source: https://doi.org/10.7892/boris.115788 | downloaded: 1.2.2022
AJH 1991; 4:348-355
Cardiovascular Pressor Reactivity After Chronic Converting Enzyme Inhibition
Michaela Bernasconi, Claudio Marone, Carlo Beretta-Piccoli, Giuseppe Lepori, Sidney Shaw, and Peter Weidmann
I n a d d i t i o n to i n h i b i t i n g t h e f o r m a t i o n of a n g i o t e n s i n II, c h r o n i c c o n v e r t i n g e n z y m e i n h i b i t i o n m a y affect o t h e r b l o o d p r e s s u r e m o d u l a t i n g factors. T h e i n f l u e n c e of a n 8 w e e k t r e a t m e n t p h a s e w i t h Cilaza
p r i l o n t h e a c t i v i t y of t h e r e n i n - a n g i o t e n s i n - a l d o s t e r o n e a n d s y m p a t h e t i c n e r v o u s s y s t e m s , t h e p r e s sor r e a c t i v i t y t o i n f u s e d a n g i o t e n s i n II or
n o r e p i n e p h r i n e , t h e c h r o n o t r o p i c r e s p o n s e to i s o p r o t e r e n o l , a n d b o d y s o d i u m a n d p l a s m a a t r i a l n a t r i u r e t i c p e p t i d e c o n c e n t r a t i o n s w a s a s s e s s e d i n 11 n o r m a l s u b j e c t s a n d 12 p a t i e n t s w i t h e s s e n t i a l h y p e r t e n s i o n . A s c o m p a r e d t o a 4 w e e k p l a c e b o p h a s e , Cilazapril d e c r e a s e d a r t e r i a l p r e s s u r e i n b o t h s t u d y g r o u p s (from 1 2 4 / 8 3 ± 9 / 6 to 1 1 4 / 7 7 ± 9 / 5 m m H g a n d f r o m 143/102 ± 1 3 / 7 to 1 3 7 / 9 6 ± 1 0 / 1 0 m m H g ; Ρ < .025); e x c h a n g e a b l e s o d i u m (—158 m m o l a n d , r e s p e c t i v e l y , —104 m m o l ) a n d u p r i g h t p l a s m a a l d o s t e r o n e (—24% a n d —15%) a l s o t e n d e d to fall.
H e a r t r a t e , t h e c h r o n o t r o p i c r e s p o n s e to p o s t u r e or
i s o p r o t e r e n o l , p l a s m a n o r e p i n e p h r i n e l e v e l s , t h e c o n c e n t r a t i o n / p r e s s o r r e s p o n s e c u r v e to n o r e p i n e p h r i n e , p l a s m a a t r i a l n a t r i u r e t i c p e p t i d e c o n c e n t r a t i o n , p l a s m a a n g i o t e n s i n II a n d t h e r e s p o n s e s of b l o o d p r e s s u r e or p l a s m a a l d o s t e r o n e t o a n g i o t e n s i n II w e r e u n c h a n g e d after 8 w e e k s of Cilazapril.
P l a s m a r e n i n a c t i v i t y i n c r e a s e d ( + 1 7 5 % t o + 650%).
T h e s e f i n d i n g s i n d i c a t e t h a t t h e b l o o d p r e s s u r e l o w e r i n g effect of Cilazapril i n t h e s t a b l e p h a s e of p h a r m a c o l o g i c a l i n t e r v e n t i o n is n o t a s s o c i a t e d w i t h m o d i f i c a t i o n s of s y m p a t h e t i c - d e p e n d e n t p r e s s o r r e a c t i v i t y or ^ - a d r e n e r g i c s e n s i t i v i t y . P l a s m a a n g i o t e n s i n II c o n c e n t r a t i o n a n d a n g i o t e n s i n I I - d e p e n - d e n t p a t h w a y s i n c l u d i n g t h e p r e s s o r a n d
a l d o s t e r o n e r e s p o n s i v e n e s s to a n g i o t e n s i n II a r e also u n c h a n g e d . A m J H y p e r t e n s 1991;4:348-355
KEY W O R D S : C i l a z a p r i l , a n g i o t e n s i n II, a l d o s t e r o n e , n o r e p i n e p h r i n e , e s s e n t i a l h y p e r t e n s i o n .
T
h e use of inhibitors of converting e n z y m e h a s b e c o m e a n established principle of a n t i h y p e r tensive p h a r m a c o t h e r a p y , b u t t h e m e c h a n i s m s relating converting e n z y m e inhibition to a d e crease of arterial pressure r e m a i n unclear. Reduction of circulating angiotensin II (All) is t h e initial e v e n t .1 U n d e r chronic conditions, t h e relationship b e t w e e n variations in arterial pressure a n d circulating All
From the Ospedale Italiano, Viganello; Ospedale S. Giovanni, Bel- linzona; and Medizinische Universitätspoliklinik Bern, Switzerland.
This work w a s supported b y a grant in aid by Hoffman-La-Roche, Basle, Switzerland.
Address correspondance and reprint requests to Prof. Dr. m e d . C.
