_~_I_
1st propranolol
Starting FEV, (L)
Subject NO.
(0.4)
597
Baseiine (L)*
Starting FEV, (L)
0. 14 0.84 0.36 0.13 0.65
3.14 3.79 2.68 3.33 2.94
3.Oh 3 h4 2 .” 3 :.29 2.78
0.X 0.2i !!.78
0.35 I .45 0.22 0.37t
3.28 2.66 3.89 3.21
2.95 2.72 3.76 3.09
O,ltc 1.47 !).35 41.3?.+
(0.44)
(0.45:r ~-.---.
FEV,
PDm (mg/ml) 0.14 ij.21
before propranolol. mean.
Control and propranolol histamine challenge
premediceted
The mean starting FEV, for the first test of control challenge was 3.17 L; the geometric mean was 1.36 mg/ ml. The mean starting FEV, and mean PDzOfor the second test of control challenges were not significantly different from those of the first challenge (p > 0.05). For the first propranolol premeditated challenge, the mean initial FEV, fell from 3.22 + 0.44 1 (mean t SD) to 3.08 + 0.47 L. The geometric mean PD,, was 0.37 mgiml. A similar effect was obtained for the second propranolol premedicated challenge with mean FEV, falling from 3.21 t 0.44 L to 3.09 ? 0.45 L. The geometric mean was 0.32 mgiml. There was no significant difference between FEV, values obtained for all four challenges (F ratio = 0.2177; p > 0.05), but there was a significant difference among the PD,, values for the four challenges (F ratio = 5.74; p < 0.005). The Duncan’s multiple-range test indicated that PD1, values for the first and second challenge after propranolol administration were significantly lower than values after placebo administration (p < 0.01).
DISCUSSION This study demonstrates that propranolol, in a dose sufficient to produce B-adrenoceptor blockade” (which here produced a reduction in pulse rate and decrease in SBP), enhances the airway responsiveness to histamine in subjects with asthma in whom propranolol has little effect on baseline FEV,. There are at least two possible explanations for these observations.
There is some evidence in literature that histamine activates the sympathetic system. I’ Experimental studies demonstrated that histamine increases circulating epinephrine, an effect that is abolished by adrenalectomy.” This suggests that administration of histamine is usually accompanied by significant airway dilator (beta) and constrictor (alpha) stimuli that are almost balanced. I3 Propranolol, blocking airway B-adrenoceptors, may therefore enhance the bronchoconstrictive effect of histamine, even in the absence of causing bronchoconstriction per se. Propranolol may have produced minimal airway narrowing not detected by FEV, but sufhcient to enhance histamine responsiveness. Airflow resistance is proportional to the fourth power of airway radius (Poiseuille’s law). If resistance is plotted against reciprocal of radius, the curve is first nearly Rat and then increases exponentially. If the administration of propranolol moves the patient’s airway caliber to the right of the curve, a minimal increase in airttow resistance would occur, but subsequent increase in airflow resistance with the administration of histamine would be enhanced.” Another way in which diminished airway caliber might inlluence bronchial responsiveness is by altering the site of deposition of histamine inhaled in the lung. Is. ” By alteration of the mode of administration of the aerosol, histamine can be preferentially deposited in the central rather than peripheral airways” and then appears to be more effective in reducing FEV, . ‘*. ” This could be because irritant receptors are more numerous centrally’O or because FEV, may be more sensitive to changes in central than in peripheral airways.”
598
Carpentiere
et al.
