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Unrelated responses of brachial artery hemodynamics and renin-angiotensin system to acute converting enzyme inhibition by enalaprilat in essential hypertension
SYSTEMIC
HYPERTENSION
Unrelated Responsesof Brachial Artery Hemodynamics and Renin-AngiotensinSystemto Acute Converting EnzymeInhibition by Enalaprilat in Essential Hypertension JAIME LEVENSON,
MD, NGUYEN PHONG CHAU, PhD, ELIANE BILLAUD, and ALAIN SIMON, MD
The simultaneous acute effects of converting enzyme inhibition by tntravenous enalaprilat on the circulating renin-angiotensin system and on the brachial artery were studied in 12 hypertensive patients by a double-blind comparison with saline effects in 14 hypertensive patients. The brachial artery was investigated in terms of arterial section (measured by pulsed Doppler technique) and wall rigidity (assessed by pulse wave velocity). Arterial and biochemical parameters were measured in baseline before injection and at 20 to 40 minutes (1,) and 80 to 100 minutes (tz) after saline and drug injections. Compared with the saline vehicle, enalaprilat significantly decreased angiotensin enzyme converting activity (p
MD,
postinjection relations were observed between: (1) enalaprilat concentration and plasma angiotensin converting enzyme activity (r = -0.72, p
I
n human hypertension, the renin-angiotensin system plays a well-known role in blood pressure [BP] regulation as well as in the control of small arteries and arterio1es.Q However, its participation in large arte-
From the Unite de Recherches Biomathematiques et Biostatistiques, Institut National de la Sante et de la Recherche Medicale U263 (INSERM U263), the Centre de Diagnostic, INSERM U28, and the Departement de Pharmacologic Clinique, Hapita Broussais, Paris, France. Manuscript received September 14, 1987; revised manuscript received February 5.1988. and accepted February 6. Address for reprints: Jaime Levenson MD, Centre de Diagnostic, Hbpital Broussais, 96 rue Didot. 75674 Paris Cedex 14, France. 1056
ries remains in question. Animal experiments have suggested that large amounts of angiotensin converting enzyme are present inside large vessel walls such as the aorta and that locally given angiotensin converting enzyme inhibitors cause their dilation.3*4 Recent studies have demonstrated that the large arteries of hypertensive patients increased their caliber and compliance in response to short-term and chronic treatments with converting enzyme inhibitors5g6 Thus, the connection between the modifications of large arteries and the blockade of the renin-angiotensin system by converting enzyme inhibitors becomes a valid study subject. To this end, we examined simultaneously in hypertensive patients the acute effects of enalaprilat, an active diacid of enalapril,7J on the brachial artery
May 1, 1988
section and wall rigidity and on the hormones related to the circulating renin-angiotensin pathway.
THE AMERICAN
TABLE Control
JOURNAL
OF CARDIOLOGY
61
1057
I Clinical, Vascular and Hormonal Characterlstlcs and Enalaprllat Groups Before Adminlstratlon’ Control Group (n = 14)
Methods Patients: Twenty-six ambulatory patients with mild to moderate systemic hypertension participated in this study [Table I). Ages ranged from 27 to 60 years. Diastolic BP was 95 to 114 mm Hg (Korotkoff phase V, average of 3 successive supine measurements on at least 2 separate outpatient visits while the patients were not under treatment for at least 1 month). The complete diagnosis included patient history, physical examination and appropriate laboratory tests.5 All patients had essential hypertension without cardiac, neurologic or renal involvement and without arteritis of the legs. Consent was given by each patient after a detailed description of the procedures. Study design: The patients were randomly assigned in a double-blind fashion to 1 of 2 groups. Those in the enalaprilat group received a bolus intravenous injection of 5 ml of saline serum with 2.5 mg of enalaprilat and those in the control group received intravenous saline serum without enalaprilat. Injections and blood withdrawal were performed in the left antecubital vein. All patients were hospitalized for 1 day. Injections were given at 9 A.M and hemodynamic and hormonal measurements were performed 15 minutes before injection (to), 20 to 40 minutes (mean 27.1 f 0.91 after injection (tl) and 80 to 100 minutes (mean 90.2 f 1) after injection (ta). Hemodynamic and biochemical measurements: Patients were placed in the recumbent position with the right arm supported at the midthoracic level in a controlled environment of 20 f 1°C. Systemic BP was