Beretta-Piccoli, Ospedale Italiano di Lugano, 6 9 6 2 Viganello, Switzer
land.
is less close,2 suggesting t h a t additional m e c h a n i s m s m a y be involved. Angiotensin II levels in tissues rather t h a n in blood m a y d e t e r m i n e arterial p r e s s u r e .3 Accu
m u l a t i o n of vasodilating k i n i n s4 or p r o s t a g l a n d i n s5 m a y occur. S y m p a t h e t i c - d e p e n d e n t cardiovascular regula
tion m a y b e modified.6 Moreover, t h e p l a s m a levels of a pressor h o r m o n e are inversely related to t h e cardiovas
cular pressor reactivity to t h e m .7 Therefore, a decrease of circulating All will result in a net depressor effect only in t h e absence of a full c o m p e n s a t i o n by a n i n c r e m e n t e d pressor sensitivity to AIL
After t h e introduction of t h e first oral acting convert
ing e n z y m e inhibitor, Captopril, m o r e p o t e n t a n d longer acting substances, such as enalapril, w e r e p r o p o s e d for clinical u s e .8 Cilazapril, o n e of t h e n e w e r substances, h a s t h e characteristics of a nonsulfhydryl p r o d r u g , ie,
© 1991 by the American Journal of Hypertension, Inc. 0895-7061/91/$3.50
AJH-APRIL 1991-VOL. 4, NO. 4, PART 1 P R E S S O R R E A C T I V I T Y 349
after oral administration it is rapidly converted to t h e active metabolite, cilazaprilat.9 P h a r m a c o d y n a m i c in
vestigations in h u m a n s suggest that this d r u g is m o r e p o t e n t a n d longer acting t h a n b o t h Captopril a n d enala
p r i l1 0 a n d does n o t a c c u m u l a t e w i t h r e p e a t e d a d m i n i s tration despite t h e long half-life.1 1 In order to investigate further t h e m e c h a n i s m of action of chronic converting e n z y m e inhibition, this long-acting c o m p o u n d w a s chosen; its s i m u l t a n e o u s effects o n several b l o o d p r e s sure m o d u l a t i n g systems including t h e pressor reactiv
ity to angiotensin II or n o r e p i n e p h r i n e w e r e e v a l u a t e d in n o r m a l subjects a n d patients w i t h essential h y p e r t e n sion.
SUBJECTS A N D M E T H O D S
T w e n t y - t h r e e subjects aged b e t w e e n 18 a n d 70 years w e r e recruited for t h e study. They included 11 n o r m a l subjects (four w o m e n a n d seven m e n ) , aged 29 to 60 years ( m e a n ± SD age 38 ± 10 years), a n d 12 patients w i t h essential h y p e r t e n s i o n (four w o m e n a n d eight m e n ) , a g e d 26 to 58 years ( m e a n age 45 ± 12 years) w i t h a diastolic blood pressure b e t w e e n 95 a n d 115 m m H g . T h e n o r m a l subjects w e r e h e a l t h y volunteers w i t h o u t p r e v i o u s episodes of h i g h blood pressure a n d w i t h a b l o o d pressure consistently < 1 4 0 / 9 0 m m H g t h r o u g h out t h e study. T h e presence of h y p e r t e n s i o n in t h e p a tients w a s defined b y obtaining r e p e a t e d blood pressure m e a s u r e m e n t s of b e t w e e n 1 4 0 / 9 0 a n d 1 8 0 / 1 1 5 m m Hg, t a k e n u n d e r o u t p a t i e n t conditions. S e c o n d a r y forms of h y p e r t e n s i o n w e r e excluded b y t h e u s u a l tests;
n o p a t i e n t h a d m a l i g n a n t h y p e r t e n s i o n ( h y p e r t e n s i v e r e t i n o p a t h y stages I I I - I V ) , e d e m a , a r r h y t h m i a , renal failure (serum creatinine > 9 5 / / m o l / L ) or h e a r t failure.
All a n t i h y p e r t e n s i v e d r u g s a n d p o t a s s i u m s u p p l e m e n t s w e r e d i s c o n t i n u e d at least 3 w e e k s before t h e s t u d y b e g a n . N o n e of t h e w o m e n w a s taking h o r m o n a l con
traceptives. Informed consent w a s o b t a i n e d from all subjects a n d t h e s t u d y protocol w a s a p p r o v e d b y t h e ethical committee of our institution.
T r e a t m e n t P l a n T h e subjects w e r e instructed to con
t i n u e eating a n o r m a l diet, avoiding very h i g h or l o w s o d i u m i n t a k e s .1 2 A placebo (one tablet daily) w a s given over a period of 4 w e e k s a n d w a s t h e n replaced b y a 2.5 m g dose of Cilazapril, given once daily at breakfast.
After 2 w e e k s of treatment, t h e dose w a s increased to 5 m g daily if diastolic blood pressure w a s n o t decreased to 90 m m H g . T h e d u r a t i o n of t h e w h o l e t r e a t m e n t p h a s e w a s 8 w e e k s .
