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Cardiopulmonary effects of celiprolol and bisoprolol in serotonin-infused cats
European Journal of Pharmacology, 151 (1988) 337-340
337
Elsevier EJP 20161 Short communication
Cardiopulmonary effects of celiprolol and bisoprolol in serotonin-infused cats Gilbert W. Carnathan *, Dennis M. Sweeney, Robert G o r d o n i and T.P. Pruss Rarer Central Research, Department of Immunobiology, Horsham, PA 19044, U.S.A.
Received 3 May 1988, accepted 10 May 1988
The effects of celiprolol and bisoprolol on cardiopulmonary function in serotonin-infused cats were compared. Celiprolol reversed the bronchoconstrictive effect of serotonin at doses >t 1.0 mg/kg. Also, decreases in mean arterial pressure and heart rate were noted after administration of 3-10 and 10 mg/kg celiprolol, respectively. In contrast, bisoprolol tended to induce bronchoconstriction. Reductions in mean arterial pressure and heart rate were observed with 1 or 3 mg/kg. Bisoprolol administration at 10 mg/kg was lethal. The unique ability of celiprolol to induce bronchodilation enhances its therapeutic potential. Celiprolol; Bisoprolol; Bronchodilation
1. Introduction
fl-Adrenoceptor antagonists are frequently used in the management of hypertension and related cardiac diseases (Conolly et al., 1976). In clinical settings, a high degree of fl~-receptor selectivity is desirable, as antagonism of fl2-receptors can lead to bronchoconstriction and severe airway obstruction in asthmatics and patients with concurrent pulmonary disease (Doshan et al., 1986). Unfortunately, cardioselectivity is a dose-dependent phenomenon (Jackson and Beevers, 1983), thus caution is usually required when a selective fl~adrenoceptor antagonist is utilized. The present study assesses the effects of two selective fl~antagonists, celiprolol (for review see, Smith and Wolf, 1984) and bisoprolol (Schliep et al., 1986),
* To whom all correspondence should be addressed: Rarer Central Research, 800 Business Center Drive, Building 3, Horsham, PA 19044, U.S.A. 1 Current address: Sterling-Winthrop Research Institute, Rensselaer, NY 12144, U.S.A.
in a cat model in which pulmonary function is compromised by a serotonin infusion. Initial studies with celiprolol in this and similar models have shown that it does not adversely effect the bronchopulmonary system. In fact, celiprolol has been shown to block the bronchoconstrictive effects of methacholine, serotonin, prostaglandin F2a and histamine in animal studies (Smith and Wolf, 1984). The effect of bisoprolol in the present model has not been assessed previously, although the compound has been reported to possess a favorable cardiotropic/bronchotropic ratio in histamine-challenged guinea pigs (Schliep et al., 1986). The cat model used in the present study has been shown to be a reliable predictor of the clinical utility of bronchodilator agents such as clenbuterol and aminophylline (Reiche and Frey, 1983). In our laboratory, propranolol, metoprolol and timolol, among others agents, cause increased bronchoconstriction in this model (Smith and Wolf, 1984). Thus, the activity of bisoprolol and celiprolol in this model may be predictive of their effects in asthmatics.
0014-2999/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
338
2. Materials and methods
2.1. Serotonin-induced bronchoconstriction Male cats (3.0-4.0 kg) were anesthetized with p e n t o b a r b i t a l s o d i u m (35 m g / k g i.p.). T h e trachea of each cat was c a n n u l a t e d , a n d Fleisch No. 00 p n e u m o t a c h o g r a p h c o n n e c t e d to a S t a t h a m P M 1 5 E T C differential pressure transducer was placed in line to m o n i t o r air flow. A second t r a n s d u c e r (Statham PM5E), used for m e a s u r i n g t r a n s p u l m o n a r y pressure, was placed between the tracheal c a n n u l a a n d a c a n n u l a in the pleural cavity. Air flow a n d t r a n s p u l m o n a r y pressure signals were converted by a Buxco p u l m o n a r y mechanics c o m p u t e r system to values of airway resistance averaged over a 6 s interval. C a n n u l a s were inserted into both femoral veins (for i n f u s i o n of s e r o t o n i n a n d drug a d m i n i s t r a t i o n ) a n d a femoral artery (for m o n i t o r i n g heart rate and blood pressure). Each a n i m a l was paralyzed with 20 mg g a l l a m i n e triethiodide a n d mechanically ventilated. T o test for b r o n c h o d i l a t o r activity, it was necessary to increase the n o r m a l l y low b r o n c h o m o t o r tone of the cat. This was accomplished by a constant i.v. i n f u s i o n of serotonin (35 # g / k g per min) which produced a n a p p r o x i m a t e 3-fold increase in airway resistance. D u r i n g this steady state b r o n c h o c o n s t r i c t i o n , each a n i m a l received isoproterenol (5 # g / k g i.v,) in order to test for reactivity to a k n o w n b r o n c h o d i l a t o r . Celiprolol or bisopro1ol was then a d m i n i s t e r e d to each cat by i.v. bolus
injection in an a s c e n d i n g dose paradigm. T o allow the cat to return to its p r e d r u g baseline, at least 15 m i n elapsed between the a d m i n i s t r a t i o n of the sequential drug treatments. F o r c o m p a r a t i v e purposes, the effect of p r o p r a n o l o l (3.0 m g / k g i.v.) on b r o n c h o c o n s t r i c t i o n was also d e t e r m i n e d .
