AJH
1991;
4.197S-199S
Effect of Isradipine and Atenolol on Lung Function in Patients With Mild Essential Hypertension Wolfram Reiterer and Wolfgang
Meisner
Twenty-six hypertensive patients took part in an o p e n , r a n d o m i z e d , p a r a l l e l - g r o u p p i l o t s t u d y of t h e effects of a n i n e - w e e k t r e a t m e n t p e r i o d w i t h t h e calcium antagonist isradipine and the -blocking agent atenolol. T h e m e a n dosage in the isradipine g r o u p w a s 7.9 ± 3.5 m g / d a y , a n d 69.2 ± 43.5 m g / d a y i n t h e a t e n o l o l g r o u p . A significant r e d u c t i o n of t h e arterial blood pressure was seen with both treat m e n t r e g i m e n s . L u n g v o l u m e s a n d a i r w a y s resist ance remained unchanged, but, in the atenololtreated group, the linear relationship between a l v e o l a r p r e s s u r e a n d a i r w a y s r e s i s t a n c e at t h e l o w e r
l u n g v o l u m e s d u r i n g forced e x p i r a t i o n at 25% of forced v i t a l capacity w a s affected b y a shift to h i g h e r a i r w a y s r e s i s t a n c e . T h i s c h a n g e can b e i n t e r p r e t e d as a n e a r l y s i g n of a l t e r e d air-flow b e h a v ior i n t h e s m a l l a i r w a y s i n subjects s u s c e p t i b l e to ^-adrenoceptor blockade. T h e calcium antagonist isradipine did not produce changes in any parame t e r s of l u n g f u n c t i o n i n t h i s g r o u p of p a t i e n t s . A m J H y p e r t e n s 1991;4:197S-199S
A
pertensive patients. Isradipine is a dihydropyridine d e rivative w i t h a high specific a n d low nonspecific affinity to the dihydropyridine binding sites a n d with minimal cardiodepressant effects.
w e l l - k n o w n side effect of /^-blockade is a n increase in b r o n c h o m o t o r tone, especially in patients with obstructive lung disease. De spite a high degree of ^-selectivity, b r o n c h o s p a s m m a y be induced in susceptible patients. Calcium antagonists such as nifedipine h a v e b e e n used in asth matics to inhibit bronchoconstriction b r o u g h t on b y a variety of provocative stimuli, including exercise. In practical terms, it m a y be a d v a n t a g e o u s in the treatment of hypertension to use drugs that do not affect the b r o n chial system, especially in potentially hyperreactive p a tients (such as smokers). The present pilot study w a s u n d e r t a k e n to compare the influence of isradipine a n d the ß -adrenoceptor a n tagonist atenolol on air flow a n d lung function in h y 1,2
x
From the Department of Internal Medicine I, Policlinic, Vienna, Austria. Address correspondence and reprint requests to Wolfram Reiterer, MD, Department of Internal Medicine I, Policlinic, Mariannengasse 10, A - 1 0 9 0 Wien, Austria.
© 1991 by the American Journal of Hypertension,
Inc.
KEY W O R D S : L u n g m e c h a n i c s , h y p e r t e n s i o n , c a l c i u m antagonist, isradipine, atenolol.