Blood P r e s s u r e , H o r m o n e s a n d I s o p r o t e r e n o l T e s t D u r i n g t h e r a p y , subjects h a d their blood pressure a n d h e a r t rate m e a s u r e d every 2 weeks, 24 to 26 h after their intake of t h e last Cilazapril dose, b e t w e e n 7:00 a n d 9:00 AM, after 10 m i n rest in t h e s u p i n e position a n d after 2 m i n in t h e s t a n d i n g position. D u r i n g t h e 4 last d a y s of t h e placebo a n d Cilazapril t r e a t m e n t p h a s e s , t h e follow
ing m e a s u r e m e n t s w e r e o b t a i n e d . A 24 h u r i n e collec
tion w a s carried out to d e t e r m i n e s o d i u m , p o t a s s i u m , a n d creatinine excretion rates. Blood p r e s s u r e ( s t a n d a r d cuff a n d s p h y g m o m a n o m e t e r ; each v a l u e w a s t h e m e a n of three readings), h e a r t rate, e x c h a n g e a b l e s o d i u m , a n d p l a s m a s o d i u m , p o t a s s i u m , calcium, p h o s p h a t e , creati
nine, uric acid, renin activity, angiotensin II (All), aldos
terone, n o r e p i n e p h r i n e (NE), e p i n e p h r i n e , a n d atrial natriuretic p e p t i d e (ANP) w e r e d e t e r m i n e d after a n overnight fast a n d after 1 h of rest in t h e s u p i n e position (subjects took only t h e u s u a l m o r n i n g dose of placebo or
C i l a z a p r i l ) . Blood pressure, h e a r t rate, p l a s m a r e n i n ac
tivity, All, aldosterone, NE, e p i n e p h r i n e , a n d A N P le
vels w e r e m e a s u r e d again after t h e subjects h a d s p e n t 60 m i n walking. After e m p t y i n g t h e b l a d d e r , subjects rested in t h e s u p i n e position a n d a n isoproterenol sensi
tivity test w a s p e r f o r m e d w i t h bolus injections accord
ing to our s t a n d a r d p r o c e d u r e .1 3'1 4
N o r e p i n e p h r i n e a n d A n g i o t e n s i n II I n f u s i o n In order to test t h e subjects' pressor or a l d o s t e r o n e r e s p o n siveness, NE a n d All w e r e infused i n t r a v e n o u s l y 1 to 3 d a y s after t h e isoproterenol test according to our stan
d a r d p r o c e d u r e .1 3 , 1 4
M e t h o d o l o g y P l a s m a a n d u r i n a r y s o d i u m w e r e m e a s u r e d by flame p h o t o m e t r y . Creatinine, uric acid a n d calcium concentrations w e r e m e a s u r e d b y a u t o a n a - lyzer, p h o s p h a t e b y colorimetric p h o s p h o m o l y b d a t e .
Plasma renin activity, aldosterone, All, a n d A N P w e r e d e t e r m i n e d b y r a d i o i m m u n o a s s a y1 5 - 1 8 a n d p l a s m a NE a n d e p i n e p h r i n e concentrations w e r e o b tained using a r a d i o e n z y m a t i c m e t h o d ,1 9 as r e p o r t e d e l s e w h e r e .2 0 Exchangeable s o d i u m w a s m e a s u r e d b y isotope dilution t e c h n i q u e using 2 4N a .2 1 Cardiovascular reactivity w a s a n a l y z e d b y calculation of t h r e s h o l d a n d pressor d o s e s1 3 , 1 4 a n d b y deriving d o s e - r e s p o n s e curves.
T h e chronotropic isoproterenol dose w a s derived using t h e d o s e - r e s p o n s e curve relating i s o p r o t e r e n o l - i n d u c e d i n c r e m e n t s of h e a r t rate to t h e isoproterenol d o s e s .2 2 Statistics Since t h e logarithmic transformation r a t h e r t h a n t h e absolute values followed a G a u s s i a n distribu
tion, t h e n a t u r a l logarithmic transformation of p l a s m a renin activity, infused NE dosage, All or isoproterenol a n d pressor or t h r e s h o l d NE a n d All dosages, a n d chronotropic isoproterenol dosages w e r e u s e d for t h e statistical analysis. Statistical analysis included t h e paired S t u d e n t ' s two-tailed t test a n d t h e Wilcoxon test (comparison of p a i r e d values within groups), regression analysis, analyses of variance (comparison of v a l u e s a m o n g t h e groups) a n d covariance (comparison of d o s e - r e s p o n s e curves).
R E S U L T S
At t h e e n d of t h e placebo p h a s e , n o r m o t e n s i v e a n d h y pertensive subjects did n o t differ significantly in m e a n
350 B E R N A S C O N I E T A L AJH-APRIL 1991-VOL 4, NO. 4, PART 1
TABLE 1. CLINICAL AND BIOCHEMICAL FINDINGS BEFORE AND AFTER CILAZAPRIL IN NORMAL AND HYPERTENSIVE SUBJECTS (MEAN ± SD)
Normal Subjects Essential Hypertension
P l a c e b o C i l a z a p r i l P l a c e b o C i l a z a p r i l
Blood pressure, mm Hg
supine 124/83 ± 9 / 6 114/77 ± 9 / 5 * 143/102 ± 13/7 137/96 ± 10/10*
upright 120/86 ± 14/8 110/81 ± 10/6* 141/110 ± 13/8 136/104 ± 8 / 7 *
Heart rate, beats/min
supine 70 ± 14 67 ± 7 71 ± 8 71 ± 10
upright 85 ± 1 4 88 ± 12 87 ± 12 82 ± 12
Body weight, kg 73.1 ± 12.3 73.1 ± 12.4 75.5 ± 1 1 . 6 75.6 ± 1 1 . 9
Exchangeable sodium, mmol 3140 ± 5 0 7 2982 ± 497 3008 ± 436 2904 ± 440
Haematocrit, % 41.5 ± 3 . 8 5 40.7 ± 4 . 0 42.7 ± 5 . 2 42.7 ± 5 . 4
Plasma sodium, mmol/L 140.6 ± 2 . 1 140 ± 1.8 140.2 ± 2 . 0 140.5 ± 2.3
potassium, mmol/L 3.95 ± 0.27 4.03 ± 0.20 4.12 ± 0 . 2 5 4.15 ± 0 . 2 8
calcium, mmol/L 2.34 ± 0.08 2.22 ± 0.08 2.36 ± 0.09 2.28 ± 0.08
phosphate, mmol/L 1.17 ± 0 . 1 3 1.08 ± 0 . 1 3 1.01 ± 0 . 1 6 1.10 ± 0 . 1 8
uric acid, //mol/L 263 ± 96 279 ± 107 258 ± 66 298 ± 68
Creatinine clearance, mL/min 134 ± 20 137 ± 3 4 113 ± 2 2 111 ± 3 1
Urinary sodium, mmol/24 h 170 ± 4 7 172 ± 3 9 137 ± 4 3 151 ± 5 9
* Ρ < .025; t Ρ < .01 ν placebo values.
age (38 ± 1 0 i ? 4 5 ± 1 2 years), b o d y weight, e x c h a n g e able s o d i u m , h e a r t rate, p l a s m a or u r i n a r y electrolytes, a n d creatinine clearance (Table 1).
