Br. J. clin. Pharmac.
(1975), 2
LETTERS TO THE EDITORS
539
EFFECTS OF PHENTOLAMINE INHALATION ON PATIENTS WITH BRONCHIAL ASTHMA Considerable controversy surrounds the presence of ax-adrenoceptors in the bronchial musculature. Several studies on experimental animals and man have shown that a-adrenoceptors are likely to occur in the airway smooth muscles, stimulation of which produces constriction (Fleish, Maling & Brodie, 1970; Simonsson, Snedmyr, Skough, Anderson & Gergh, 1973; Anthracite, Vachon & Knapp, 1971; and Mathe, Astrom & Persson, 1971). However, other investigators have failed to demonstrate any at-adrenergic effects (Cabezas, Graf & Nadel, 1971; Stone, Sarkar & Heltz, 1973). The discrepancy may be attributed in part to differences in species, drug dosage, route of administration, physiological states of bronchial muscles, and the technique used. A functional imbalance of the (x- and ,B-adrenoceptoritesponses has been suggested as one of the fundamental abnormalities in asthma. Also, in asthmatics, there is hypersensitive a-adrenoceptors (Szentivamzi, 1968). The use of a-adrenoceptors blocking agents in asthma was suggested (Gould & Dilieto, 1970; and Griffin, Kamburoff & Prime, 1972). In this study we investigated and compared the effects of phentolamine, an ca-adrenoceptor blockade, isoprenaline, a ,B-adrenoceptor stimulant, and placebo administered by inhalation in six asthmatic patients. Six asthmatic outpatients (four women and two
men) suffering from reversible obstructive airways disease for 2-15 years were investigated. The mean age was 43.7 (range 29-59 years), height 168 cm (range 160-188 cm), and weight 58.9 kg (range 52.7-65.8 kg). At the time of investigation all had stable ventilatory functions. Bronchodilator drugs were discontinued for 12 h before the experiment. The nature of the experiment was explained to them and all gave their consent. On the first day of the study, after resting for 20 min, the blood pressure was taken and an ECG was made. Heart rate was read from ECG. Forced spirometric measurements using a dry wedge spirometry included expiratory volume in one second (FEV1) and forced midexpiratory flow (FEF2s-75% (the best of three attempts). Two sets of control values 15 mn apart were obtained. A placebo of 1 ml sterile water was nebulized with air at 6 litres/min from a Bennett twinjet nebulizer. Values for all the parameters were then measured at 5, 15, 20 and 60 minutes. When FEV1 had returned to the preinhalation control level ± 10%, isoprenaline hydrochloride (2.5 mg in 1 ml sterile water) was inhaled and its effect was studied for 60 minutes. On the second day the experiment was repeated with phentolamine mesylate, first with 1 mg then with a 10 mg dose. On the third day phentolamine (10 mg) plus isoprenaline (2.5 mg) was given. Each test drug was diluted to 1 ml total volume with
Table 1 Effects of phentolamine, isoprenaline and placebo administered by inhalation on six patients with bronchial asthma (mean ± s.e. mean) % change in FEy1 and FEF2s-7S% Treatment
15min
5 min Placebo (1 ml water) Phentolamine (1 mg) Phentolamine (1 0 mg) Isoprenal ine (2.5 mg)
FEVI
Isoprenaline (2.5 mg)
FEV1
FEF2s57s%
-5.3 ± 2.6 -11.7 ± 5.0
FEV1 FEF2s-7s% FEV1
-2.5± 2.6 9.6 ± 6.6 -9.1 ±3.7 FEF25s7s% - 21.0 ± 6.6 + 26.8 ±4.3* FEVI FEF2s-7s% + 92.0 ± 17.4*
-5.3+2.7 11.4 ± 5.5 -0.91 .6 - 0.6 ± 3.8 - 5.8 ± 3.9 12.0+7.8 + 21.3 ± 4.3* + 73.0 ± 18.2* + 28.1 ±5.9*
-
-
-
+ 30.0 ± 6.3*
-
-
30 min
60 min
3.8 ±1.4 7.0 ± 2.8
-0.3+1.3 -3.1 +3.3 -2.5+1.8 -1.9+3.7
0.3 ± 1.4 1.9 ± 3.7
5.5 ± 4.7 -10.4 ±9.0 +13.0±1.9* -
-2.5+4.0 2.3 ± 7.3 +7.6±3.3 -
35.6 ± 6.3*
+ 25.1 ±10.2
+21.0±4.1*
+ 14.0 ±3.3*
+ 87.3
+
+
plus
phentolamine (10mg) FEF25 75% *P < 0.05.