2.2. Statistics The degree of change in airway resistance in response to celiproiol a n d bisoprolol was expressed as a percent change from baseline s e r o t o n i n - i n d u c e d b r o n c h o c o n s t r i c t i o n . In addition, changes in heart rate (beats per min) a n d m e a n arterial pressure ( m m Hg) were recorded. All data were analyzed by a one-tail S t u d e n t ' s t-test.
2.3. Compounds Celiprolol HCI was provided by Rorer C e n t r a l Research. Bisoprolol h e m i f u m a r a t e was generously d o n a t e d by Dr. Kling (E. Merck, G e r m a n y ) . All other drugs were purchased from Sigma Chemical Co. (St. Louis, MO). All doses are expressed as the free base.
3. Results The effect of celiprolol a n d bisoprolol o n m e a n arterial pressure a n d heart rate in cats infused with serotonin is shown in table 1. Both corn-
TABLE 1 Effect of i.v. administered celiprolol and bisoprolol on changes in heart rate (HR) and mean arterial pressure (MAP) in serotonin-infused cats. Changes are expressed as a decrease from baseline values. Data represent means ( + S.E.) of five cats in each treatment. Dose
Celiprolol
Bisoprolol
(mg/kg i.v.)
HR a
MAP "
HR ~'
MAP "
Control 0.1 0.3 1.0 3.0 10.0
-1.8+2.0 -4.0-t-1.8 -3.3+0.5 -4.3+0.6 -8.8+ 1.1 -- 21.3 + 6.1 o
11.3+2.1 1.3+3.2 3.8+1.1 -2.5+2.2" -26.3-t-4.8 ~ -- 38.8 + 6.2 d
-4.0+ 2.7 -11.0-+ 3.3 -13.0-+ 1.1 ¢ -22.4+_10.0 ~ --67.0-t- 12.9 ~ (Lethal)
8.6_+ 1.7 -9.6-+ 2.6" -6.0-+ 2.2 ~ -22.4± 3.8d - 54.8+_10.7 d (Lethal)
Change (beats per min) relative to baseline (278.8 + 7.0) heart rate. , Change in pressure (mm Hg) relative to baseline (99.7 + 15.0) MAP. ~ P < 0.01; d p < 0.001. Student's one-tail t-test compared to the control (PEG-200) response.
339
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II
z
m
.-~
tl
..... t~ >-
•
.....
BISOPFIOLOL
4p ~ ' ~ ' ~
....
B....
0 CELIPROLOL
-till
~
~
0 PROPRANOLOL
p
-Ill -,4O
~
~
p
"~ I
0.t
0.$
t
. . . I.
'
....
t0
DOSE |ag/kQ t.v.1 Fig. 1. Effect of i.v. administered celiprolol, bisoprolol and propranoiol on changes in airway resistance in serotonin-infused cats. Data represent means ( + S.E.) of five cats at each point.
pounds significantly decreased mean arterial pressure in a dose-dependent manner. This effect was paralleled by a significant bradycardia in cats treated with bisoprolol. Animals treated with celiprolol did not exhibit bradycardia, except following administration of a high i.v. dose (10 mg/kg) of the compound. Shown in fig. 1 are the effects of cehprolol, bisoprolol and propranolol on airway resistance. Celiprolol treatment caused dose-dependent bronchodilation as evidenced by significant decreases in airway resistance. In contrast, bisopro1ol failed to induce a significant change in bronchomotor tone in serotonin-infused cats, although there was a trend towards bronchoconstriction. As expected, propranolol potentiated the bronchoconstriction response to serotonin in this model.
