Eur J Clin Pharmacol (1990) 39 [Suppl 1]: S 39-S 40
poaoJo0ma, Eo o, © Springer-Verlag 1990
The influence of chronic treatment with verapamil on plasma atrial natriuretic peptide levels in young and elderly hypertensive patients L. M. A . B. V a n B o r t e l 1, E M. H. Schiffers 1, R. O. B. B 6 h m 1, J. M. V. M o o i j ; , K. H. R a h n 2 a n d H. A. J. S t r u y k e r B o u d i e r t Departments of ~ Pharmacology and 2 Medicine, UniversityofLimburg, Maastricht, The Netherlands
Summary. In a double-blind, p l a c e b o - c o n t r o l l e d crossover study, the plasma atrial natriuretic peptide ( A N P ) levels of nine y o u n g and ten elderly hypertensive patients were c o m p a r e d after placebo and after t r e a t m e n t with 120 mg verapamil given three times daily over 4 weeks. D u r i n g placebo, plasma A N P levels p r o v e d to be higher in elderly patients than in y o u n g subjects. Chronic t r e a t m e n t with verapamil i n d u c e d a rise in A N P levels in b o t h y o u n g and elderly patients with hypertension.
Key words: A N R verapamil, hypertension, age
Atrial natriuretic peptide ( A N P ) has natriuretic, diuretic and vascular s m o o t h - m u s c l e relaxing activity; its release into the circulation seems to be regulated mainly by atrial distension. T h e calcium channel agonist B A Y K 8644 stimulates A N P secretion in isolated rat hearts (Saito et al. 1986) and in cultured rat cardiocytes (Matsubara et al. 1988); this effect is inhibited by nifedipine. A 5-mg dose of verapamil does not change b l o o d pressure in m a n but blocks the stimulatory effects of a s u d d e n increase in right atrial pressure u p o n release of A N P ( H a u f e et al. 1988). T h e aim of this study was to investigate the effect of chronic t r e a t m e n t with verapamil on plasma A N P levels in y o u n g and elderly hypertensive patients.
Patients and methods A total of 19 patients with essential hypertension (systolic blood pressure, 90 but < 120mmHg) took part in this study; they were divided into 2 groups consisting of 9 young subjects (2 women and 7 men; mean age, 33 + 2 years) and 10 elderly patients (2 women and 8 men; mean age, 64 + 2 years) (Table 1). Determination of plasma ANP levels were carried out according to the following protocol: Plasma ANP levels were measured after patients had spent 30 min at supine rest
and after they had remained in 30 ° head-down tilt for 15 min (Fig. 1). In a double-blind, placebo-controlled cross-over study (Table 2), patients were given in a randomized order either a 120-rag tablet of verapamil or an apparently identical tablet of placebo three times daily for 4 weeks. At the end of each 4-week period, blood pressures were measured with an automated device (Dinamap) at 2 h after the last dose of verapamil and plasma ANP levels were determined 3 h after the last verapamil tablet by radioimmunoassay [INC-star: intraassay coefficient of variation, 8.6% (n = 10); interassay coefficient of variation, 11.6% (n = 10)]. All data are presented as the mean + SEM. Statistical analysis was performed according to the nonparametric Koch procedure for cross-over design using the Mann-Whitney and Wilcoxon tests.