+
144.0 ±48.1 *
+
125.0 ± 36.1 *
±
24.4*
54.0 ± 16.6*
540
Br. J. clin. Pharmac. (1 975), 2
LETTERS TO THE EDITORS
sterile water. Data were analyzed statistically using the Student's t-test. Values for P below 0.05 were considered significant. The mean pretreatment FEV1 and FEF15-75% in the six patients (mean ± s.e. mean) were 2.187 ±0.171 litres (67.5 ± 6.8% of predicted normal value) and 1.277 ± 0.192 litres/s (36.7 ± 6.1 % of predicted normal value) respectively. The effects of placebo, isoprenaline, and phentolamine alone or in combination are summarized in Table 1. Placebo and phentolamine (1 mg or 10 mg) produced no significant change (P> 0.05) while isoprenaline produced a significant increase (P< 0.01) in both FEV1 and FEF2575%0..When combined with isoprenaline, phentolamine potentialed its bronchodilator action in both magnitude and duration. The synergistic effect of phentolamine and isoprenaline could be due to ax-adrenoceptor blockage by phentolamine making the isoprenaline effect on ,B-adrenoceptors unopposed. Our results are in agreement with those of Mathe et al. (1971) who reported that human bronchial muscle possesses a sparce population of ca-adrenoceptors. Logsdon, Carnight, Middleton & Coffey (1973) found that phentolamine alone evoked a minimal increase in cyclic AMP, but acted synergistically with isoprenaline to produce marked increase in cyclic AMP in leucocytes of normal and asthmatic children. Orange, Kaliner, Laraia & Austen (1971) also reported synergism between a ,-adrenoceptor agonist and an a-adrenoceptor blockade in producing an increase cyclic AMP in human lungs. Anthracite et al. (1971) and Gould & Dilieto (1970) found that phentolamine administered by aerosol produced bronchodilation in normal subjects and in patients with chronic pulmonary emphysema. Our study did not confirm these
findings. The increase in heart rate after phentolamine (10 mg) was in close agreement with earlier reports (Das & Parratt, 1971). In light of our results, it is clear that the role of the oz-adrenoceptor is limited and that a-adrenoceptor blocking agents alone cannot be used in bronchoconstrictive disorders; however, beneficial bronchodilator effects may be obtained when phentolamine is combined with ,B-adrenoceptor stimulant. This work was supported in part by USPHS grant HL 05396. The authors also acknowledge the support of Ciba-Geigy. Reprint requests should be addressed to W.F.M.
AIDA GEUMEI, J.R. MILLER & W.F. MILLER Department of Internal Medicine, Southwestern Medical School, University of Texas Health Science Centre and Pulmonary Division Methodist Hospitals of Dallas, Dallas, Texas, US.A. Received April 18,1975
References ANTHRACITE, R.F., VACHON, L. & KNAPP, P.H.