4. Discussion The cardiovascular effects of bisoprolol and celiprolol in the present study are consistent with their respective pharmacology (Smith and Wolf, 1984; Schliep et al., 1986). In the present study,
bisoprolol was shown to be more potent in reducing heart rate and blood pressure than celiprolol. In this regard, the present data confirm an earlier study in which the potency of bisoprolol was shown to be greater than that of celiproloi (Schliep and Harting, 1984). It is important to note that treatment with 10 m g / k g bisoprolol was lethal to all cats tested in the present study. The antihypertensive effects of cehprolol may be due in part to other mechanisms in addition to fl:antagonism, as at a dose of 3 mg/kg, celiproiol was able to significantly decrease mean arterial pressure while affecting only a minimal decrease in heart rate. This suggests a partial agonist profile, which has been noted in earlier studies (Smith and Wolf, 1984). Of more immediate interest are the contrasting effects of these compounds on pulmonary function. In this model, all other fl-blockers tested have been shown to potentiate serotonin-induced bronchoconstriction (Smith and Wolf, 1984). As shown in the present study, celiprolol treatment caused dose-dependent bronchodilation. In contrast, bisoprolol failed to significantly effect bronchomotor tone in serotonin-infused cats, although a trend towards bronchoconstriction was observed. The results reported here with bisopro-
340
1oi confirm earlier reports that, at best, this compound has a neutral effect on airway resistance at fl~-antagonist doses (Schliep and Harting, 1984; Schliep et al., 1986). Finally, propranolol treatment caused severe bronchoconstriction. The bronchodilatory effect of celiprolol has been noted in serotonin- and prostaglandin F2,-infused cats and methacholine-infused rats in earlier studies (Smith and Wolf, 1984). In contrast, Schliep and Harting (1984) report that celiprolol treatment enhances histamine-induced bronchoconstriction in guinea pigs. In our laboratory, celiprolol has no significant effect on histamineinduced bronchoconstriction in dogs (unpublished observations). The effect of celiprolol on pulmonary function in laboratory animals, therefore, appears to be influenced by the species as well as the spasmogen used in any particular study. None of this abrogates the fact that unlike most /3antagonists, celiprolol induces bronchodilation in a variety of animal models. The bronchodilator effect of celiprolol is probably mediated through a partial agonist activity in addition to an as yet unidentified ancillary property (Smith and Wolf, 1984). The mild intrinsic sympathomimetic activity noted above does not fully account for bronchodilation since this effect is not blocked by propranolol (Smith and Wolf, 1984). While it is possible that celiprolol acts as an inhibitor of serotonin in this model, this possibility is remote. Celiprolol only weakly binds to the serotonin receptor (Van Inwegen et al., 1984) and celiprolol is an inhibitor of bronchoconstriction induced by several agonists (Smith and Wolf, 1984). In general, /3-adrenoceptor blockade is contraindicated in patients with chronic pulmonary disease. Mixed flt/B2-antagonists, such as propranolol, as well as most selective/3vantagonists, such as metoprolol, have been shown to cause dose-dependent bronchoconstriction in patients with chronic pulmonary disease (Chester et al., 1981; Jackson and Beevers, 1983). In contrast, celiprolol has been associated with bronchodilation in asthmatics (Doshen et al., 1986) and has been shown to be highly bronchosparing in propranolol-sensitive asthmatics (Matthys et al., 1986). These studies suggest that celiprolol may
have a bronchosparing property unique among B-blockers. The evidence of significant bronchodilation after treatment with celiprolol in the present study, therefore, enhances the therapeutic potential of this compound. In fact, the bronchodilator effect of celiprolol coupled with its activity as a fl~-antagonist suggests that it might be the fl~-adrenoceptor blocker of choice in hypertensive or anginal patients with concurrent chronic obstructive pulmonary disease.
Acknowledgements We wish to thank Dr. R. Van Inwegen and J. Travis for helpful comments and E. Reardon for preparing the manuscript.