Results N o interaction or periodic effects were seen b e t w e e n the cross-over periods. Verapamil t r e a t m e n t decreased b l o o d pressure f r o m 158 + 4/97 + 2 to 145 + 4/87 + 2 m m H g in elderly patients (P < 0.02) (Fig. 2). Figure 3 shows the effect of p l a c e b o vs verapamil on plasma A N P values deterTable 1. Patient characteristics according to group Group
Patients (n)
Men
Women
Age (years)
Young 9 7 2 33 (range, 21-40) Elderly 10 8 2 64 (range, 60-73) Patients showed normal liver-function tests and normal serum levels of creatinine, protein and albumin Table 2. Study design Single-blind
Double-blind
Double-blind
Washout
Verapamil 3 x 120 mg/day
Placebo
Placebo
Verapamil 3 x 120 mg/day 4 weeks
4 weeks
4 weeks
L. M. A. B. Van Bortel et al.: The influence of chronic treatment with verapamil
S 40 pg/ml
Horizontal
Head down 30°,
120 t
'°°t 8°1
®
040°1 0 young
elderly
young
elderly
Fig. 1. Plasma ANP levels in 9 young and 10 elderly hypertensive patients. * P
poaoJo0ma, Eo o, © Springer-Verlag 1990
The influence of chronic treatment with verapamil on plasma atrial natriuretic peptide levels in young and elderly hypertensive patients L. M. A . B. V a n B o r t e l 1, E M. H. Schiffers 1, R. O. B. B 6 h m 1, J. M. V. M o o i j ; , K. H. R a h n 2 a n d H. A. J. S t r u y k e r B o u d i e r t Departments of ~ Pharmacology and 2 Medicine, UniversityofLimburg, Maastricht, The Netherlands
Summary. In a double-blind, p l a c e b o - c o n t r o l l e d crossover study, the plasma atrial natriuretic peptide ( A N P ) levels of nine y o u n g and ten elderly hypertensive patients were c o m p a r e d after placebo and after t r e a t m e n t with 120 mg verapamil given three times daily over 4 weeks. D u r i n g placebo, plasma A N P levels p r o v e d to be higher in elderly patients than in y o u n g subjects. Chronic t r e a t m e n t with verapamil i n d u c e d a rise in A N P levels in b o t h y o u n g and elderly patients with hypertension.
Key words: A N R verapamil, hypertension, age
Atrial natriuretic peptide ( A N P ) has natriuretic, diuretic and vascular s m o o t h - m u s c l e relaxing activity; its release into the circulation seems to be regulated mainly by atrial distension. T h e calcium channel agonist B A Y K 8644 stimulates A N P secretion in isolated rat hearts (Saito et al. 1986) and in cultured rat cardiocytes (Matsubara et al. 1988); this effect is inhibited by nifedipine. A 5-mg dose of verapamil does not change b l o o d pressure in m a n but blocks the stimulatory effects of a s u d d e n increase in right atrial pressure u p o n release of A N P ( H a u f e et al. 1988). T h e aim of this study was to investigate the effect of chronic t r e a t m e n t with verapamil on plasma A N P levels in y o u n g and elderly hypertensive patients.
Patients and methods A total of 19 patients with essential hypertension (systolic blood pressure, 90 but < 120mmHg) took part in this study; they were divided into 2 groups consisting of 9 young subjects (2 women and 7 men; mean age, 33 + 2 years) and 10 elderly patients (2 women and 8 men; mean age, 64 + 2 years) (Table 1). Determination of plasma ANP levels were carried out according to the following protocol: Plasma ANP levels were measured after patients had spent 30 min at supine rest
and after they had remained in 30 ° head-down tilt for 15 min (Fig. 1). In a double-blind, placebo-controlled cross-over study (Table 2), patients were given in a randomized order either a 120-rag tablet of verapamil or an apparently identical tablet of placebo three times daily for 4 weeks. At the end of each 4-week period, blood pressures were measured with an automated device (Dinamap) at 2 h after the last dose of verapamil and plasma ANP levels were determined 3 h after the last verapamil tablet by radioimmunoassay [INC-star: intraassay coefficient of variation, 8.6% (n = 10); interassay coefficient of variation, 11.6% (n = 10)]. All data are presented as the mean + SEM. Statistical analysis was performed according to the nonparametric Koch procedure for cross-over design using the Mann-Whitney and Wilcoxon tests.
Results N o interaction or periodic effects were seen b e t w e e n the cross-over periods. Verapamil t r e a t m e n t decreased b l o o d pressure f r o m 158 + 4/97 + 2 to 145 + 4/87 + 2 m m H g in elderly patients (P < 0.02) (Fig. 2). Figure 3 shows the effect of p l a c e b o vs verapamil on plasma A N P values deterTable 1. Patient characteristics according to group Group
Patients (n)
Men
Women
Age (years)
Young 9 7 2 33 (range, 21-40) Elderly 10 8 2 64 (range, 60-73) Patients showed normal liver-function tests and normal serum levels of creatinine, protein and albumin Table 2. Study design Single-blind
Double-blind
Double-blind
Washout
Verapamil 3 x 120 mg/day
Placebo
Placebo
Verapamil 3 x 120 mg/day 4 weeks
4 weeks
4 weeks
L. M. A. B. Van Bortel et al.: The influence of chronic treatment with verapamil
S 40 pg/ml
Horizontal
Head down 30°,
120 t
'°°t 8°1
®
040°1 0 young
elderly
young
elderly
Fig. 1. Plasma ANP levels in 9 young and 10 elderly hypertensive patients. * P