T h e dose of Cilazapril w a s increased after t w o treat
m e n t w e e k s in n i n e of 11 p a t i e n t s ( m e a n d o s e 4.6 ± 1.0 mg); in order to h a v e a c o m p a r a b l e dosage, t h e dose w a s also increased in six of t h e n o r m a l subjects ( m e a n d o s e 3.8 ± 1 . 3 mg).
As c o m p a r e d w i t h t h e placebo p h a s e , Cilazapril d e creased s u p i n e a n d u p r i g h t arterial p r e s s u r e in b o t h s t u d y g r o u p s (Table 1). H e a r t rate, b o d y weight, p l a s m a a n d u r i n a r y electrolytes, a n d creatinine clearance w e r e u n c h a n g e d (Table 1). Exchangeable s o d i u m t e n d e d to
decrease, b u t in t h e individual g r o u p s t h e c h a n g e did n o t reach statistical significance.
R e n i n - A n g i o t e n s i n - A l d o s t e r o n e S y s t e m a n d R e a c t i v i t y to A l l As c o m p a r e d to placebo conditions, Cilaza
pril caused a significant increase of s u p i n e a n d u p r i g h t p l a s m a r e n i n activity a n d a fall of u p r i g h t p l a s m a aldos
t e r o n e in t h e t w o s t u d y groups; s u p i n e p l a s m a aldoster
o n e decreased only in h y p e r t e n s i v e s (Table 2). P l a s m a All levels r e m a i n e d o n average u n c h a n g e d (Table 2).
As c o m p a r e d to placebo conditions, s u p i n e , preinfu
sion p l a s m a All did n o t c h a n g e significantly after Cila
zapril in t h e t w o s t u d y g r o u p s w h i l e p l a s m a aldosterone
TABLE 2. RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND REACTIVITY TO ANGIOTENSIN II BEFORE AND AFTER CILAZAPRIL (MEAN ± SD)
Normal Subjects Essential Hypertension
P l a c e b o C i l a z a p r i l P l a c e b o C i l a z a p r i l
Plasma Reinin Activity, n g / m L - h
supine 1.78
±
0.7 7.69±
5.92* 1.81±
1.31 4.95±
3.94*upright 5.29
±
2.03 31.54±
20.48t 4.20±
2.76 31.4±
34.5tPlasma Angiotensin II, pg/mL
supine 6.1
±
3.6 6.6±
2.0 8.7±
3.7 8.8±
4.7upright 13.1
±
7.9 9.9±
3.2 16.3±
10.6 13.9±
7.6Plasma Aldosterone, n g / d L
supine 7.2
±
2.9 6.2±
1.5 7.8±
2.1 6.2±
1.5*upright 13.1
±
7.9 9.9±
3.2* 16.3±
10.6 13.9±
7.6*Preinfusion plasma angiotensin II, pg/mL 7.7
±
4.5 8.3±
1.9 10.5±
2.4 8.5±
3.6Angiotensin II threshold dose, n g / k g - m i n 1.12
±
0.56 1.57±
1.45 0.83±
0.33 0.90±
0.62Angiotensin II pressor dose, n g / k g · min 12.12
±
6.5 8.92±
5.13 6.33±
2.4 7.0±
4.2* Ρ < .05; t Ρ < -005 ν placebo.
AJH-APRIL 1991-VOL. 4, NO. 4, PART 1 P R E S S O R REACTIVITY 351
t e n d e d to fall slightly a l t h o u g h n o t significantly (Figure 1). After placebo, t h e pressor reactivity, as j u d g e d b y t h e All pressor a n d t h r e s h o l d doses, w a s slightly, b u t n o t significantly, lower in h y p e r t e n s i v e t h a n in n o r m a l s u b jects a n d did not c h a n g e after Cilazapril in t h e t w o s t u d y g r o u p s (Table 2). After placebo, in n o r m a l subjects, t h e increase in systolic blood pressure d u r i n g All infusion at t h e dose rate of 10 n g / k g · m i n ( + 22 ± 12 m m Hg) w a s associated w i t h a significant (P < .005) decrease of h e a r t rate (—9 ± 8 b e a t s / m i n ) ; in patients w i t h essential h y p e r t e n s i o n t h e A l l - i n d u c e d increase of systolic b l o o d p r e s s u r e ( + 3 1 ± 11 m m Hg) w a s n o t a c c o m p a n i e d b y a decrease of h e a r t rate (— 1 ± 6 b e a t s / m i n ) . T h e rela
tionship b e t w e e n A l l - i n d u c e d increases in b l o o d p r e s sure a n d concomitant d e c r e m e n t s of h e a r t rate differed significantly b e t w e e n t h e t w o s t u d y g r o u p s (F = 21.2;
Ρ < .01). After C i l a z a p r i l , h e a r t rate decreased d u r i n g All infusion in n o r m a l ( + 26 ± 14 m m H g a n d —10 ± 6 b e a t s / m i n ) a n d h y p e r t e n s i v e subjects ( + 2 9 ± 16 m m H g a n d — 6 ± 4 b e a t s / m i n ; Ρ < .01) a n d t h e relation
s h i p b e t w e e n A l l - i n d u c e d i n c r e m e n t s of blood pressure
a n d d e c r e m e n t s of h e a r t rate did n o t differ b e t w e e n t h e t w o s t u d y g r o u p s (F = 0.48).