References Chester, E.H., H.J. Schwartz and G.M. Fleming, 1981, Adverse effect of propranolol on airway function in nonasthmatic chronic obstructive lung disease, Chest 79, 540. Conoily, M.E., F. Kersting and C.T. Dollery, 1976, The clinical pharmacology of beta-adrenoceptor-blocking drugs, Prog. Cardiovasc. Dis. 19, 203. Doshan, H.D., R.R. Rosenthal, R. Brown, A. Slutsky, W.J. Applin and F.S. Caruso, 1986, Celiprolol, atenolol and propranolol: A comparison of pulmonary effects in asthmatic patients, J. Cardiovasc. Pharmacol. 8 (Suppl. 4), S105. Jackson, S.H.D. and D.G. Beevers, 1983, Comparison of the effects of single doses of atenolol and labetolol on airways obstruction in patients with hypertension and asthma, Br. J. Clin. Pharmacol. 15, 553. Matthys, H., H.D. Doshan, K.H. Ruhle, W.J. Applin, H. Braig and M. Pohl, 1986, Bronchosparing properties of celiprolol, a new Bl,a2-blocker in propranolol sensitive asthmatic patients, J. Cardiovasc. Pharmacol. 8 (Suppl. 4), $40. Reiche, R. and H.H. Frey, 1983, Antagonism of the 5-HTinduced bronchoconstriction in the cat, Arch. Int. Pharmacodyn. 263, 139. Schliep, H.J. and J. Hatting, 1984, BvSelectivity of bisoprolol, a new B-adrenoceptor antagonist, in anesthetized dogs and guinea pigs, J. Cardiovasc. Pharmacol. 6, 1156. Schliep, H.J., E. Schuize, J. Harding and G. Haeusler, 1986. Antagonistic effects of bisoprolol on several B-adrenocepfor mediated actions in anaesthetized cats, European J. Pharmacol. 123, 253. Smith, R.D. and P.S. Wolf, 1984, Celiproiol, in: New Drugs Annual: Cardiovascular Drugs, Vol. 2., ed. A. Scfiabine (Raven Press, New York) p. 19. Van lnwegen, R., A. Khandwala, R. Ingrain, Y. Kharode, C. Sutherland, S. Coutts. I. Weinryb and T. Pruss, 1984, Effects of celiprolol on the interaction of serotonin on tracheal rings, Fed. Proc. 43, 2689.
337
Elsevier EJP 20161 Short communication
Cardiopulmonary effects of celiprolol and bisoprolol in serotonin-infused cats Gilbert W. Carnathan *, Dennis M. Sweeney, Robert G o r d o n i and T.P. Pruss Rarer Central Research, Department of Immunobiology, Horsham, PA 19044, U.S.A.
Received 3 May 1988, accepted 10 May 1988
The effects of celiprolol and bisoprolol on cardiopulmonary function in serotonin-infused cats were compared. Celiprolol reversed the bronchoconstrictive effect of serotonin at doses >t 1.0 mg/kg. Also, decreases in mean arterial pressure and heart rate were noted after administration of 3-10 and 10 mg/kg celiprolol, respectively. In contrast, bisoprolol tended to induce bronchoconstriction. Reductions in mean arterial pressure and heart rate were observed with 1 or 3 mg/kg. Bisoprolol administration at 10 mg/kg was lethal. The unique ability of celiprolol to induce bronchodilation enhances its therapeutic potential. Celiprolol; Bisoprolol; Bronchodilation
1. Introduction
fl-Adrenoceptor antagonists are frequently used in the management of hypertension and related cardiac diseases (Conolly et al., 1976). In clinical settings, a high degree of fl~-receptor selectivity is desirable, as antagonism of fl2-receptors can lead to bronchoconstriction and severe airway obstruction in asthmatics and patients with concurrent pulmonary disease (Doshan et al., 1986). Unfortunately, cardioselectivity is a dose-dependent phenomenon (Jackson and Beevers, 1983), thus caution is usually required when a selective fl~adrenoceptor antagonist is utilized. The present study assesses the effects of two selective fl~antagonists, celiprolol (for review see, Smith and Wolf, 1984) and bisoprolol (Schliep et al., 1986),
* To whom all correspondence should be addressed: Rarer Central Research, 800 Business Center Drive, Building 3, Horsham, PA 19044, U.S.A. 1 Current address: Sterling-Winthrop Research Institute, Rensselaer, NY 12144, U.S.A.