However, our study, demonstrating that propranolol may enhance the bronchoconstrictor response to histamine without causing bronchoconstriction per se, suggests that we should be more concerned than we have been about the use of P-adrenoceptor-blocking drugs in subjects with asthma. REFERENCES I. McNeil1 RS. Effect of a B-adrenergic blocking agent, propranolol, on asthmatics. Lancet 1964;2:1101. 2. Benson MK, Berrill WT, Sterling GM, Decalmer PB, Chatteriee SS, Croxson RS, Cruickshank JM. Cardioselective and noncardioselective beta blockers in reversible obstructive airways disease. Postgrad Med J 1977;53(suppl 3):143. 3. Cauld DR, Pain MCF, Rubinfield AR. Beta-blocking drugs and airway obstruction. Med J Aust 1979;11:88. 4. Maconochie JG, Woodings EP, Richards DA. Effects of labetalol and propranolol on histamine-induced bronchoconstriction in normal subjects. Br J Clin Pharmacol 1977;4:157. 5. Orehek J, Gayrard P, Gtimaud CH, Charpin J. Effect of beta adrenergic blockade on bronchial sensitivity to inhaled acetylcholine in normal subjects. J ALLERGY CLIN IMMUNOL 1975;55:164. 6. Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargreave FE. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 1978;33:705. 7. Chester EH, Schwartz HJ, Fleming GM. Adverse effect of propranolol on airway function in nonasthmatic chronic obstmctive lung disease. Chest 1981;79:540. 8. Duncan DB. Multiple range, multiple F-test. Biometrics 1952;ll:l. 9. Cockcroft DW, Berscheid BA, Murdock KY. Measurement of
J. ALLERGY CLIN. IMMUNOL. OCTOBER 1988
10. 1I. 12. 13. 14. 15. 16.
17. 18. 19. 20. 21.
responsiveness to inhaled histamine using FEV,: comparison of PCZOand threshold. Thorax 1983;38:523. Coltart DJ, Shand DG. Plasma propranolol levels in the quantitative assessmentof B-adrenergic blockade in man. Br Med J 1970;111:731. Seidler A, Garrard CS, McAlpine L, Gordon D. Autonomic nervous system responses to inhaled histamine in normal subjects and asthmatics. Am Rev Respir Dis 1987;4:A478. Piper PJ, Collier HOJ, Vane JR. Release of catecholamines in the guinea pig by substance involved in anaphylaxis. Nature 1967;213:838. Drazen JM. Adrenergic intluences on histamine-mediated bronchoconstriction in the guinea pig. J Appl Physiol 1978; 44:340. Benson MK. Bronchial hyperreactivity. Br J Dis Chest 1975;69:227. McFadden ER, Lyons HA. Airway resistance and uneven ventilation in bronchial asthma. J Appl Physiol 1968;25:365. Wanner A, Brodnan JM, Perez J, Henke KG, Kim CS. Variability of airway responsiveness to histamine aerosol in normal subjects: role of deposition. Am Rev Respir Dis 1985;131:3. Dolovich MB, Ryan G, Newhouse MT. Aerosol penetration into the lung. Chest 1981;8O(suppl):834. Ruffin RE, Dolovich MB, Wolff RK, Newhouse MT. The effects of preferential deposition of histamine in the human airway. Am Rev Respir Dis 1978;117:485. Widdicombe JG. Pulmonary and respiratory tract receptors. J Exp Biol 1982;100:41. Newhouse MT, Ruffin MB. Deposition and fate of aerosolized drugs. Chest 1978;735:936. Ankin MG, Peterman VI, Fish JE. Effects of lung inflation on maximum flow responses to methacholine and antigen in hay fever and asthma subjects. Am Rev Respir Dis 1979;119(suppl 2):55.
Carpentiere, MD, Francesco Marino, MD Palermo, Italy
Castello,
after
MD, and
Eight nonsmoking subjects with asthma, nonresponsive to the bronchoconstrictive effect of oral propranolol, were studied. The airway response to increasing concentrations of histamine aerosol was assessed by measuring FEV,. The threshold provocative dose of histamine needed to cause a 20% fall in starting FEV, (PD,,) was measured by log dose-response curve. Histamine challenge was performed in duplicate after premeditation with placebo or 40 mg of propranolol on separate days. The mean starting FEV, did not change significantly after placebo and after propranolol administration. The mean PD,, values after propranolol(O.37 mglml and 0.32 mglml, respectively, for the first and the second challenge) were signl$cantly lower (p < 0.01) than mean control PD,, values (I .36 mglml and 1.48 mglml, respectively, for the first and the second challenge). These results indicate that propranolol increases airway responsiveness to histamine, even in those subjects with asthma in whom propranolol has little bronchoconstrictive @ect. (.I ALLERGY CLIN IMMLJNOL 1988;82:595-8.)