T h e p l a s m a All levels m e a s u r e d at t h e e n d of each All infusion dose rate correlated closely w i t h t h e corre
s p o n d i n g dose rate; t h e correlation w a s similar after placebo a n d Cilazapril in n o r m a l subjects (respectively:
r = 0.87; Ρ < . 0 0 1 ; lny = 0.991nx + 2.76, a n d r = 0.87;
Ρ < . 0 0 1 ; lny = 0.991nx + 2.89) a n d h y p e r t e n s i v e p a tients (r = 0.77; Ρ < . 0 0 1 ; lny = 0.891nx + 3.20 a n d r = 0.87; Ρ < . 0 0 1 ; lny = 1.061nx + 2.82). T h e relation
ship b e t w e e n t h e A l l - i n d u c e d increases in diastolic arte
rial pressure a n d p l a s m a All concentrations w a s n o t modified b y Cilazapril as c o m p a r e d w i t h placebo condi
tions (F = 2.07 a n d 1.86; Ρ = NS) (Figure 1).
After placebo, All caused a significant increase of p l a s m a aldosterone in n o r m a l subjects a n d p a t i e n t s w i t h essential h y p e r t e n s i o n (Figure 1). After Cilazapril, t h e p l a s m a levels of aldosterone increased to a c o m p a r a b l e extent d u r i n g All infusion in n o r m a l subjects a n d in h y p e r t e n s i v e patients. T h e relationship b e t w e e n p l a s m a aldosterone a n d p l a s m a All concentration o b t a i n e d
Λ Diastolic B l o o d Pressure
3 0 η m m H g
2 0
10
N o r m a l S u b j e c t s Essential H y p e r t e n s i o n
O Placebo
• Cilazapril
oJ
6 10 2 0 5 0 1 0 0 2 0 0 4 0 0 6 10 2 0 5 0 1 0 0 2 0 0 4 0 0
P l a s m a A l d o s t e r o n e 3 0
2 0
1 0 n g / d l
Placebo Δ Cilazapril A
7 10 2 0 ~50 1 0 0 2 0 0 4 0 0 7~10 2 0 ~
FIGURE 1. Relationship between diastolic blood pressure or plasma al
dosterone and plasma angiotensin II during angiotensin II infusion before and after Cilazapril in normal subjects (left panel) and patients with essential hypertension (right panel). Open sym
bols indicate mean values after pla
cebo; black symbols mean values after Cilazapril. Bars indicate SEM. The curves are not significantly different.
5 0 1 0 0 2 0 0 4 0 0 P l a s m a A n g i o t e n s i n II, p g / m l
352 B E R N A S C O N I ET AL AJH-APRIL 1991-VOL. 4, NO. 4, PART 1
d u r i n g ΑΠ infusion w a s n o t modified b y Cilazapril as c o m p a r e d to placebo conditions in t h e t w o s t u d y g r o u p s (F = 0.03 a n d 0.86; NS) (Figure 1).
S y m p a t h e t i c N e r v o u s S y s t e m At t h e e n d of t h e pla
cebo p h a s e , n o r m a l subjects a n d patients w i t h essential h y p e r t e n s i o n did n o t differ significantly in s u p i n e a n d u p r i g h t p l a s m a NE a n d e p i n e p h r i n e levels as well as in N E t h r e s h o l d a n d pressor doses (Table 3). Cilazapril did n o t modify either p l a s m a NE a n d e p i n e p h r i n e levels or t h e pressor reactivity to infused NE, as j u d g e d b y t h e NE t h r e s h o l d a n d pressor doses (Table 3).
U n d e r placebo conditions, t h e increase in systolic b l o o d p r e s s u r e d u r i n g NE infusion at t h e d o s e of 200 n g / k g · m i n w a s associated w i t h a significant d e crease of h e a r t rate in n o r m a l subjects ( + 30 ± 8 m m H g a n d — 8 ± 6 b e a t s / m i n ; Ρ < .01). H y p e r t e n s i v e patients r e s p o n d e d to a lower NE dose rate (100 n g / k g · min) w i t h a c o m p a r a b l e increase of arterial pressure a n d d e crease of h e a r t rate ( + 3 3 ± 9 m m H g a n d —6 ± 5 b e a t s / m i n ; Ρ < .025). After Cilazapril, t h e N E - i n d u c e d increase in m e a n blood pressure w a s a c c o m p a n i e d b y a similar decrease of h e a r t rate in t h e t w o s t u d y g r o u p s ( + 3 3 ± 10 m m H g a n d - 8 ± 6 b e a t s / m i n a n d + 3 6 ± 14 m m H g a n d — 5 ± 4 b e a t s / m i n , respectively). T h e relationship b e t w e e n t h e N E - i n d u c e d increases in arte
rial p r e s s u r e a n d t h e c o n c o m i t a n t d e c r e m e n t s of h e a r t rate did n o t differ b e t w e e n n o r m a l a n d h y p e r t e n s i v e subjects u n d e r placebo conditions a n d it w a s unaffected b y Cilazapril (F = 0.06 to 0.46).