in a cat model in which pulmonary function is compromised by a serotonin infusion. Initial studies with celiprolol in this and similar models have shown that it does not adversely effect the bronchopulmonary system. In fact, celiprolol has been shown to block the bronchoconstrictive effects of methacholine, serotonin, prostaglandin F2a and histamine in animal studies (Smith and Wolf, 1984). The effect of bisoprolol in the present model has not been assessed previously, although the compound has been reported to possess a favorable cardiotropic/bronchotropic ratio in histamine-challenged guinea pigs (Schliep et al., 1986). The cat model used in the present study has been shown to be a reliable predictor of the clinical utility of bronchodilator agents such as clenbuterol and aminophylline (Reiche and Frey, 1983). In our laboratory, propranolol, metoprolol and timolol, among others agents, cause increased bronchoconstriction in this model (Smith and Wolf, 1984). Thus, the activity of bisoprolol and celiprolol in this model may be predictive of their effects in asthmatics.
0014-2999/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
338
2. Materials and methods
2.1. Serotonin-induced bronchoconstriction Male cats (3.0-4.0 kg) were anesthetized with p e n t o b a r b i t a l s o d i u m (35 m g / k g i.p.). T h e trachea of each cat was c a n n u l a t e d , a n d Fleisch No. 00 p n e u m o t a c h o g r a p h c o n n e c t e d to a S t a t h a m P M 1 5 E T C differential pressure transducer was placed in line to m o n i t o r air flow. A second t r a n s d u c e r (Statham PM5E), used for m e a s u r i n g t r a n s p u l m o n a r y pressure, was placed between the tracheal c a n n u l a a n d a c a n n u l a in the pleural cavity. Air flow a n d t r a n s p u l m o n a r y pressure signals were converted by a Buxco p u l m o n a r y mechanics c o m p u t e r system to values of airway resistance averaged over a 6 s interval. C a n n u l a s were inserted into both femoral veins (for i n f u s i o n of s e r o t o n i n a n d drug a d m i n i s t r a t i o n ) a n d a femoral artery (for m o n i t o r i n g heart rate and blood pressure). Each a n i m a l was paralyzed with 20 mg g a l l a m i n e triethiodide a n d mechanically ventilated. T o test for b r o n c h o d i l a t o r activity, it was necessary to increase the n o r m a l l y low b r o n c h o m o t o r tone of the cat. This was accomplished by a constant i.v. i n f u s i o n of serotonin (35 # g / k g per min) which produced a n a p p r o x i m a t e 3-fold increase in airway resistance. D u r i n g this steady state b r o n c h o c o n s t r i c t i o n , each a n i m a l received isoproterenol (5 # g / k g i.v,) in order to test for reactivity to a k n o w n b r o n c h o d i l a t o r . Celiprolol or bisopro1ol was then a d m i n i s t e r e d to each cat by i.v. bolus
injection in an a s c e n d i n g dose paradigm. T o allow the cat to return to its p r e d r u g baseline, at least 15 m i n elapsed between the a d m i n i s t r a t i o n of the sequential drug treatments. F o r c o m p a r a t i v e purposes, the effect of p r o p r a n o l o l (3.0 m g / k g i.v.) on b r o n c h o c o n s t r i c t i o n was also d e t e r m i n e d .
2.2. Statistics The degree of change in airway resistance in response to celiproiol a n d bisoprolol was expressed as a percent change from baseline s e r o t o n i n - i n d u c e d b r o n c h o c o n s t r i c t i o n . In addition, changes in heart rate (beats per min) a n d m e a n arterial pressure ( m m Hg) were recorded. All data were analyzed by a one-tail S t u d e n t ' s t-test.
2.3. Compounds Celiprolol HCI was provided by Rorer C e n t r a l Research. Bisoprolol h e m i f u m a r a t e was generously d o n a t e d by Dr. Kling (E. Merck, G e r m a n y ) . All other drugs were purchased from Sigma Chemical Co. (St. Louis, MO). All doses are expressed as the free base.
3. Results The effect of celiprolol a n d bisoprolol o n m e a n arterial pressure a n d heart rate in cats infused with serotonin is shown in table 1. Both corn-
TABLE 1 Effect of i.v. administered celiprolol and bisoprolol on changes in heart rate (HR) and mean arterial pressure (MAP) in serotonin-infused cats. Changes are expressed as a decrease from baseline values. Data represent means ( + S.E.) of five cats in each treatment. Dose
Celiprolol
Bisoprolol
(mg/kg i.v.)