Beta-adrenoceptor-blocking drugs are known to carry the risk of inducing bronchoconstriction in subjects with asthma.lm3 In addition to the initial bronchoconstriction, these drugs have been found to enhance responsiveness of the airways to other bronchoconstrictive agents, such as histamine and acetylcholine.“. ’ _ However, it is not well-known whether, in the absence of a significant bronchoconstrictive effect, padrenoceptor-blocking drugs can equally potentiate the nonspecific airway responsiveness in subjects with asthma. This is an important clinical problem because until now we have tried to assessthe risk of using padrenoceptor-blocking drugs in subjects with asthma on the basis of bronchoconstriction induced by test doses. If no bronchoconstriction was observed, we believed we could begin regular therapy with this drug under careful observation.
the Medical Clinical Institute of University of Palermo, Palermo, Italy. Received for publication Sept. 16, 1987. Accepted for publication April 2, 1988. Reprint requests: G. Carpentiere, MD, Medical Clinic Institute, University of Palenno, Piazza delle Cliniche 2, 90127 Palenno, Italy. Fmm
Abbreviations used PD,,: Provocative dose of histamine causing a 20%
drop in FEV, SBP:,~ Systolic blood pressure
This study was therefore designed to investigate whether propranolol, a nonselective P-adrenoceptorblocking drug, enhances airway responsiveness to histamine in subjects with asthma nonresponsive to the bronchoconstrictive effect of propranolol. METHODS Subjects Eight nonsmoking subjectswith asthma (five male subjects) of mean age 25.7 years (range 21 to 32 years) were selected on the basis of a reduction of FEV, <15% from the pretreatment value after oral dose of 40 mg of propran0101.All subjects had mild atopic asthma, as defined by American Thoracic Societycriteria. At the time of the study, all subjects were in stable condition, requiring only occasional inhalation of P-adrenergic agents. None was receiving oral corticosteroids and cromoglycate treatments. None had suffered an exacerbation of wheeze or a respiratory infection in the preceeding 3 months. All subjectsgave their informed consent.
J.ALLERGYCLIN.IMMUNOL. OCTOBER 1988
595 Carpentiere et al.
TABLE
I. Effect of propranolol
on pulse
rate and SBP in eight
subjects
Comparison between two tests
asthma
After propranololt
Baselink*
1st test 2nd test
with
Pulse rate (beatslmin)
SBP (mm Hg)
Pulse rate (beats/min)
84 (9.5) 82 (8.6) NS
122 (10.2) 123 (9.2) NS
73 (7.1) 75 (8.4) NS
SBP (mm Hg)
(p < 0.01) (p < 0.01)
116 (12.3) 118 (11.4)
(p < 0.05) (p < 0.05)
NS
NS = not significant. *Mean (SD) values before propranolol administration. ‘IMean (SD) values 2 hours after propranolol administration; p values refer to comparison with baseline values.
Histamine
challenge
Histamine challenge was performed by inhalation of his-
tamine in increasingconcentrations(0.03,0.06,0.125, 1.O, 2.0, 4.0. 8.0, and 16.0 mg/ml) until FEV, fell 20% from the preinhalation baseline. Histamine aerosols were generated by a nebulizer calibratedto deliver an output of 0.130 to 0.135 ml/mm at a flow rate of 8 L/min. Subjectsinhaled five inspiratory capacities of each concentration with a 5minute interval between successivedosage to prevent any cumulative effect of histamine.6 FEV, was measured immediately before challenge and 1 minute after the administration of each histamine dosage. PD, was obtained from the individual dose-responsecurves, and geometric mean values were calculated.
of either propranolol(40 mg) or placebo. At 2 hours, pulse rate, blood pressure,and FEV, were recorded. Immediately after these procedures, the histamine challenge was performed as previously described.
Statistical
analysis
Reproducibility of the values for PD, obtained on the first and secondtests after placebo treatment were examined by calculating the intraclasscorrelation coefficient. Mean values of pulse rate and SBP were compared with Student’s paired t test. The responsesof histamine challenges were compared with analysisof variance followed by Duncan’s multiple range test’ where significant differences were recorded. We accepted a p value of CO.05 as indicating a significant difference.
