AJH
1991;
4:191S-193S
Acute Antihypertensive and Renal Effects of Isradipine in Hypertensive Patients With Normal and Reduced Renal Function C Wittenberg and J. B. Rosenfeld
T h e r e n a l effects of a s i n g l e o r a l dose of p l a c e b o υ a new d i h y d r o p y r i d i n e calcium antagonist, isradi p i n e , w e r e i n v e s t i g a t e d i n 12 p a t i e n t s w i t h m i l d - t o - m o d e r a t e e s s e n t i a l h y p e r t e n s i o n . Six p a t i e n t s ( g r o u p A) h a d n o r m a l c r e a t i n i n e c o n c e n t r a tions a n d a f u r t h e r six ( g r o u p B) h a d c r e a t i n i n e con centrations > 1 . 6 m g / d L . Patients maintained a c o n s t a n t d a i l y i n t a k e of a p p r o x i m a t e l y 120 m m o l of s o d i u m a n d 50 m m o l of p o t a s s i u m . M e a s u r e m e n t s w e r e t a k e n at 30, 60, a n d 90 m i n after d r u g a d m i n istration.
R e s u l t s i n d i c a t e d t h a t i s r a d i p i n e at a d o s e of 5 m g o n c e d a i l y p r o d u c e d significant a n t i h y p e r t e n s i v e a n d r e n a l r e s p o n s e s . I n c o n c l u s i o n , t h e r e is t h e r a p e u t i c benefit w i t h i s r a d i p i n e i n d e p e n d e n t of t h e s t a t u s of r e n a l f u n c t i o n . A m J H y p e r t e n s 1991;4:191S193S
I
(creatinine concentrations > 1 . 6 m g / d L ) . Patients w e r e to maintain a constant daily intake of 1 2 0 m m o l of so d i u m a n d 5 0 m m o l of potassium. S u p i n e blood pressure a n d heart rate m e a s u r e m e n t s w e r e taken at 3 0 - , 6 0 - , a n d 9 0 - m i n intervals after a single oral dose of 5 m g isradi pine, a n d t h e antihypertensive effects of active treat m e n t w e r e b a s e d on the m e a n of t h e last t w o m e a s u r e m e n t s only (at 6 0 a n d 9 0 min). Renal effects of isradi pine treatment w e r e assessed t h r o u g h renal plasma flow ( C 1 ) , glomerular filtration rate (CIJN), urine volume, a n d s o d i u m excretion, m e a s u r e d at three 2 0 - m i n inter vals within the first h o u r after isradipine administration, a l t h o u g h , again, t h e m e a n of only t h e last t w o m e a s u r e m e n t s (at 4 0 a n d 6 0 min) w e r e u s e d in the calcula tions.
sradipine, a n e w calcium antagonist of t h e d i h y d r o pyridine group, is a potent vasodilator with a long duration of action. Recent s t u d i e s h a v e s h o w n that isradipine as m o n o t h e r a p y or combined with other antihypertensive agents is effective in lowering blood pressure in patients with mild-to-moderate h y pertension. The objective of the present study w a s to evaluate the antihypertensive, renal, a n d natriuretic ef fects of a single oral administration of isradipine in h y pertensive p a t i e n t s . 1
2 - 9
10,11
PATIENTS A N D
METHODS
Twelve patients with mild-to-moderate hypertension were included in the study: six patients (group A) h a d normal renal function (creatinine concentrations, 0 . 6 1.2 m g / d L ) a n d six (group B) h a d reduced renal function
KEY W O R D S : H y p e r t e n s i o n , i s r a d i p i n e , r e n a l f u n c tion.
P A H
STUDY DESIGN From the Hypertension Clinic, Beilinson Medical Center, Petah Tikva; Tel Aviv University Sackler School of Medicine; Israel. Address correspondence and reprint requests to C. Wittenberg, M D , Hypertension Clinic, Beilinson Medical Center, Petah Tikva, Israel.
© 1991 by the American Journal of Hypertension,
Inc.
After four w e e k s of placebo w a s h o u t , patients w e r e e n tered into the study if their supine diastolic blood pres sure ( D B P ) w a s greater t h a n 9 5 m m H g on three con-
0895-7061/'91/'$3.50
192S
AJH-FEBRUARY
WITTENBERG A N D R O S E N F E L D
1991-VOL.