HR a
MAP "
HR ~'
MAP "
Control 0.1 0.3 1.0 3.0 10.0
-1.8+2.0 -4.0-t-1.8 -3.3+0.5 -4.3+0.6 -8.8+ 1.1 -- 21.3 + 6.1 o
11.3+2.1 1.3+3.2 3.8+1.1 -2.5+2.2" -26.3-t-4.8 ~ -- 38.8 + 6.2 d
-4.0+ 2.7 -11.0-+ 3.3 -13.0-+ 1.1 ¢ -22.4+_10.0 ~ --67.0-t- 12.9 ~ (Lethal)
8.6_+ 1.7 -9.6-+ 2.6" -6.0-+ 2.2 ~ -22.4± 3.8d - 54.8+_10.7 d (Lethal)
Change (beats per min) relative to baseline (278.8 + 7.0) heart rate. , Change in pressure (mm Hg) relative to baseline (99.7 + 15.0) MAP. ~ P < 0.01; d p < 0.001. Student's one-tail t-test compared to the control (PEG-200) response.
339
"F t4O I1.1
II
z
m
.-~
tl
..... t~ >-
•
.....
BISOPFIOLOL
4p ~ ' ~ ' ~
....
B....
0 CELIPROLOL
-till
~
~
0 PROPRANOLOL
p
-Ill -,4O
~
~
p
"~ I
0.t
0.$
t
. . . I.
'
....
t0
DOSE |ag/kQ t.v.1 Fig. 1. Effect of i.v. administered celiprolol, bisoprolol and propranoiol on changes in airway resistance in serotonin-infused cats. Data represent means ( + S.E.) of five cats at each point.
pounds significantly decreased mean arterial pressure in a dose-dependent manner. This effect was paralleled by a significant bradycardia in cats treated with bisoprolol. Animals treated with celiprolol did not exhibit bradycardia, except following administration of a high i.v. dose (10 mg/kg) of the compound. Shown in fig. 1 are the effects of cehprolol, bisoprolol and propranolol on airway resistance. Celiprolol treatment caused dose-dependent bronchodilation as evidenced by significant decreases in airway resistance. In contrast, bisopro1ol failed to induce a significant change in bronchomotor tone in serotonin-infused cats, although there was a trend towards bronchoconstriction. As expected, propranolol potentiated the bronchoconstriction response to serotonin in this model.
4. Discussion The cardiovascular effects of bisoprolol and celiprolol in the present study are consistent with their respective pharmacology (Smith and Wolf, 1984; Schliep et al., 1986). In the present study,
bisoprolol was shown to be more potent in reducing heart rate and blood pressure than celiprolol. In this regard, the present data confirm an earlier study in which the potency of bisoprolol was shown to be greater than that of celiproloi (Schliep and Harting, 1984). It is important to note that treatment with 10 m g / k g bisoprolol was lethal to all cats tested in the present study. The antihypertensive effects of cehprolol may be due in part to other mechanisms in addition to fl:antagonism, as at a dose of 3 mg/kg, celiproiol was able to significantly decrease mean arterial pressure while affecting only a minimal decrease in heart rate. This suggests a partial agonist profile, which has been noted in earlier studies (Smith and Wolf, 1984). Of more immediate interest are the contrasting effects of these compounds on pulmonary function. In this model, all other fl-blockers tested have been shown to potentiate serotonin-induced bronchoconstriction (Smith and Wolf, 1984). As shown in the present study, celiprolol treatment caused dose-dependent bronchodilation. In contrast, bisoprolol failed to significantly effect bronchomotor tone in serotonin-infused cats, although a trend towards bronchoconstriction was observed. The results reported here with bisopro-
340
1oi confirm earlier reports that, at best, this compound has a neutral effect on airway resistance at fl~-antagonist doses (Schliep and Harting, 1984; Schliep et al., 1986). Finally, propranolol treatment caused severe bronchoconstriction. The bronchodilatory effect of celiprolol has been noted in serotonin- and prostaglandin F2,-infused cats and methacholine-infused rats in earlier studies (Smith and Wolf, 1984). In contrast, Schliep and Harting (1984) report that celiprolol treatment enhances histamine-induced bronchoconstriction in guinea pigs. In our laboratory, celiprolol has no significant effect on histamineinduced bronchoconstriction in dogs (unpublished observations). The effect of celiprolol on pulmonary function