measured at the left arm with a noninvasive device (Dinamap type).g Mean BP was calculated as diastolic BP plus one-third of the difference between systolic and diastolic BP. The brachial artery section was studied by a bidimensional pulsed Doppler velocimeter (Echovar Doppler Pulse, Alvar Electronic].10 Its dominant feature was a range-gated time system of reception that enabled us, with a sample volume moving across the brachial lumen, to determine the arterial diameter. The reproducibility of the method was 7 f 2%.l” Assuming a cylindrical model, brachial artery section was calculated and expressed in cm2. Pulse wave velocity from the brachial to the radial arteries was determined using 2 transcutaneous strain gauge transducers (VR 12 Simultrace, Electronics for Medicine) affixed to the skin over the most prominent part of the brachial and radial arteries.” The pulse transducer was connected to a preamplifier optimized to respond to frequencies in the range of 0.1 to 50 Hz. The foot-to-foot arterial wave velocity was calculated as the ratio of the distance separating the 2 transducers and the time interval separating the feet of the brachial and radial waves, recorded simultaneously with a paper speed of 150 mm/s. The length of the arterial segment between the brachial and radial sites was taken as the distance separating the 2 skin marks of the transducers.‘* This interval was measured in at least 10 pairs of pulses and their mean value was used to de-
Volume
M/F ratio Age Ws) Weight (kg) Height (cm) Mean blood pressure (mm Hg) Brachial artery section (cm’) Pulse wave velocity (m/s) Angiotensin converting enzyme activity (mU/ml) Plasma renin activity (nghr/ml) Plasma aldosterone concentration (ng/lOOml) * Mean f + p <0.05.
standard
error
1212 47 f 75 f 172f 115f3 0.161 f 9.9 f 31 f3 0.92 f 12.1 f
2 3 2 0.009 0.5
In the
Enalaprilat Group (n = 12) 1072 45 f 73 f 172f2 118f4 0.168 f 9 9 f 28 f
0.21 16
1.97 f 13.0 f
3 2
0.016 0.2 2 0 41’ 16
of the mean
TABLE II Matrix of Correlation Coefflclents Between Values Hemodynamlc and Hormonal Parameters Measured at Times and t2 After Injection In the Control Group
BAS PWV ACEA PRA APC
MBP 0.40’ 0.10 -0.39 -0.36 0.26
BAS 0.10 0.24 0.02 0.17
PWV 0.14 -0.28 -0.20
ACEA -0.03 -0.22
of 11
PRA 0 05
* p <0.05. ACEA = angiotensin converting enzyme activity in plasma; APC = aldosterone plasma concentration; BAS = brachial artery section: EPC = enalaprilat PRA = plasma renin plasma concentration; MBP = mean blood pressure; activity; PWV = pulse wave velocity
fine pulse wave velocity in meters/second. Reproducibility of the method was 8 f 5% .ll Biochemical determinations of hormones were performed in plasma. Plasma renin activity was measured by radioimmunoassay and expressed in ng hour/ml? Angiotensin converting enzyme activity was measured by an enzymatic assay and expressed in mU/ml.13 Plasma aldosterone concentrations were also determined and expressed in ng/lOO ml. l4 Enalaprilat concentrations were measured in plasma by a specific radioimmunoassay and expressed in ng/ml.15 Statistical analyses: Data were reported as mean f standard error of the mean. Serial measurements in the enalaprilat group were compared to serial measurements in the control group by a profile analysis of repeated measurements using the SYSTAT computer program of Wilkinson. 16.17Linear correlation was performed by the least-squares method. Mean values between the 2 groups were compared by the Student t test (independent samples).
Results Comparison of enalaprilat and saline effects: Fourteen patients (12 men and 2 women) were randomly assigned to saline vehicle injection and 12 (10 men and 2 women) to enalaprilat injection, The 2 groups had basically the same age, sex ratio, weight,
BRACHIAL
1058
ARTERY
AND
ACUTE
CONVERTING
ENZYME
INHIBITION
height, preinjection hemodynamics and hormonal status [Table I). Notice, however, that basal plasma renin activity in the enalaprilat group was somewhat higher (O.OZ
Postinjection correlations in the control and enalaprilat groups: When the measurements at time t1 and tz were pooled together in the control group (Table II), no correlation existed between arterial and hormonal parameters measured after injecting the saline vehicle, except for the brachial artery section and mean BP, which were positively related (r = 0.40,p
Enalaprilat ‘i
Mean
blood
pressure
1
plasma concentration
(rig/ml)
mean;-
(mmHg) ) p
100 I to Brachial
artery
(cm21
} p
to
t1
Plasma renin activity
-14
Pulse wave velocity
t1
to vehicle
(m/set)
Plasma aldosterone
0
t1 periods *
FIGURE 1. Mean blood pressure, wave velocity after Intravenous vehicle (to, 11 and tl deslgnate ment).