4, NO. 2, PART 2
TABLE 1. BLOOD PRESSURE AND HEART RATE OF HYPERTENSIVE PATIENTS WITH NORMAL AND REDUCED RENAL FUNCTION IN THE STUDY Normal Renal Function Baseline
Supine blood pressure (mm Hg) Systolic 163 ± 8 Diastolic 104 ± 3 Supine heart rate (beats/min) 78 ± 10
30 m i n
Reduced Renal Function
60 m i n
90 m i n
158 ± 5 152 ± 8* 94 ± 16 87 ± 14 — —
148 ± 8* 91 ± 13 82 ± 9
Baseline
30 m i n
178 ± 13 163 ± 1 3 * 92 ± 6 * 107 ± 9 75 ±7
60 m i n
90 m i n
166 ± 1 7 160 ± 13* 95 ± 12* 96 ± 13* 80 ± 4
* Ρ < .05 ν baseline.
TABLE 2. RENAL FUNCTION AND ELECTROLYTE EXCRETION BEFORE AND 90 MIN AFTER ISRADIPINE ADMINISTRATION
Glomerular filtration rate (inulin clearance) (mL/min) Renal plasma flow (PAH clearance) (mL/min) Urinary sodium (mmol/min) PAH, para-aminohippuric
Normal Renal Function
Reduced Renal Function
Baseline
90 m i n
Baseline
90 m i n
108 ± 12 452 ± 121 0.3 ± 0.09
123 ± 18* 606 ± 166* 1.0 ± 0.3**
52 ± 2 180 ± 5 6 0.33 ± 0 . 1 7
57 ± 6 * 252 ± 48* 0.6 ± 0.3**
acid.
* Ρ < .05 ν baseline. ** Ρ < .01 ν baseline.
secutive visits. The h e m o d y n a m i c a n d laboratory m e a s u r e m e n t s were performed at the e n d of the placebo period for baseline values. O n the day of the study, blood pressure w a s taken with the patient supine, fol l o w e d by a 60-min equilibration period. A priming dose of p a r a - a m i n o h i p p u r i c acid (PAH) w a s t h e n adminis tered, followed by three evaluations of renal function taken at 20 min intervals. After these m e a s u r e m e n t s for control data, 5 m g isradipine w a s given as a single dose orally, a n d a further three evaluations of renal p a r a m e ters w e r e performed at 20 m i n intervals.
RESULTS Blood pressure a n d heart rate are s h o w n in Table 1. Systolic blood pressure (SBP) w a s significantly d e creased in g r o u p A, b a s e d on values taken 60 to 90 min after isradipine administration, b u t reduction of DBP w a s not statistically significant. C h a n g e s in heart rate w e r e also n o t significant. In g r o u p B, there w e r e significant reductions of b o t h SBP a n d DBP at 30, 60, a n d 90 min after d r u g adminis tration, a n d , again, n o significant changes in heart rate were found.
R e n a l F u n c t i o n a n d Electrolyte Excretion C h a n g e s from baseline in these parameters 90 min after isradi pine administration are s h o w n in Table 2. There w e r e increases in glomerular filtration rate (inulin clearance)
a n d in renal plasma flow as well as in s o d i u m excretion. All of these changes were statistically significant. DISCUSSION In this study, the single 5 m g dose of isradipine, a n e w dihydropyridine calcium antagonist, p r o d u c e d a signifi cant reduction (P < .05) in blood pressure in patients with n o r m a l a n d reduced renal function. Because t h e study period w a s of short duration — 90 m i n after oral administration of the d r u g — t h e duration of the antihy pertensive effect w a s not évaluable. The increase of renal plasma flow a n d glomerular filtration rate in b o t h groups of patients suggests that it is possible to use this d r u g effectively a n d safely in h y p e r tensives with reduced renal function. Because of the small size of the study, however, further studies are n e e d e d in order to clarify these effects. In b o t h groups, natriuretic a n d diuretic effects w e r e observed as described with other calcium antagonists. There w e r e n o side effects with this dose of isradipine. In conclusion, the d r u g w a s effective a n d well tolerated in this g r o u p of patients. REFERENCES 1.
De Keyser P, Bouve J, Clement D, et al: Isradipine in essential hypertension: the Belgian General Practi tioners' Study. Am J Med 1989;86(suppl 4A):103-109.