P l a s m a NE concentration, m e a s u r e d at t h e e n d of each NE infusion step, correlated closely w i t h t h e corre
s p o n d i n g N E infusion rates a n d correlations w e r e simi
lar in n o r m a l subjects before (r = 0.94; lny = 0.831nx + 1.5; Ρ < .001) a n d after (r = 0.98; lny = 0.931nx + 1.09;
Ρ < .001) Cilazapril; t h e c o r r e s p o n d i n g correlations w e r e also c o m p a r a b l e in h y p e r t e n s i v e patients (r = 0.92; lny = 0 . 8 3 1 n x + 1 . 4 9 ; Ρ < .001 a n d r = 0.94;
lny = 0 . 9 1 1 n x + 1 . 2 1 ; Ρ < .001). T h e concentration- r e s p o n s e curve of arterial pressure a n d p l a s m a NE con
centration w a s n o t modified b y Cilazapril in t h e t w o s t u d y g r o u p s as c o m p a r e d to placebo conditions (Fig
u r e 2) ( F = 1 . 4 4 a n d 2.95).
A t r i a l N a t r i u r e t i c P e p t i d e At t h e e n d of t h e placebo p h a s e , s u p i n e a n d u p r i g h t p l a s m a A N F levels w e r e lower (P < .05) in n o r m a l subjects (27.5 ± 19.4 a n d 18.6 ± 16.0 p g / m L ) t h a n in h y p e r t e n s i v e p a t i e n t s (52.5 ± 28.5 a n d 38.3 ± 20.5 p g / m L ) . There w a s n o c h a n g e after Cilazapril, w i t h a persistent elevation in h y p e r t e n s i v e s (30.5 ± 21.3 a n d 19.8 ± 13.3 p g / m L in n o r m a l subjects ν 62.5 ± 39.1 a n d 34.3 ± 15.1 p g / m L in h y p e r t e n s i v e patients).
S e n s i t i v i t y to I s o p r o t e r e n o l C h r o n o t r o p i c effects of isoproterenol, as j u d g e d b y t h e m e a n t h r e s h o l d a n d chronotropic doses, w e r e c o m p a r a b l e b e t w e e n n o r m a l a n d h y p e r t e n s i v e subjects (0.3 ± 0.3 a n d 1.6 ± 1.5 //g ν 0.2 + 0.2 a n d 1.8 ± 1.3 //g). Both variables w e r e u n c h a n g e d after Cilazapril (0.4 ± 0.7 a n d 1.3 ± 1.1 //g in n o r m a l subjects, 0.2 + 0.2 a n d 2.0 ± 1.5 //g in h y p e r tensive patients) (Figure 3).
With respect to d o s e - r e s p o n s e curves, t h e h e a r t r a t e - isoproterenol relationships w e r e similar in n o r m a l a n d h y p e r t e n s i v e subjects after placebo (Figure 3). After Ci
lazapril, the d o s e - r e s p o n s e curve w a s slightly, n o n s i g - nificantly displaced to t h e right in n o r m a l subjects (F = 3.47; Ρ = NS) a n d w a s u n c h a n g e d in h y p e r t e n s i v e s (F = 0.002; Ρ = NS).
S i d e Effects Side effects w e r e n o t r e p o r t e d b y n o r m a l a n d h y p e r t e n s i v e subjects, except for t h e report of mild c o u g h b y o n e h e a l t h y m a n . T h e hematological a n d bio
chemical control p a r a m e t e r s did n o t c h a n g e d u r i n g the study, except for a transient slight increase of t h e s e r u m aspartate a n d alanine aminotransferase in o n e n o r m a l subject.
TABLE 3. PLASMA CATECHOLAMINES AND NOREPINEPHRINE INFUSION BEFORE AND AFTER CILAZAPRIL (MEAN ± SD)
Normal Subjects Essential Hypertension
P l a c e b o C i l a z a p r i l P l a c e b o C i l a z a p r i l
Plasma Norepinephrine, n g / d L
supine 21.2
±
6.4 19.3±
6.7 23.8±
9.5 24±
9upright 41.9
±
13.7 34.8±
7.4 41.4±
17 50.7±
24.5Plasma Epinephrine, n g / d L
supine 3.1
±
1.6 2.9±
2.2 3.5±
3.3 3.5±
3.2upright 6.6
±
3.9 5.0±
2.8 6.0±
4.1 7.4±
6.8Preinfusion plasma angiotensin II, pg/mL 8.7
±
5.0 7.1±
2.2 10.4±
3.0 8.0±
2.5Preinfusion plasma norepinephrine, n g / d L 20.5
±
9.8 18.4±
2.8 24±
9.1 24.4±
7.7Norepinephrine threshold dose, n g / k g - m i n 51
±
79 48±
39 25±
14 33±
35pressor dose, n g / k g · min 143
±
58 190±
79 163±
80 206±
205AJH-APRIL 1991-VOL 4, NO. 4, PART 1 P R E S S O R R E A C T I V I T Y 353
Δ Mean B l o o d Pressure
3 0 - 1 m m Hg
20H
10
Normal Subjects
O Placebo
• Cilazapril
Essential Hypertension
Δ Placebo
ι 1 1 1 —
10 2 0 3 0 5 0 100 2 0 0 6 0 0 1 0 2 0 3 0 5 0 100 2 0 0 Plasma Norepinephrine, ng/dl
6 0 0
FIGURE 2. Relationship between mean blood pressure and plasma nor
epinephrine during norepinephrine infusion before and after Cilazapril in normal subjects (left panel) and pa
tients with essential hypertension (right panel). Open symbols indicate mean values after placebo; black sym
bols mean values after Cilazapril. Bars indicate SEM. The curves are not sig
nificantly different.