(1971). Alpha-adrenergic receptors in human lung. PsychosomaticMed., 33,481489. CABEZAS, G.A., GRAF, P.D. & NADEL, J.A. (1971). Sympathetic versus parasympathetic nervous regula-
tion of airways in dogs.. J. appl. Physiol., 31, 651-655. DAS, P.K. & PARRATT, J.R. (1971). Myocardial and haemodynamic effects of phentolamine. Br. J. Pharmac., 41, 437444. FLEISCH, J.H., MALING, H.M. & BRODIE, B.B. (1970). Evidence for existence of alpha-adrenergic receptors in the mammalian trachea. Am. J. Physiol., 218, 596-599. GOULD, L. & DILIETO, M. (1970). Phentolamine, New bronchodilator. N. Y. State J. Med., 70, 2332-2337. GRIFFIN, J.P., KAMBUROFF, P.L. & PRIME, F.J.
(1972). Thymoxamine and airways obstruction. Lancet, i, 1288. LOGSDON, P.J., CARNIGHT, D.V., MIDDLETON, E. Jr. & COFFEY, R.G. (1973). The effect of phentolamine on adenylate cyclase and on isoproterenol stimulation
in leukocytes from asthmatic and non-asthmatic subjects. J. Allergy clin. Immunol., 52, 148-157. MATHE, A.A., ASTROM, A. & PERSSON, N.A. (1971). Some broncho-constricting and bronchodilating responses of human isolated bronchi: evidence for the existence of a-adrenoceptors. J. Pharm. Pharmac., 23, 905-910. ORANGE, R.P., KALINER, M.A., LARAIA, P.J. &
AUSTEN, K.F. (1971).Immunologic release of histamine and slow reacting substance of anaphylaxis from human lung. Influenoe of cellular levels of cyclic AMP. Fed. Proc., 30, 1725-1729. SIMONSSON, B.G., SVEDMYR, N., SKOUGH, B.E., ANDERSON, R. & BERGH, N.P. (1973). In vivo and in vitro studies on alpha-receptors in human airways; potentiation with bacterial endotoxins. Chem, 63, 35. STONE, D.J., SARKAR, T.K. & HELTZ, H. (1973). Effect of adrenergic stimulation and inhalation in human airways. J. appl. Physiol., 34, 624-627. SZENTIVAMZI, A. (1968). The beta adrenergic theory of the atopic abnormality in bronchial asthma. J. Allergy,
42, 203-232.
(1975), 2
LETTERS TO THE EDITORS
539
EFFECTS OF PHENTOLAMINE INHALATION ON PATIENTS WITH BRONCHIAL ASTHMA Considerable controversy surrounds the presence of ax-adrenoceptors in the bronchial musculature. Several studies on experimental animals and man have shown that a-adrenoceptors are likely to occur in the airway smooth muscles, stimulation of which produces constriction (Fleish, Maling & Brodie, 1970; Simonsson, Snedmyr, Skough, Anderson & Gergh, 1973; Anthracite, Vachon & Knapp, 1971; and Mathe, Astrom & Persson, 1971). However, other investigators have failed to demonstrate any at-adrenergic effects (Cabezas, Graf & Nadel, 1971; Stone, Sarkar & Heltz, 1973). The discrepancy may be attributed in part to differences in species, drug dosage, route of administration, physiological states of bronchial muscles, and the technique used. A functional imbalance of the (x- and ,B-adrenoceptoritesponses has been suggested as one of the fundamental abnormalities in asthma. Also, in asthmatics, there is hypersensitive a-adrenoceptors (Szentivamzi, 1968). The use of a-adrenoceptors blocking agents in asthma was suggested (Gould & Dilieto, 1970; and Griffin, Kamburoff & Prime, 1972). In this study we investigated and compared the effects of phentolamine, an ca-adrenoceptor blockade, isoprenaline, a ,B-adrenoceptor stimulant, and placebo administered by inhalation in six asthmatic patients. Six asthmatic outpatients (four women and two
men) suffering from reversible obstructive airways disease for 2-15 years were investigated. The mean age was 43.7 (range 29-59 years), height 168 cm (range 160-188 cm), and weight 58.9 kg (range 52.7-65.8 kg). At the time of investigation all had stable ventilatory functions. Bronchodilator drugs were discontinued for 12 h before the experiment. The nature of the experiment was explained to them and all gave their consent. On the first day of the study, after resting for 20 min, the blood pressure was taken and an ECG was made. Heart rate was read from ECG. Forced spirometric measurements using a dry wedge spirometry included expiratory volume in one second (FEV1) and forced