2.
Burger KJ, Weidinger G, Welzel D: Efficacy and tolera bility of the new calcium antagonist isradipine in essen tial hypertension. J Cardiovasc Pharmacol 1989 (in press).
3.
Burger KJ, Weidinger G, Welzel D: Superior tolerability
AJH-FEBRUARY
1991-VOL
4, NO. 2, PART 2
of isradipine compared to nifedipine in mild essential hypertension. J Cardiovasc Pharmacol 1989 (in press). 4.
5.
Chellingsworth MC, Willis JV, Jack DB, et al: Pharmaco kinetics and pharmacodynamics of isradipine (PN-200110) in young and elderly patients. Am J Med 1988;84(suppl 3B):72-79. Dahlöf Β: Hemodynamic response, safety, and efficacy of isradipine in the treatment of essential hypertension. Am J Med 1989;86(suppl 4A):19-25.
6. Hamilton B: Treatment of essential hypertension with PN200-110 (isradipine). Am J Cardiol 1987;59:141B145B. 7. Lederballe Pedersen O, Krusell LR, et al: Long-term ef fects of isradipine on blood pressure and renal function. Am J Med 1989;86(suppl 4A):15-18.
ISRADIPINE A N D N O R M A L RENAL FUNCTION
193S
8.
Persson B, Anderson OK, Wysocki M, et al: Renal and hemodynamic effects of isradipine in essential hyper tension. Am J Med 1989;86(suppl 4A):60-64.
9.
The British Isradipine Hypertension Group: Evaluation of the safety and efficacy of isradipine in elderly patients with essential hypertension. Am J Med 1989;86(suppl 4A):110-114.
10.
Krusell LR, Jespersen LT, Schmitz A, et al: Repetitive natriuresis and blood pressure, long-term calcium entry blockade with isradipine. Hypertension 198 7; 10:577581.
11.
Krusell LR, Christensen CK, Pedersen OL: Acute na triuretic effect of nifedipine in hypertensive patients and normotensive controls—a proximal tubular effect? Eur J Pharmacol 1987;32:121-126.
1991;
4:191S-193S
Acute Antihypertensive and Renal Effects of Isradipine in Hypertensive Patients With Normal and Reduced Renal Function C Wittenberg and J. B. Rosenfeld
T h e r e n a l effects of a s i n g l e o r a l dose of p l a c e b o υ a new d i h y d r o p y r i d i n e calcium antagonist, isradi p i n e , w e r e i n v e s t i g a t e d i n 12 p a t i e n t s w i t h m i l d - t o - m o d e r a t e e s s e n t i a l h y p e r t e n s i o n . Six p a t i e n t s ( g r o u p A) h a d n o r m a l c r e a t i n i n e c o n c e n t r a tions a n d a f u r t h e r six ( g r o u p B) h a d c r e a t i n i n e con centrations > 1 . 6 m g / d L . Patients maintained a c o n s t a n t d a i l y i n t a k e of a p p r o x i m a t e l y 120 m m o l of s o d i u m a n d 50 m m o l of p o t a s s i u m . M e a s u r e m e n t s w e r e t a k e n at 30, 60, a n d 90 m i n after d r u g a d m i n istration.
R e s u l t s i n d i c a t e d t h a t i s r a d i p i n e at a d o s e of 5 m g o n c e d a i l y p r o d u c e d significant a n t i h y p e r t e n s i v e a n d r e n a l r e s p o n s e s . I n c o n c l u s i o n , t h e r e is t h e r a p e u t i c benefit w i t h i s r a d i p i n e i n d e p e n d e n t of t h e s t a t u s of r e n a l f u n c t i o n . A m J H y p e r t e n s 1991;4:191S193S
I
(creatinine concentrations > 1 . 6 m g / d L ) . Patients w e r e to maintain a constant daily intake of 1 2 0 m m o l of so d i u m a n d 5 0 m m o l of potassium. S u p i n e blood pressure a n d heart rate m e a s u r e m e n t s w e r e taken at 3 0 - , 6 0 - , a n d 9 0 - m i n intervals after a single oral dose of 5 m g isradi pine, a n d t h e antihypertensive effects of active treat m e n t w e r e b a s e d on the m e a n of t h e last t w o m e a s u r e m e n t s only (at 6 0 a n d 9 0 min). Renal effects of isradi pine treatment w e r e assessed t h r o u g h renal plasma flow ( C 1 ) , glomerular filtration rate (CIJN), urine volume, a n d s o d i u m excretion, m e a s u r e d at three 2 0 - m i n inter vals within the first h o u r after isradipine administration, a l t h o u g h , again, t h e m e a n of only t h e last t w o m e a s u r e m e n t s (at 4 0 a n d 6 0 min) w e r e u s e d in the calcula tions.