to
t2
1
1
. saline
t2
(mg.h/ml)
v
I
1 to
6
t2 (mu /ml)
1 t2
t1 section
to t1 conver Ung enzyme activity
t2 of measure enalaprilat
brachlal artery section and pulse Injection of enalaprllat or saline the different periods of measure-
t1 concentration
15 r
T
10
\q------!
-
t2 (mg/ 1 OOml) T
) P
5 1 to
t1 periods
. saline vehicle
t2
of measure * enalaprilat
FIGURE 2. Enalaprllat plasma concentration, plasma anglotensln converting enzyme actlvlty, plasma renln actlvlty and plasma aldosterone concentration after Intravenous lnjectlon of enalaprllat or saline vehicle (to, t, and t2 deslgnate the different periods of measurement).
May
period (r = -0.75, p
Discussion The brachial artery, taken as a model of peripheral large arteries,ll was investigated by means of its section (measured by pulsed Doppler technique)lO and its wall rigidity [assessed by pulse wave velocity).*l Compared with the vehicle, enalaprilat reduced BP even at the low doses used18 and increased the brachial artery section, although it did not modify the arterial wall stiffness. The increase in section was due to a direct dilatory effect of the drug on the arterial walls because, without such a direct effect, the systemic BP fall induced by enalaprilat would reduce the mechanical stretch on the arterial walls and decrease the arterial section.1g In the same line, a decrease in pulse wave velocity, taken as an index of arterial wall rigidity,*lJg could be expected as a result of BP reduction. However, the pulse wave velocity remained unchanged,
1, 1988
THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
61
1059
probably because the drug-induced increase in arterial section had annihilated the BP fall effect on the arterial walls by enhancing arterial wall distensibility. The explanation was supported by the positive relation found between pulse wave velocity and arterial section in the enalaprilat group. Compared with the saline vehicle, enalaprilat reduced plasma angiotensin converting enzyme activity, decreased plasma aldosterone concentration and increased plasma renin activity?O A close relation was observed between plasma enalaprilat concentration and plasma converting enzyme activity. Regarding the connection between circulating hormones and hemodynamics, no correlation was observed after injecting the vehicle in the control group, which indicated that the circulating renin-angiotensin system did not influence directly the control of the vascular parameters measured in steady state. After the injection of enalaprilat, a negative relation was found between transient levels of mean BP and plasma renin activity. Thus, the inhibition of the circulating renin-angiotensin system participated in the regu-
0
135 Q g aJ
0
130 125
4
I
0 r = 0 42, 4
a
75..
p < 065
4 I 0 35
7.0 0 05
0.10
0.15
0.20
0.25
0.30
Brachial artery section km 2,
2
l t1 FIGURE 3: Relation between pulse wave velocity and brachlal artery section afler enalaprllat injection (1, and t2 designate the measurement periods after the lnjectlon).
4
7r
6
8
Plasma renin activity
ot2
10
12
(mg.h/ml)
l t1
FIGURE 5. Relation between mean activity after enalaprllat Injection measurement periods).
0’2 blood pressure and plasma renln (t, and t2 are the posinjection
0 11.5,
-2 2 3 a 2 a, +-
11 0 105 t 10.0~. 95.. 9.0 . .
d$
8.9 . .
%
8.0 ..
01.. 20
40
60
Enalaprilat
80
100
120
140
160
plasma concentration
200 7.0 J 20
40
60
80
100
120
140
Enalaprilat concentration
t1
0 t2 FIGURE 4. Ftelatlon between plasma anglotensln zyme activity and enalaprllat plasma concentration lnjectlon (the measurement periods after injections and tr). l
180
(mg/ml)
converting enafter enalaprilat are shown as 1,
FIGURE 6. Relation plasma concentration jectlon measurement
160
180
1 200
(rig/ml)
l ‘l 0’2 between pulse wave velocity and enalaprilat afler enalaprilat Injection (1, and t2: postlnperiods).