3
PATIENTS A N D METHODS After obtaining informed consent to the study protocol a n d procedures, 26 patients with mild-to-moderate h y pertension (diastolic blood pressure [DBP] 95 to 115 m m Hg), w h o w e r e otherwise healthy, w e r e included in a n o p e n pilot trial. Patients w e r e r a n d o m i z e d to receive either isradipine (n = 13, age 53.9 ± 1 5 years, five w o m e n , six smokers) or atenolol (n = 13, age 53.4 ± 11.2 years, t w o w o m e n , seven smokers). After discontinuation of all previous antihypertensive drugs, a t w o - to four-week placebo period w a s followed by nine weeks of active treatment with isradipine 2.5 mg, 5 mg, or 7.5 m g twice daily, or atenolol 50 mg, 100 m g , or 200 m g / d a y . If, after three weeks, DBP w a s m o r e t h a n 90 m m Hg, the doses w e r e increased. Sitting
0895-7061/'91/'$3.50
198S
AJH-FEBRUARY
REITERER A N D MEISNER
blood pressure w a s m e a s u r e d after at least 5 min of rest with a s t a n d a r d mercury s p h y g m o m a n o m e t e r . The pulse rate w a s m e a s u r e d b y counting the n u m b e r of pulse beats in 60 sec. Repeated m e a s u r e m e n t s , including basic spirometry data a n d b o d y p l e t h y s m o g r a p h y with flow-volume pressure analysis of forced expiration, were also per formed at each visit. The analysis of lung function in cluded data as follows: Vital capacity (VC, L); forced vital capacity during expiration (FVC, L, largest of three readings); forced vital capacity after 1 sec of expiration (FVC-1, L, %VC); expiratory flow rates (L/sec) at mid(50% FVC, M E F ) a n d end-expiration ( 2 5 % FVC, M E F ) ; m a x i m u m ventilation volume ( M W , L / m i n ) ; total lung capacity (TLC, L); intrathoracic gas v o l u m e (L, %IGV); residual v o l u m e (RV, L, %TLC); total airways resistance (Rawt, cm H 0 / L / s e c ) ; specific airways re sistance (SRaw, cm H 0 / s e c ) ; i n s t a n t a n e o u s resistance a n d alveolar pressure during forced expiration at 5 0 % a n d 2 5 % of FVC (Ri25, Ri50, cm H 0 / L / s e c ; palv25, palv50, cm H 0 ) . At the e n d of t h e placebo period, patients with abnor mal lung function, defined by a n Rawt m o r e t h a n 3.0 cm H 0 / L / s e c , a n d air flow at 2 5 % FVC less t h a n 1.0 L / s e c in smokers a n d 1.5 L / s e c in n o n s m o k e r s , were excluded from the active-treatment p h a s e of t h e study. All results are presented as m e a n values ± SD. P a r a m e t ric a n d nonparametric analyses w e r e used to verify sig nificant changes (homogeneity of variance, n o r m a l distribution; Student's t test, analysis of variance, Wilcoxon's U test, Friedman's test). Multiple regression analyses w e r e performed by the least-squares m e t h o d . 50
25
2
2
2
2
2
1991-VOL
4, NO. 2, PART 2
A Ρ value of .05 w a s considered to be significant for statistical evaluation. RESULTS At the e n d of the placebo period, there w a s n o signifi cant difference b e t w e e n t h e t w o study groups w i t h re gard to blood pressure readings a n d lung function data. At the e n d of the nine weeks of active treatment, the m e a n dosage w a s 7.9 ± 3.5 m g / d a y in the isradipine group, a n d 69.2 ± 43.5 m g / d a y in t h e atenolol g r o u p . M e a n blood pressure w a s significantly reduced in b o t h groups (isradipine: from 1 5 6 . 5 / 1 0 0 . 8 to 1 4 3 . 4 / 92.6 m m Hg; atenolol: from 153.4/103.0 to 1 3 8 . 4 / 9 0 . 0 m m Hg), w h e r e a s decreases in heart rate were significant only in those taking atenolol (—10%), as expected. Lung volumes (VC, FVC, TLC, IGV, RV) a n d d y n a m i c parameters (FVC-1, M W , M E F , M E F ) w e r e unaf fected by either atenolol or isradipine. Total a n d instan t a n e o u s airways resistance during forced expiration at 2 5 % a n d 5 0 % of FVC were identical for b o t h groups during placebo, but, at the e n d of active treatment, a t e n d e n c y of the i n s t a n t a n e o u s airways resistance to b e raised at mid-expiration w a s observed in the atenolol g r o u p ( + 3.2 U) in comparison w i t h the g r o u p receiving isradipine ( + 0 . 1 U). Air-flow rates a n d alveolar pres sure at lower l u n g v o l u m e s w e r e not affected. W h e n the t w o groups were further divided into smok ers a n d n o n s m o k e r s , an increase of 3.33 U in instanta n e o u s airways resistance during forced expiration at 5 0 % of FVC w a s observed only in t h e smokers taking atenolol (isradipine: decrease of 1.12 U). At t h e e n d of 5 0
25
Ri 70^ 60 h
FIGURE 1. Correlation between instantaneous resistance (Ri) and al veolar pressure (palv) on forced expi ration at 25°/o of forced vital capac ity with isradipine ( 7 , + , r = 0.8, VK.001) and atenolol (A, M, r = 0.27, Ρ = value not significant).