sradipine, a n e w calcium antagonist of t h e d i h y d r o pyridine group, is a potent vasodilator with a long duration of action. Recent s t u d i e s h a v e s h o w n that isradipine as m o n o t h e r a p y or combined with other antihypertensive agents is effective in lowering blood pressure in patients with mild-to-moderate h y pertension. The objective of the present study w a s to evaluate the antihypertensive, renal, a n d natriuretic ef fects of a single oral administration of isradipine in h y pertensive p a t i e n t s . 1
2 - 9
10,11
PATIENTS A N D
METHODS
Twelve patients with mild-to-moderate hypertension were included in the study: six patients (group A) h a d normal renal function (creatinine concentrations, 0 . 6 1.2 m g / d L ) a n d six (group B) h a d reduced renal function
KEY W O R D S : H y p e r t e n s i o n , i s r a d i p i n e , r e n a l f u n c tion.
P A H
STUDY DESIGN From the Hypertension Clinic, Beilinson Medical Center, Petah Tikva; Tel Aviv University Sackler School of Medicine; Israel. Address correspondence and reprint requests to C. Wittenberg, M D , Hypertension Clinic, Beilinson Medical Center, Petah Tikva, Israel.
© 1991 by the American Journal of Hypertension,
Inc.
After four w e e k s of placebo w a s h o u t , patients w e r e e n tered into the study if their supine diastolic blood pres sure ( D B P ) w a s greater t h a n 9 5 m m H g on three con-
0895-7061/'91/'$3.50
192S
AJH-FEBRUARY
WITTENBERG A N D R O S E N F E L D
1991-VOL.
4, NO. 2, PART 2
TABLE 1. BLOOD PRESSURE AND HEART RATE OF HYPERTENSIVE PATIENTS WITH NORMAL AND REDUCED RENAL FUNCTION IN THE STUDY Normal Renal Function Baseline
Supine blood pressure (mm Hg) Systolic 163 ± 8 Diastolic 104 ± 3 Supine heart rate (beats/min) 78 ± 10
30 m i n
Reduced Renal Function
60 m i n
90 m i n
158 ± 5 152 ± 8* 94 ± 16 87 ± 14 — —
148 ± 8* 91 ± 13 82 ± 9
Baseline
30 m i n
178 ± 13 163 ± 1 3 * 92 ± 6 * 107 ± 9 75 ±7
60 m i n
90 m i n
166 ± 1 7 160 ± 13* 95 ± 12* 96 ± 13* 80 ± 4
* Ρ < .05 ν baseline.
TABLE 2. RENAL FUNCTION AND ELECTROLYTE EXCRETION BEFORE AND 90 MIN AFTER ISRADIPINE ADMINISTRATION
Glomerular filtration rate (inulin clearance) (mL/min) Renal plasma flow (PAH clearance) (mL/min) Urinary sodium (mmol/min) PAH, para-aminohippuric
Normal Renal Function
Reduced Renal Function
Baseline
90 m i n
Baseline
90 m i n
108 ± 12 452 ± 121 0.3 ± 0.09
123 ± 18* 606 ± 166* 1.0 ± 0.3**
52 ± 2 180 ± 5 6 0.33 ± 0 . 1 7
57 ± 6 * 252 ± 48* 0.6 ± 0.3**
acid.
* Ρ < .05 ν baseline. ** Ρ < .01 ν baseline.
secutive visits. The h e m o d y n a m i c a n d laboratory m e a s u r e m e n t s were performed at the e n d of the placebo period for baseline values. O n the day of the study, blood pressure w a s taken with the patient supine, fol l o w e d by a 60-min equilibration period. A priming dose of p a r a - a m i n o h i p p u r i c acid (PAH) w a s t h e n adminis tered, followed by three evaluations of renal function taken at 20 min intervals. After these m e a s u r e m e n t s for control data, 5 m g isradipine w a s given as a single dose orally, a n d a further three evaluations of renal p a r a m e ters w e r e performed at 20 m i n intervals.