1060
BRACHIAL
ARTERY
AND
ACUTE
CONVERTING
ENZYME
INHIBITION
TABLE III Matrix of Correlation CoeH lclents Between Values Hemodynamlc and Hormonal Parameters and of Enalaprllat Plasma Concentration Measured at 1, and t2 After Admlnlstratlon In the Enalaprllat Group
BAS PWV ACEA PRA EPC APC
MBP 0.40 0.20 -0.15 -0.46‘ -0.10 -0.03
BAS 0.42t 0.04 0.05 -0.01 0.22
PWV 0.34 -0.04 -0.50 -0.06
of
Acknowledgment: We thank Muriel Lefort, Christine Beretti, Caroline PCtrBs, T. Tam Guyene and Christine Beuzet for technical and secretarial assistance.
References ACEA -0.33 -0.725 -0.15
PRA -0.10 0.06
EPC 0.21
l p <0.02; t b <0.05; t p
lation of BP in acute conditions. No correlation was bbserved after qnalaprilat between circulating hormones and brachial arteiy properties, suggesting that the inhibition of the circulating renin-angiotensin system did not influence the brachial artery changes after drug administration. A direct action of enalaprilat on the brachial artery was attested to by the existence of a negative telation between pulse wave velocity and plasma enalaprilat concentration: the higher the enalaprilat concentration, the lower the pulse wave velocity, i.e., the higher the distensibility of the brachial artery. The interpretation of such a relation merits 2 remarks. First, the lack of correlation between pulse wave velocity and circulating hormones suggests that enalaprilat action on arterial stiffness was mediated by mechanisms other than the inhibition of the circulating renin-angiotensin system. Second, the relation between pulse wave velocity and enalaprilat concentration in plasma was significant at measurement times tI and t2 and the sldpe of this relation was higher at t2 that at tl. Thus, the action of enalaprilat on pulse wave velocity was time-dependent and more efficient when the time of measurement after drug injection was delayed. That a time delay from the moment of injection improved the efficiency of plasma enalaprilat on pulse wave velocity constituted an additional argument in favor of the inhibition of angiotensin converting enzyme in a compartment other than plasma and of such a compartment possibly being the arterial tissue.1-4
1. Swales JD. Arterial wall or plasma renin in hypertension. Clin Sci 1979;56:293-96. 2. D,zau VJ. Significance of the vascular renin-angiatensin pathway. Hypertension 1966;6:553-559. 3. Okamura T. Mivazaki M. Toda N. Vascular renin-anniotensin svstem in two-kidney, one clip hyperiedsive rat. Hypertension 19&;6:560-585. 4. Cohen MI,, Kurt KD. Angiotensin converting-enzyme inhibition in tissues from spontaneously hypert.&sive rats after treitment with captopril or MK 421. 1 Phormacol Exe Ther 1962:220:63-69. 5. Simon A, Levensdn JA, Bouthier JD, Benetos AM, Achimastos AP. Fouchard AM; Maarek BC. Safar ME. Comparison of oral MK 421 and propanofol in mild to moderate essential hypertension and their effects on arterial and venous vessels of the forearm. Am J Cardiol 1964:53:761-767. 6. Simon AC, L$venson JA, Bouthier JD, Maarek BC, Safar ME: Effects of acute ahd chronic angiotensin-converting enzyme inhibition on large arteries in human hypertension. J Cardiovasc Pharmacol 1965;7:S45-551. 7. Simon AC, Levenson JA, Bouthier JD, Safar ME. Effects of chronic enalapril and propanolol on human hypertensive large arteries. J Cardiovasc Pharmacol 1865;7:656-661. 8. Gross DM, Sweet CS, Ulm EH, Backlund EP, Morris AA, Weitz D, Bohn DI+ Wenger HC, Vassil TC, Stone CA. Effects of N-((f-1-carboxy-3-phenylpropy)-L-Ala-L-Pro and its ethyl ester (MK 421) on angiotehsin converting enzyme in vitro and angiotensin I pressor response in vivo. / Pharmacol Exp Ther 1961;216:552-559. 9. Silas JH. Barker AT, Ramsay LE. Clinical evaluation of Dinamap 645 automatid blood pressure recorder. Br Heart J 1960;43:202-205. 