50 40 30 20
10
10
20
30
40
50 palv
60
70
80
90
AJH-FEBRUARY
1991-VOL.
4, NO. 2, PART 2
the placebo period, in b o t h treatment groups the air w a y s resistance during forced expiration at an expira tory level of 2 5 % of F VC w a s linearly correlated to the alveolar pressure to a significant degree (isradipine: r = 0.6, Ρ < .05; atenolol: r = 0.7, Ρ < .05). With atenolol, the linear relationship w a s lost (isradipine: r = 0.8, Ρ < .001; atenolol: r = 0.27, Ρ = .36) d u e to a shift of resist ance to a higher value in four patients, three of w h o m were smokers (Figure 1). DISCUSSION /?-Blocking agents are contraindicated for hypertensive patients with asthma. It w a s h o p e d that calcium antago nists w o u l d result in bronchodilatation in patients with chronic obstructive lung disease a n d bronchial asthma. A l t h o u g h these h o p e s n o w a p p e a r to be u n f o u n d e d , it should be noted that calcium antagonists do not nega tively influence airways resistance. Despite the small n u m b e r of patients in this present study a n d the low dose of the β -adrenoceptor antago nist atenolol, the results indicate some deterioration of lung function in patients with hypertension, b u t w h o are otherwise healthy, on receiving atenolol c o m p a r e d with isradipine. Lung volumes a n d basic (simple) lung function m e a s u r e m e n t s (flow-volume curve) d o not re veal early alterations of the lung, especially of the small 4
ISRADIPINE, ATENOLOL, A N D LUNG FUNCTION
199S
airways. N o significant changes w e r e found in the air flow rates during the FVC m a n e u v e r . In some patients, an increase of the instantaneous airways resistance at lower lung volumes during treatment with atenolol b e came evident on flow-volume pressure analysis during forced expiration. These asymptomatic patients a p p e a r to be sensitive responders to the influence of /?-blockade on airway t o n u s regulation. However, only sophisti cated m e a s u r e m e n t s of lung function are likely to reveal such early side effects of /J-blockers. The calcium a n t a g o nist isradipine does not affect the flow-volume pressure relationship of the bronchial system. REFERENCES 1.
Corns PA, Nariman S, Gibson GJ: Nifedipine in the pre vention of asthma induced by exercise and histamine. Am Rev Respir Dis 1983,128:991-992.
2.
Patel KR, Al-Shamma M: Effect of nifedipine on hista mine reactivity in asthma. Br Med J 1982;284:1916-1918.
3.
Hof RP, Rüegg UT: Pharmacology of the new calcium antagonist isradipine and its metabolites. Am J Med 1988;84(suppl 3B):13-17.
4.
Massey KL, Hendeles L: Calcium antagonists in the man agement of asthma: breakthrough or ballyhoo? Drug Intell Clin Pharm 1987;21:505-509.
5.
Hendeles L, Harman E: Should we abandon the notion that calcium channel blockers are potentially useful for asthma? J Allergy Clin Immunol 1987;79(6):853-855.