D I S C U S S I O N
T h e findings of t h e p r e s e n t s t u d y indicate t h a t t h e b l o o d p r e s s u r e lowering effect of a n 8 w e e k converting e n z y m e inhibition w i t h t h e long acting c o m p o u n d Cilaza
pril w a s n o t a c c o m p a n i e d b y modifications of t h e p h y s i ological relationship b e t w e e n t h e e n d o g e n o u s nor
adrenergic activity a n d t h e cardiovascular pressor reac-
Normal Subjects Essential H y p e r t e n s i o n Δ H e a r t Rate
30-, b p m
2 0
10
O Placebo
• Cilazapril
Δ Placebo
• Cilazapril
1 1 1 1 ι 1 1 1 1
0.2 0. 4 0.8 1.6 3.2 0.2 0. 4 0.8 1.6 3.2 Isoproterenol, u g
FIGURE 3. Dose response curves for isoproterenol-induced in
creases in heart rate before and after Cilazapril in normal subjects (left panel) and patients with essential hypertension (right panel).
Open symbols indicate mean values after placebo; black symbols mean values after Cilazapril. Bars indicate SEM. The curves are not significantly different.
tivity to N E . Despite c o n c o m i t a n t r e n i n activation a n d a l d o s t e r o n e s u p p r e s s i o n , as indices of effective convert
ing e n z y m e inhibition, t w o angiotensin I I - d e p e n d e n t p a t h w a y s , t h e cardiovascular pressor reactivity a n d t h e a d r e n a l release of aldosterone, w e r e u n a l t e r e d . P l a s m a levels of A N F w e r e also u n c h a n g e d . O n t h e o t h e r h a n d , a t e n d e n c y for s u p p r e s s e d p l a s m a a l d o s t e r o n e a n d b o d y s o d i u m depletion m a y identify t w o contributory factors in t h e h y p o t e n s i v e m e c h a n i s m of converting e n z y m e inhibition.
Cilazapril, given for 8 w e e k s , significantly decreased arterial p r e s s u r e in b o t h n o r m a l a n d h y p e r t e n s i v e s u b jects, w i t h o u t modification of t h e h e a r t rate, t h e c h r o n o tropic r e s p o n s e to a s s u m p t i o n of t h e u p r i g h t p o s t u r e , isoproterenol injection or, as d e m o n s t r a t e d in a p r e v i o u s study, to e x e r c i s e .2 3 T h e decrease of h e a r t rate d u r i n g acute, N E - i n d u c e d elevation of arterial p r e s s u r e w a s also u n c h a n g e d , p o i n t i n g to a n u n a l t e r e d baroreflex s e n sitivity. In our h y p e r t e n s i v e patients, t h e bradycardie r e s p o n s e to All infusion w a s f o u n d to b e b l u n t e d after placebo a n d n o r m a l after Cilazapril. T h e m e a n i n g of this observation is unclear. A dissociation b e t w e e n a n o r m a l h e a r t rate r e s p o n s i v e n e s s to N E a n d a b l u n t e d r e s p o n s e to All is n o t a feature of h y p e r t e n s i v e patients a n d w a s n o t o b s e r v e d previously in our l a b o r a t o r y .1 3 O n t h e o t h e r h a n d , Cilazapril did n o t alter t h e h e a r t rate re
s p o n s e to All in n o r m a l subjects, despite t h e significant decrease of arterial pressure. In single dose studies, Cila
zapril did n o t modify h e a r t rate, s y m p a t h e t i c n e r v o u s activity a n d baroreflex sensitivity, b u t e n h a n c e d p a r a s y m p a t h e t i c a c t i v i t y ,2 4 suggesting a w i t h d r a w a l of t h e vagolytic actions of AIL Similar findings w e r e r e p o r t e d after administration of other c o m p o u n d s s u c h as C a p t o
pril or e n a l a p r i l ,1 4 , 2 5 indicating a similar cardiovascular profile for these c o m p o u n d s .
354 B E R N A S C O N I ET A L AJH-APRIL 1991-VOL 4, NO. 4, PART 1
N o r a d r e n e r g i c activity a n d pressor reactivity to NE did n o t c h a n g e in b o t h n o r m a l a n d h y p e r t e n s i v e s u b jects after Cilazapril. P l a s m a NE a n d e p i n e p h r i n e levels w e r e r e p o r t e d to b e u n c h a n g e d after Captopril2 6'2 7 or e n a l a p r i l .2 8 T h e pressor effects to infused NE, studied after s h o r t - t e r m converting e n z y m e blockade (up to 2 weeks) w a s n o t e d to b e b l u n t e d2 9 or u n c h a n g e d .3 0 , 3 1 A limited sensitivity of t h e pressor r e s p o n s e curves w i t h o u t c o n c o m i t a n t m e a s u r e m e n t s of t h e p l a s m a NE con
centration could, at least partly, explain these discrepan
cies. After m o r e p r o l o n g e d t r e a t m e n t , t h e pressor reactivity r e m a i n e d u n c h a n g e d in n o r m a l subjects b u t in patients w i t h essential h y p e r t e n s i o n a decrease of t h e slope of t h e pressor r e s p o n s e curve to NE w a s r e p o r t e d .2 8 In t h e latter investigation, t h e b l u n t e d pressor reactivity to NE e m e r g e d only at very h i g h concentra
tions of p l a s m a NE, w h i l e at physiological or m o d e r ately elevated levels t h e r e s p o n s i v e n e s s of b l o o d p r e s sure to N E w a s n o r m a l .