midexpiratory flow (FEF2s-75% (the best of three attempts). Two sets of control values 15 mn apart were obtained. A placebo of 1 ml sterile water was nebulized with air at 6 litres/min from a Bennett twinjet nebulizer. Values for all the parameters were then measured at 5, 15, 20 and 60 minutes. When FEV1 had returned to the preinhalation control level ± 10%, isoprenaline hydrochloride (2.5 mg in 1 ml sterile water) was inhaled and its effect was studied for 60 minutes. On the second day the experiment was repeated with phentolamine mesylate, first with 1 mg then with a 10 mg dose. On the third day phentolamine (10 mg) plus isoprenaline (2.5 mg) was given. Each test drug was diluted to 1 ml total volume with
Table 1 Effects of phentolamine, isoprenaline and placebo administered by inhalation on six patients with bronchial asthma (mean ± s.e. mean) % change in FEy1 and FEF2s-7S% Treatment
15min
5 min Placebo (1 ml water) Phentolamine (1 mg) Phentolamine (1 0 mg) Isoprenal ine (2.5 mg)
FEVI
Isoprenaline (2.5 mg)
FEV1
FEF2s57s%
-5.3 ± 2.6 -11.7 ± 5.0
FEV1 FEF2s-7s% FEV1
-2.5± 2.6 9.6 ± 6.6 -9.1 ±3.7 FEF25s7s% - 21.0 ± 6.6 + 26.8 ±4.3* FEVI FEF2s-7s% + 92.0 ± 17.4*
-5.3+2.7 11.4 ± 5.5 -0.91 .6 - 0.6 ± 3.8 - 5.8 ± 3.9 12.0+7.8 + 21.3 ± 4.3* + 73.0 ± 18.2* + 28.1 ±5.9*
-
-
-
+ 30.0 ± 6.3*
-
-
30 min
60 min
3.8 ±1.4 7.0 ± 2.8
-0.3+1.3 -3.1 +3.3 -2.5+1.8 -1.9+3.7
0.3 ± 1.4 1.9 ± 3.7
5.5 ± 4.7 -10.4 ±9.0 +13.0±1.9* -
-2.5+4.0 2.3 ± 7.3 +7.6±3.3 -
35.6 ± 6.3*
+ 25.1 ±10.2
+21.0±4.1*
+ 14.0 ±3.3*
+ 87.3
+
+
plus
phentolamine (10mg) FEF25 75% *P < 0.05.
+
144.0 ±48.1 *
+
125.0 ± 36.1 *
±
24.4*
54.0 ± 16.6*
540
Br. J. clin. Pharmac. (1 975), 2
LETTERS TO THE EDITORS
sterile water. Data were analyzed statistically using the Student's t-test. Values for P below 0.05 were considered significant. The mean pretreatment FEV1 and FEF15-75% in the six patients (mean ± s.e. mean) were 2.187 ±0.171 litres (67.5 ± 6.8% of predicted normal value) and 1.277 ± 0.192 litres/s (36.7 ± 6.1 % of predicted normal value) respectively. The effects of placebo, isoprenaline, and phentolamine alone or in combination are summarized in Table 1. Placebo and phentolamine (1 mg or 10 mg) produced no significant change (P> 0.05) while isoprenaline produced a significant increase (P< 0.01) in both FEV1 and FEF2575%0..When combined with isoprenaline, phentolamine potentialed its bronchodilator action in both magnitude and duration. The synergistic effect of phentolamine and isoprenaline could be due to ax-adrenoceptor blockage by phentolamine making the isoprenaline effect on ,B-adrenoceptors unopposed. Our results are in agreement with those of Mathe et al. (1971) who reported that human bronchial muscle possesses a sparce population of ca-adrenoceptors. Logsdon, Carnight, Middleton & Coffey (1973) found that phentolamine alone evoked a minimal increase in cyclic AMP, but acted synergistically with isoprenaline to produce marked increase in cyclic AMP in leucocytes of normal and asthmatic children. Orange, Kaliner, Laraia & Austen (1971) also reported synergism between a ,-adrenoceptor agonist and an a-adrenoceptor blockade in producing an increase cyclic AMP in human lungs. Anthracite et al. (1971) and Gould & Dilieto (1970) found that phentolamine administered by aerosol produced bronchodilation in normal subjects and in patients with chronic pulmonary emphysema. Our study did not confirm these
findings. The increase in heart rate after phentolamine (10 mg) was in close agreement with earlier reports (Das & Parratt, 1971). In light of our results, it is clear that the role of the oz-adrenoceptor is limited and that a-adrenoceptor blocking agents alone cannot be used in bronchoconstrictive disorders; however, beneficial bronchodilator effects may be obtained when phentolamine is combined with ,B-adrenoceptor stimulant. This work was supported in part by USPHS grant HL 05396. The authors also acknowledge the support of Ciba-Geigy. Reprint requests should be addressed to W.F.M.