5
ί
1991;
4.197S-199S
Effect of Isradipine and Atenolol on Lung Function in Patients With Mild Essential Hypertension Wolfram Reiterer and Wolfgang
Meisner
Twenty-six hypertensive patients took part in an o p e n , r a n d o m i z e d , p a r a l l e l - g r o u p p i l o t s t u d y of t h e effects of a n i n e - w e e k t r e a t m e n t p e r i o d w i t h t h e calcium antagonist isradipine and the -blocking agent atenolol. T h e m e a n dosage in the isradipine g r o u p w a s 7.9 ± 3.5 m g / d a y , a n d 69.2 ± 43.5 m g / d a y i n t h e a t e n o l o l g r o u p . A significant r e d u c t i o n of t h e arterial blood pressure was seen with both treat m e n t r e g i m e n s . L u n g v o l u m e s a n d a i r w a y s resist ance remained unchanged, but, in the atenololtreated group, the linear relationship between a l v e o l a r p r e s s u r e a n d a i r w a y s r e s i s t a n c e at t h e l o w e r
l u n g v o l u m e s d u r i n g forced e x p i r a t i o n at 25% of forced v i t a l capacity w a s affected b y a shift to h i g h e r a i r w a y s r e s i s t a n c e . T h i s c h a n g e can b e i n t e r p r e t e d as a n e a r l y s i g n of a l t e r e d air-flow b e h a v ior i n t h e s m a l l a i r w a y s i n subjects s u s c e p t i b l e to ^-adrenoceptor blockade. T h e calcium antagonist isradipine did not produce changes in any parame t e r s of l u n g f u n c t i o n i n t h i s g r o u p of p a t i e n t s . A m J H y p e r t e n s 1991;4:197S-199S
A
pertensive patients. Isradipine is a dihydropyridine d e rivative w i t h a high specific a n d low nonspecific affinity to the dihydropyridine binding sites a n d with minimal cardiodepressant effects.
w e l l - k n o w n side effect of /^-blockade is a n increase in b r o n c h o m o t o r tone, especially in patients with obstructive lung disease. De spite a high degree of ^-selectivity, b r o n c h o s p a s m m a y be induced in susceptible patients. Calcium antagonists such as nifedipine h a v e b e e n used in asth matics to inhibit bronchoconstriction b r o u g h t on b y a variety of provocative stimuli, including exercise. In practical terms, it m a y be a d v a n t a g e o u s in the treatment of hypertension to use drugs that do not affect the b r o n chial system, especially in potentially hyperreactive p a tients (such as smokers). The present pilot study w a s u n d e r t a k e n to compare the influence of isradipine a n d the ß -adrenoceptor a n tagonist atenolol on air flow a n d lung function in h y 1,2
x
From the Department of Internal Medicine I, Policlinic, Vienna, Austria. Address correspondence and reprint requests to Wolfram Reiterer, MD, Department of Internal Medicine I, Policlinic, Mariannengasse 10, A - 1 0 9 0 Wien, Austria.
© 1991 by the American Journal of Hypertension,
Inc.
KEY W O R D S : L u n g m e c h a n i c s , h y p e r t e n s i o n , c a l c i u m antagonist, isradipine, atenolol.