in laboratory animals, therefore, appears to be influenced by the species as well as the spasmogen used in any particular study. None of this abrogates the fact that unlike most /3antagonists, celiprolol induces bronchodilation in a variety of animal models. The bronchodilator effect of celiprolol is probably mediated through a partial agonist activity in addition to an as yet unidentified ancillary property (Smith and Wolf, 1984). The mild intrinsic sympathomimetic activity noted above does not fully account for bronchodilation since this effect is not blocked by propranolol (Smith and Wolf, 1984). While it is possible that celiprolol acts as an inhibitor of serotonin in this model, this possibility is remote. Celiprolol only weakly binds to the serotonin receptor (Van Inwegen et al., 1984) and celiprolol is an inhibitor of bronchoconstriction induced by several agonists (Smith and Wolf, 1984). In general, /3-adrenoceptor blockade is contraindicated in patients with chronic pulmonary disease. Mixed flt/B2-antagonists, such as propranolol, as well as most selective/3vantagonists, such as metoprolol, have been shown to cause dose-dependent bronchoconstriction in patients with chronic pulmonary disease (Chester et al., 1981; Jackson and Beevers, 1983). In contrast, celiprolol has been associated with bronchodilation in asthmatics (Doshen et al., 1986) and has been shown to be highly bronchosparing in propranolol-sensitive asthmatics (Matthys et al., 1986). These studies suggest that celiprolol may
have a bronchosparing property unique among B-blockers. The evidence of significant bronchodilation after treatment with celiprolol in the present study, therefore, enhances the therapeutic potential of this compound. In fact, the bronchodilator effect of celiprolol coupled with its activity as a fl~-antagonist suggests that it might be the fl~-adrenoceptor blocker of choice in hypertensive or anginal patients with concurrent chronic obstructive pulmonary disease.
Acknowledgements We wish to thank Dr. R. Van Inwegen and J. Travis for helpful comments and E. Reardon for preparing the manuscript.
References Chester, E.H., H.J. Schwartz and G.M. Fleming, 1981, Adverse effect of propranolol on airway function in nonasthmatic chronic obstructive lung disease, Chest 79, 540. Conoily, M.E., F. Kersting and C.T. Dollery, 1976, The clinical pharmacology of beta-adrenoceptor-blocking drugs, Prog. Cardiovasc. Dis. 19, 203. Doshan, H.D., R.R. Rosenthal, R. Brown, A. Slutsky, W.J. Applin and F.S. Caruso, 1986, Celiprolol, atenolol and propranolol: A comparison of pulmonary effects in asthmatic patients, J. Cardiovasc. Pharmacol. 8 (Suppl. 4), S105. Jackson, S.H.D. and D.G. Beevers, 1983, Comparison of the effects of single doses of atenolol and labetolol on airways obstruction in patients with hypertension and asthma, Br. J. Clin. Pharmacol. 15, 553. Matthys, H., H.D. Doshan, K.H. Ruhle, W.J. Applin, H. Braig and M. Pohl, 1986, Bronchosparing properties of celiprolol, a new Bl,a2-blocker in propranolol sensitive asthmatic patients, J. Cardiovasc. Pharmacol. 8 (Suppl. 4), $40. Reiche, R. and H.H. Frey, 1983, Antagonism of the 5-HTinduced bronchoconstriction in the cat, Arch. Int. Pharmacodyn. 263, 139. Schliep, H.J. and J. Hatting, 1984, BvSelectivity of bisoprolol, a new B-adrenoceptor antagonist, in anesthetized dogs and guinea pigs, J. Cardiovasc. Pharmacol. 6, 1156. Schliep, H.J., E. Schuize, J. Harding and G. Haeusler, 1986. Antagonistic effects of bisoprolol on several B-adrenocepfor mediated actions in anaesthetized cats, European J. Pharmacol. 123, 253. Smith, R.D. and P.S. Wolf, 1984, Celiproiol, in: New Drugs Annual: Cardiovascular Drugs, Vol. 2., ed. A. Scfiabine (Raven Press, New York) p. 19. Van lnwegen, R., A. Khandwala, R. Ingrain, Y. Kharode, C. Sutherland, S. Coutts. I. Weinryb and T. Pruss, 1984, Effects of celiprolol on the interaction of serotonin on tracheal rings, Fed. Proc. 43, 2689.