RESULTS Blood pressure a n d heart rate are s h o w n in Table 1. Systolic blood pressure (SBP) w a s significantly d e creased in g r o u p A, b a s e d on values taken 60 to 90 min after isradipine administration, b u t reduction of DBP w a s not statistically significant. C h a n g e s in heart rate w e r e also n o t significant. In g r o u p B, there w e r e significant reductions of b o t h SBP a n d DBP at 30, 60, a n d 90 min after d r u g adminis tration, a n d , again, n o significant changes in heart rate were found.
R e n a l F u n c t i o n a n d Electrolyte Excretion C h a n g e s from baseline in these parameters 90 min after isradi pine administration are s h o w n in Table 2. There w e r e increases in glomerular filtration rate (inulin clearance)
a n d in renal plasma flow as well as in s o d i u m excretion. All of these changes were statistically significant. DISCUSSION In this study, the single 5 m g dose of isradipine, a n e w dihydropyridine calcium antagonist, p r o d u c e d a signifi cant reduction (P < .05) in blood pressure in patients with n o r m a l a n d reduced renal function. Because t h e study period w a s of short duration — 90 m i n after oral administration of the d r u g — t h e duration of the antihy pertensive effect w a s not évaluable. The increase of renal plasma flow a n d glomerular filtration rate in b o t h groups of patients suggests that it is possible to use this d r u g effectively a n d safely in h y p e r tensives with reduced renal function. Because of the small size of the study, however, further studies are n e e d e d in order to clarify these effects. In b o t h groups, natriuretic a n d diuretic effects w e r e observed as described with other calcium antagonists. There w e r e n o side effects with this dose of isradipine. In conclusion, the d r u g w a s effective a n d well tolerated in this g r o u p of patients. REFERENCES 1.
De Keyser P, Bouve J, Clement D, et al: Isradipine in essential hypertension: the Belgian General Practi tioners' Study. Am J Med 1989;86(suppl 4A):103-109.
2.
Burger KJ, Weidinger G, Welzel D: Efficacy and tolera bility of the new calcium antagonist isradipine in essen tial hypertension. J Cardiovasc Pharmacol 1989 (in press).
3.
Burger KJ, Weidinger G, Welzel D: Superior tolerability
AJH-FEBRUARY
1991-VOL
4, NO. 2, PART 2
of isradipine compared to nifedipine in mild essential hypertension. J Cardiovasc Pharmacol 1989 (in press). 4.
5.
Chellingsworth MC, Willis JV, Jack DB, et al: Pharmaco kinetics and pharmacodynamics of isradipine (PN-200110) in young and elderly patients. Am J Med 1988;84(suppl 3B):72-79. Dahlöf Β: Hemodynamic response, safety, and efficacy of isradipine in the treatment of essential hypertension. Am J Med 1989;86(suppl 4A):19-25.
6. Hamilton B: Treatment of essential hypertension with PN200-110 (isradipine). Am J Cardiol 1987;59:141B145B. 7. Lederballe Pedersen O, Krusell LR, et al: Long-term ef fects of isradipine on blood pressure and renal function. Am J Med 1989;86(suppl 4A):15-18.
ISRADIPINE A N D N O R M A L RENAL FUNCTION
193S
8.
Persson B, Anderson OK, Wysocki M, et al: Renal and hemodynamic effects of isradipine in essential hyper tension. Am J Med 1989;86(suppl 4A):60-64.
9.
The British Isradipine Hypertension Group: Evaluation of the safety and efficacy of isradipine in elderly patients with essential hypertension. Am J Med 1989;86(suppl 4A):110-114.
10.
Krusell LR, Jespersen LT, Schmitz A, et al: Repetitive natriuresis and blood pressure, long-term calcium entry blockade with isradipine. Hypertension 198 7; 10:577581.
11.
Krusell LR, Christensen CK, Pedersen OL: Acute na triuretic effect of nifedipine in hypertensive patients and normotensive controls—a proximal tubular effect? Eur J Pharmacol 1987;32:121-126.