3
PATIENTS A N D METHODS After obtaining informed consent to the study protocol a n d procedures, 26 patients with mild-to-moderate h y pertension (diastolic blood pressure [DBP] 95 to 115 m m Hg), w h o w e r e otherwise healthy, w e r e included in a n o p e n pilot trial. Patients w e r e r a n d o m i z e d to receive either isradipine (n = 13, age 53.9 ± 1 5 years, five w o m e n , six smokers) or atenolol (n = 13, age 53.4 ± 11.2 years, t w o w o m e n , seven smokers). After discontinuation of all previous antihypertensive drugs, a t w o - to four-week placebo period w a s followed by nine weeks of active treatment with isradipine 2.5 mg, 5 mg, or 7.5 m g twice daily, or atenolol 50 mg, 100 m g , or 200 m g / d a y . If, after three weeks, DBP w a s m o r e t h a n 90 m m Hg, the doses w e r e increased. Sitting
0895-7061/'91/'$3.50
198S
AJH-FEBRUARY
REITERER A N D MEISNER
blood pressure w a s m e a s u r e d after at least 5 min of rest with a s t a n d a r d mercury s p h y g m o m a n o m e t e r . The pulse rate w a s m e a s u r e d b y counting the n u m b e r of pulse beats in 60 sec. Repeated m e a s u r e m e n t s , including basic spirometry data a n d b o d y p l e t h y s m o g r a p h y with flow-volume pressure analysis of forced expiration, were also per formed at each visit. The analysis of lung function in cluded data as follows: Vital capacity (VC, L); forced vital capacity during expiration (FVC, L, largest of three readings); forced vital capacity after 1 sec of expiration (FVC-1, L, %VC); expiratory flow rates (L/sec) at mid(50% FVC, M E F ) a n d end-expiration ( 2 5 % FVC, M E F ) ; m a x i m u m ventilation volume ( M W , L / m i n ) ; total lung capacity (TLC, L); intrathoracic gas v o l u m e (L, %IGV); residual v o l u m e (RV, L, %TLC); total airways resistance (Rawt, cm H 0 / L / s e c ) ; specific airways re sistance (SRaw, cm H 0 / s e c ) ; i n s t a n t a n e o u s resistance a n d alveolar pressure during forced expiration at 5 0 % a n d 2 5 % of FVC (Ri25, Ri50, cm H 0 / L / s e c ; palv25, palv50, cm H 0 ) . At the e n d of t h e placebo period, patients with abnor mal lung function, defined by a n Rawt m o r e t h a n 3.0 cm H 0 / L / s e c , a n d air flow at 2 5 % FVC less t h a n 1.0 L / s e c in smokers a n d 1.5 L / s e c in n o n s m o k e r s , were excluded from the active-treatment p h a s e of t h e study. All results are presented as m e a n values ± SD. P a r a m e t ric a n d nonparametric analyses w e r e used to verify sig nificant changes (homogeneity of variance, n o r m a l distribution; Student's t test, analysis of variance, Wilcoxon's U test, Friedman's test). Multiple regression analyses w e r e performed by the least-squares m e t h o d . 50
25
2
2
2
2
2
1991-VOL
4, NO. 2, PART 2
A Ρ value of .05 w a s considered to be significant for statistical evaluation. RESULTS At the e n d of the placebo period, there w a s n o signifi cant difference b e t w e e n t h e t w o study groups w i t h re gard to blood pressure readings a n d lung function data. At the e n d of the nine weeks of active treatment, the m e a n dosage w a s 7.9 ± 3.5 m g / d a y in the isradipine group, a n d 69.2 ± 43.5 m g / d a y in t h e atenolol g r o u p . M e a n blood pressure w a s significantly reduced in b o t h groups (isradipine: from 1 5 6 . 5 / 1 0 0 . 8 to 1 4 3 . 4 / 92.6 m m Hg; atenolol: from 153.4/103.0 to 1 3 8 . 4 / 9 0 . 0 m m Hg), w h e r e a s decreases in heart rate were significant only in those taking atenolol (—10%), as expected. Lung volumes (VC, FVC, TLC, IGV, RV) a n d d y n a m i c parameters (FVC-1, M W , M E F , M E F ) w e r e unaf fected by either atenolol or isradipine. Total a n d instan t a n e o u s airways resistance during forced expiration at 2 5 % a n d 5 0 % of FVC were identical for b o t h groups during placebo, but, at the e n d of active treatment, a t e n d e n c y of the i n s t a n t a n e o u s airways resistance to b e raised at mid-expiration w a s observed in the atenolol g r o u p ( + 3.2 U) in comparison w i t h the g r o u p receiving isradipine ( + 0 . 1 U). Air-flow rates a n d alveolar pres sure at lower l u n g v o l u m e s w e r e not affected. W h e n the t w o groups were further divided into smok ers a n d n o n s m o k e r s , an increase of 3.33 U in instanta n e o u s airways resistance during forced expiration at 5 0 % of FVC w a s observed only in t h e smokers taking atenolol (isradipine: decrease of 1.12 U). At t h e e n d of 5 0
25
Ri 70^ 60 h
FIGURE 1. Correlation between instantaneous resistance (Ri) and al veolar pressure (palv) on forced expi ration at 25°/o of forced vital capac ity with isradipine ( 7 , + , r = 0.8, VK.001) and atenolol (A, M, r = 0.27, Ρ = value not significant).