AIDA GEUMEI, J.R. MILLER & W.F. MILLER Department of Internal Medicine, Southwestern Medical School, University of Texas Health Science Centre and Pulmonary Division Methodist Hospitals of Dallas, Dallas, Texas, US.A. Received April 18,1975
References ANTHRACITE, R.F., VACHON, L. & KNAPP, P.H.
(1971). Alpha-adrenergic receptors in human lung. PsychosomaticMed., 33,481489. CABEZAS, G.A., GRAF, P.D. & NADEL, J.A. (1971). Sympathetic versus parasympathetic nervous regula-
tion of airways in dogs.. J. appl. Physiol., 31, 651-655. DAS, P.K. & PARRATT, J.R. (1971). Myocardial and haemodynamic effects of phentolamine. Br. J. Pharmac., 41, 437444. FLEISCH, J.H., MALING, H.M. & BRODIE, B.B. (1970). Evidence for existence of alpha-adrenergic receptors in the mammalian trachea. Am. J. Physiol., 218, 596-599. GOULD, L. & DILIETO, M. (1970). Phentolamine, New bronchodilator. N. Y. State J. Med., 70, 2332-2337. GRIFFIN, J.P., KAMBUROFF, P.L. & PRIME, F.J.
(1972). Thymoxamine and airways obstruction. Lancet, i, 1288. LOGSDON, P.J., CARNIGHT, D.V., MIDDLETON, E. Jr. & COFFEY, R.G. (1973). The effect of phentolamine on adenylate cyclase and on isoproterenol stimulation
in leukocytes from asthmatic and non-asthmatic subjects. J. Allergy clin. Immunol., 52, 148-157. MATHE, A.A., ASTROM, A. & PERSSON, N.A. (1971). Some broncho-constricting and bronchodilating responses of human isolated bronchi: evidence for the existence of a-adrenoceptors. J. Pharm. Pharmac., 23, 905-910. ORANGE, R.P., KALINER, M.A., LARAIA, P.J. &
AUSTEN, K.F. (1971).Immunologic release of histamine and slow reacting substance of anaphylaxis from human lung. Influenoe of cellular levels of cyclic AMP. Fed. Proc., 30, 1725-1729. SIMONSSON, B.G., SVEDMYR, N., SKOUGH, B.E., ANDERSON, R. & BERGH, N.P. (1973). In vivo and in vitro studies on alpha-receptors in human airways; potentiation with bacterial endotoxins. Chem, 63, 35. STONE, D.J., SARKAR, T.K. & HELTZ, H. (1973). Effect of adrenergic stimulation and inhalation in human airways. J. appl. Physiol., 34, 624-627. SZENTIVAMZI, A. (1968). The beta adrenergic theory of the atopic abnormality in bronchial asthma. J. Allergy,
42, 203-232.