Study design Each subject performed four histamine challenges at about the same time of day on 4 separatedays. Subjectsin two challengeswere premeditated with placebo tablet (control) to assessreproducibility. Subjects in two challenges were premeditated with a 40 mg propranolol tablet administered 2 hours before the first challenge dose of histamine. This time interval was allowed so that the histamine challengecoincided with postulated peak pharmacologiceffect of propranolol.’ The order by which subjectstook propranolol or placebowas randomized. Subjects were unaware of the nature of the premeditating tablets. At least 3 days elapsed between successivechallenge studies. For each study, subjectswere asked to refrain from coffee, tea, and alcohol for a minimum of 12 hours. All treatment was withdrawn for 24 hours before testing. Two hours after a light breakfast, subjects rested in the 45” semirecumbent position, except when FEV, or the inhaling of histamine was recorded. Arterial blood pressurewas measured by the same investigator throughout the experiment using a mercury sphygmomanometer. Radial pulse rate was taken by palpation. Pulse rate and blood pressurewere recorded until they were steady, and then FEV, was recorded with a computerized spirometer (Compuspir, COSMED, Rome, Italy). The subjectsthen received a single oral dose
RESULTS Effect of propranolol
on pulse rate and SBP
There was no statistically significant difference either in initial pulse rate and SBP between days of propranolol administration (p > 0.05). The mean pulse rate was significantly reduced from 84 to 73 beats/min for the first test (p < 0.01) and from 82 to 75 for the second test (p < 0.01). The mean SBP was significantly reduced from 122 to 116 mm Hg for the first test (p < 0.05) and from 122 to 115 for the second test (p < 0.05). Variability of FEV, and reproducibility PC& values
of
There was no >lO% difference in the FEV, measured on the 4 study days in individual subjects. On the first and second control test, the response to inhaled histamine was reproducible, being within one doubling concentration.’ The correlation for repeated PD, determinations was 0.798 (p < 0.05), and the mean percentage difference between two control tests was 16 + 12%.
Responsiveness
VOLUME 82 NUMBER 4
to histamine
after
~ro~)l-~rl~lo~
TABLE II. individual starting values of FEV, and PD, for histamine challenges 1St control
2nd control
2nd propranolol -_I--
PDzo (mglml)
Starting FEV, (L)
PDa (m&ml)
Baseline FEV, (L)”
Starting FEV, (L)
PD, (mg/ml)
2 3 4 5
3.08 3.82 2.57 3.32 2.84
1.13 2.10 1.70 0.70 2.30
3.16 3.88 2.64 3.27 2.88
1.11 2.08 2.44 0.50 3.10
3.18 3.84 2.65 3.32 2.97
2.97 3.69 2.45 3.24 2.87
6 7 8 Mean
3.25 2.76 3.78 3.17
0.45 4.00 0.90 I .36t
3.32 2.73 3.88 3.22
0.78 3.10 1.10 I .48t
3.25 2.75 3.86 3.22
SD
(0.52)
3.08 2.64 3.75 3.08 (0.47)
I
*Measured t Geometric
(0.47)
_~_I_
1st propranolol
Starting FEV, (L)
Subject NO.
(0.4)
597
Baseiine (L)*
Starting FEV, (L)
0. 14 0.84 0.36 0.13 0.65
3.14 3.79 2.68 3.33 2.94
3.Oh 3 h4 2 .” 3 :.29 2.78
0.X 0.2i !!.78
0.35 I .45 0.22 0.37t
3.28 2.66 3.89 3.21
2.95 2.72 3.76 3.09
O,ltc 1.47 !).35 41.3?.+
(0.44)
(0.45:r ~-.---.
FEV,
PDm (mg/ml) 0.14 ij.21
before propranolol. mean.