50 40 30 20
10
10
20
30
40
50 palv
60
70
80
90
AJH-FEBRUARY
1991-VOL.
4, NO. 2, PART 2
the placebo period, in b o t h treatment groups the air w a y s resistance during forced expiration at an expira tory level of 2 5 % of F VC w a s linearly correlated to the alveolar pressure to a significant degree (isradipine: r = 0.6, Ρ < .05; atenolol: r = 0.7, Ρ < .05). With atenolol, the linear relationship w a s lost (isradipine: r = 0.8, Ρ < .001; atenolol: r = 0.27, Ρ = .36) d u e to a shift of resist ance to a higher value in four patients, three of w h o m were smokers (Figure 1). DISCUSSION /?-Blocking agents are contraindicated for hypertensive patients with asthma. It w a s h o p e d that calcium antago nists w o u l d result in bronchodilatation in patients with chronic obstructive lung disease a n d bronchial asthma. A l t h o u g h these h o p e s n o w a p p e a r to be u n f o u n d e d , it should be noted that calcium antagonists do not nega tively influence airways resistance. Despite the small n u m b e r of patients in this present study a n d the low dose of the β -adrenoceptor antago nist atenolol, the results indicate some deterioration of lung function in patients with hypertension, b u t w h o are otherwise healthy, on receiving atenolol c o m p a r e d with isradipine. Lung volumes a n d basic (simple) lung function m e a s u r e m e n t s (flow-volume curve) d o not re veal early alterations of the lung, especially of the small 4
ISRADIPINE, ATENOLOL, A N D LUNG FUNCTION
199S
airways. N o significant changes w e r e found in the air flow rates during the FVC m a n e u v e r . In some patients, an increase of the instantaneous airways resistance at lower lung volumes during treatment with atenolol b e came evident on flow-volume pressure analysis during forced expiration. These asymptomatic patients a p p e a r to be sensitive responders to the influence of /?-blockade on airway t o n u s regulation. However, only sophisti cated m e a s u r e m e n t s of lung function are likely to reveal such early side effects of /J-blockers. The calcium a n t a g o nist isradipine does not affect the flow-volume pressure relationship of the bronchial system. REFERENCES 1.
Corns PA, Nariman S, Gibson GJ: Nifedipine in the pre vention of asthma induced by exercise and histamine. Am Rev Respir Dis 1983,128:991-992.
2.
Patel KR, Al-Shamma M: Effect of nifedipine on hista mine reactivity in asthma. Br Med J 1982;284:1916-1918.
3.
Hof RP, Rüegg UT: Pharmacology of the new calcium antagonist isradipine and its metabolites. Am J Med 1988;84(suppl 3B):13-17.
4.
Massey KL, Hendeles L: Calcium antagonists in the man agement of asthma: breakthrough or ballyhoo? Drug Intell Clin Pharm 1987;21:505-509.
5.
Hendeles L, Harman E: Should we abandon the notion that calcium channel blockers are potentially useful for asthma? J Allergy Clin Immunol 1987;79(6):853-855.
5
ί