Body s o d i u m , m e a s u r e d in patients w i t h essential or renovascular h y p e r t e n s i o n , w a s r e p o r t e d to b e u n c h a n g e d after Captopril or e n a l a p r i l .1'8 In contrast, a slight decrease w a s r e p o r t e d in 16 h y p e r t e n s i v e patients treated for 6 w e e k s w i t h e n a l a p r i l .2 8 In t h e p r e s e n t s t u d y , exchangeable s o d i u m t e n d e d to decrease in b o t h n o r m a l a n d h y p e r t e n s i v e subjects. It a p p e a r s possible t h a t a decrease of p l a s m a aldosterone m a y h a v e in
fluenced s o d i u m metabolism. H o w e v e r , a fall in p l a s m a a l d o s t e r o n e w a s n o t o b s e r v e d in all studies w i t h con
verting e n z y m e inhibitors, since after s u p p r e s s i o n in t h e early p h a s e , p l a s m a a l d o s t e r o n e t e n d s to rise in t h e chronic p h a s e of t r e a t m e n t .3 2 This p a t t e r n of a d r e n a l r e s p o n s e m a y reflect t h e complex regulation of aldos
t e r o n e secretion, since in addition to All, o t h e r m o d u l a t ing factors s u c h as s o d i u m a n d p o t a s s i u m b a l a n c e are potentially influenced b y converting e n z y m e inhibi
t i o n .1
T h e profile of t h e r e n i n - a n g i o t e n s i n - a l d o s t e r o n e sys
t e m after Cilazapril w a s characterized b y u n c h a n g e d All levels, a m a r k e d l y stimulated p l a s m a r e n i n activity, a n d a t e n d e n c y for decreased p l a s m a a l d o s t e r o n e concen
tration. T h e failure to detect a persistent d e c r e m e n t of circulating All d u r i n g chronic converting e n z y m e inhibi
tion w i t h Cilazapril or o t h e r c o m p o u n d s2 8 m a y b e at least partly related to crossreactivity of h i g h angiotensin I levels in t h e r a d i o i m m u n o a s s a y of A I L1 O n t h e o t h e r h a n d , activation of angiotensin I m a y partly o v e r c o m e t h e competitive inhibition of converting e n z y m e .3 3 T h e association of u n c h a n g e d p l a s m a All levels a n d d e creased p l a s m a a l d o s t e r o n e levels m a y s u p p o r t t h e p o s sibility of a dissociation in t h e r e n i n - a n g i o t e n s i n - a l d o s t e r o n e axis. This m a y reflect t h e partly different regulation of t h e t w o h o r m o n e s a n d h a s b e e n r e p o r t e d u n d e r o t h e r circumstances, such as a rapid c h a n g e in dietary s o d i u m i n t a k e .3 4 U n c h a n g e d p l a s m a All levels w e r e associated w i t h u n c h a n g e d pressor a n d a d r e n a l
responses to AIL T h u s , it w o u l d a p p e a r t h a t after chronic converting e n z y m e inhibition t h e r e n i n - a n g i o tensin system m a y b e able to recover, at least partly, a physiological acute regulation of t h e pressor a n d a l d o s t e r o n e regulating p a t h w a y s . This m a y also imply t h a t u n d e r these circumstances t h e All receptor n u m b e r a n d t h e receptor-agonist affinity are n o t modified. Previous data in t h e literature are consistent w i t h this h y p o t h e s i s ; after acute blockade w i t h converting e n z y m e t h e r e is a n acute fall of p l a s m a All w i t h a n e n h a n c e d r e s p o n s e of blood pressure or p l a s m a aldosterone to infused A I L2 9-3 1 U n d e r m o r e chronic conditions, 1 to 8 w e e k s of treat
m e n t w i t h Captopril, t h e pressor reactivity to All w a s n o t m o d i f i e d .1 4 , 3 5 After 6 w e e k s of t r e a t m e n t w i t h enalapril, t h e acute aldosterone r e s p o n s e to infused All w a s u n c h a n g e d in n o r m a l a n d h y p e r t e n s i v e s u b j e c t s .2 8
Plasma A N F concentration w e r e significantly ele
v a t e d in the p r e s e n t g r o u p of p a t i e n t s w i t h essential h y p e r t e n s i o n . This could n o t b e explained b y differ
ences in age or renal function. Cilazapril did n o t alter p l a s m a A N F levels in t h e t w o s t u d y g r o u p s . This s u g gests t h a t Cilazapril is a n effective a n t i h y p e r t e n s i v e agent, w i t h a cardiovascular profile c o m p a r a b l e to t h a t of other available converting e n z y m e inhibitors. Its m e c h a n i s m of action m a y b e partly related to s o d i u m depletion a n d aldosterone suppression, b u t n o t to m o d i fications of s y m p a t h e t i c - d e p e n d e n t p r e s s u r e regula
tion, atrial natriuretic p e p t i d e concentration, or All d e p e n d e n t p a t h w a y s for acute blood p r e s s u r e or aldosterone regulation.
A C K N O W L E D G M E N T S
We acknowledge the technical assistance of Gudrun Haueter, Ruth Mosimann, Elisabeth Oldenberg, Stephanie Schwenk, Ritva Takkinen, and Jane Boden, and the secretarial assistance of Daniela Lazzaretti.
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