Control and propranolol histamine challenge
premediceted
The mean starting FEV, for the first test of control challenge was 3.17 L; the geometric mean was 1.36 mg/ ml. The mean starting FEV, and mean PDzOfor the second test of control challenges were not significantly different from those of the first challenge (p > 0.05). For the first propranolol premeditated challenge, the mean initial FEV, fell from 3.22 + 0.44 1 (mean t SD) to 3.08 + 0.47 L. The geometric mean PD,, was 0.37 mgiml. A similar effect was obtained for the second propranolol premedicated challenge with mean FEV, falling from 3.21 t 0.44 L to 3.09 ? 0.45 L. The geometric mean was 0.32 mgiml. There was no significant difference between FEV, values obtained for all four challenges (F ratio = 0.2177; p > 0.05), but there was a significant difference among the PD,, values for the four challenges (F ratio = 5.74; p < 0.005). The Duncan’s multiple-range test indicated that PD1, values for the first and second challenge after propranolol administration were significantly lower than values after placebo administration (p < 0.01).
DISCUSSION This study demonstrates that propranolol, in a dose sufficient to produce B-adrenoceptor blockade” (which here produced a reduction in pulse rate and decrease in SBP), enhances the airway responsiveness to histamine in subjects with asthma in whom propranolol has little effect on baseline FEV,. There are at least two possible explanations for these observations.
There is some evidence in literature that histamine activates the sympathetic system. I’ Experimental studies demonstrated that histamine increases circulating epinephrine, an effect that is abolished by adrenalectomy.” This suggests that administration of histamine is usually accompanied by significant airway dilator (beta) and constrictor (alpha) stimuli that are almost balanced. I3 Propranolol, blocking airway B-adrenoceptors, may therefore enhance the bronchoconstrictive effect of histamine, even in the absence of causing bronchoconstriction per se. Propranolol may have produced minimal airway narrowing not detected by FEV, but sufhcient to enhance histamine responsiveness. Airflow resistance is proportional to the fourth power of airway radius (Poiseuille’s law). If resistance is plotted against reciprocal of radius, the curve is first nearly Rat and then increases exponentially. If the administration of propranolol moves the patient’s airway caliber to the right of the curve, a minimal increase in airttow resistance would occur, but subsequent increase in airflow resistance with the administration of histamine would be enhanced.” Another way in which diminished airway caliber might inlluence bronchial responsiveness is by altering the site of deposition of histamine inhaled in the lung. Is. ” By alteration of the mode of administration of the aerosol, histamine can be preferentially deposited in the central rather than peripheral airways” and then appears to be more effective in reducing FEV, . ‘*. ” This could be because irritant receptors are more numerous centrally’O or because FEV, may be more sensitive to changes in central than in peripheral airways.”
598
Carpentiere
et al.
However, our study, demonstrating that propranolol may enhance the bronchoconstrictor response to histamine without causing bronchoconstriction per se, suggests that we should be more concerned than we have been about the use of P-adrenoceptor-blocking drugs in subjects with asthma. REFERENCES I. McNeil1 RS. Effect of a B-adrenergic blocking agent, propranolol, on asthmatics. Lancet 1964;2:1101. 2. Benson MK, Berrill WT, Sterling GM, Decalmer PB, Chatteriee SS, Croxson RS, Cruickshank JM. Cardioselective and noncardioselective beta blockers in reversible obstructive airways disease. Postgrad Med J 1977;53(suppl 3):143. 3. Cauld DR, Pain MCF, Rubinfield AR. Beta-blocking drugs and airway obstruction. Med J Aust 1979;11:88. 4. Maconochie JG, Woodings EP, Richards DA. Effects of labetalol and propranolol on histamine-induced bronchoconstriction in normal subjects. Br J Clin Pharmacol 1977;4:157. 5. Orehek J, Gayrard P, Gtimaud CH, Charpin J. Effect of beta adrenergic blockade on bronchial sensitivity to inhaled acetylcholine in normal subjects. J ALLERGY CLIN IMMUNOL 1975;55:164. 6. Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargreave FE. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 1978;33:705. 7. Chester EH, Schwartz HJ, Fleming GM. Adverse effect of propranolol on airway function in nonasthmatic chronic obstmctive lung disease. Chest 1981;79:540. 8. Duncan DB. Multiple range, multiple F-test. Biometrics 1952;ll:l. 9. Cockcroft DW, Berscheid BA, Murdock KY. Measurement of
J. ALLERGY CLIN. IMMUNOL. OCTOBER 1988
10. 1I. 12. 13. 14. 15. 16.
17. 18. 19. 20. 21.
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