10. Levenson J, Peronneau P, Simon A, Safar M. Pulsed Doppler: determination of diameter, blood flow velocity and volumic flow of brachial artery in man. Cardiovasc Res 1961;15:164-170. 11. Simon A, Levenson J. Bouthier JD, Safar M, Avolio AP. Evidence of early degenerative changes of large arteries in human essential hypertension. Hypertension 1965;7:675-660. 12. Menard j, Catt KJ. Measurement of renin activity, concentration and sdbstrate in rat plasma by radio-immunoassay of ongiotensin I. J Endocrinol 1972;90:422-430. 13. Lieberman 1. Elevation of serum aneiotensin convertinn ” enzvme IACEl I . , level in sarcaidbsis. Am J Mkd 1975;59:;65-372. 14. Pham Huu Trong MT, Corvol P. A direct determination of plasma aldosterone. Steroids 1975,24:365-372. 15. Hichen M. Hand EL, Mulcahy WS. Methodology for MK421, MK422 and MK521. Ligands 1961;4:43. 16. Wilkinson L. REGM: a multivariate general linear hypothesis program. Am Stat 1960;34:162. 17. SYSTAT. A System for Statistics. Evanston, Illinois Systat, 1965. 18. Navis Gl. De lonn PE. Donker AIM. Van der Hem GK. De Zeeuw D. Blood pressure res$onsk toinaiaprilic acd ii essential hypertension: dose-response and effect of pre-treatment with furosemid. Eur r Clih Pharmacol1965;29:915.
19. Hallock P, Benson IC. Studies on the elastic properties of human elastic aorta. J Clin Invest 1937;16:595-602. 20. Till AE. Irvin JO, Hichens M, Lee RB. Davies RO. Swanson B, Vlasses PH. Pharmacodynamics and disposition of intravenous MK-422, the diacid metabolite of enolapril maleate. Clin Pharmacol Ther 1962;31:275.
HYPERTENSION
Unrelated Responsesof Brachial Artery Hemodynamics and Renin-AngiotensinSystemto Acute Converting EnzymeInhibition by Enalaprilat in Essential Hypertension JAIME LEVENSON,
MD, NGUYEN PHONG CHAU, PhD, ELIANE BILLAUD, and ALAIN SIMON, MD
The simultaneous acute effects of converting enzyme inhibition by tntravenous enalaprilat on the circulating renin-angiotensin system and on the brachial artery were studied in 12 hypertensive patients by a double-blind comparison with saline effects in 14 hypertensive patients. The brachial artery was investigated in terms of arterial section (measured by pulsed Doppler technique) and wall rigidity (assessed by pulse wave velocity). Arterial and biochemical parameters were measured in baseline before injection and at 20 to 40 minutes (1,) and 80 to 100 minutes (tz) after saline and drug injections. Compared with the saline vehicle, enalaprilat significantly decreased angiotensin enzyme converting activity (p
MD,
postinjection relations were observed between: (1) enalaprilat concentration and plasma angiotensin converting enzyme activity (r = -0.72, p
I
n human hypertension, the renin-angiotensin system plays a well-known role in blood pressure [BP] regulation as well as in the control of small arteries and arterio1es.Q However, its participation in large arte-
From the Unite de Recherches Biomathematiques et Biostatistiques, Institut National de la Sante et de la Recherche Medicale U263 (INSERM U263), the Centre de Diagnostic, INSERM U28, and the Departement de Pharmacologic Clinique, Hapita Broussais, Paris, France. Manuscript received September 14, 1987; revised manuscript received February 5.1988. and accepted February 6. Address for reprints: Jaime Levenson MD, Centre de Diagnostic, Hbpital Broussais, 96 rue Didot. 75674 Paris Cedex 14, France. 1056
ries remains in question. Animal experiments have suggested that large amounts of angiotensin converting enzyme are present inside large vessel walls such as the aorta and that locally given angiotensin converting enzyme inhibitors cause their dilation.3*4 Recent studies have demonstrated that the large arteries of hypertensive patients increased their caliber and compliance in response to short-term and chronic treatments with converting enzyme inhibitors5g6 Thus, the connection between the modifications of large arteries and the blockade of the renin-angiotensin system by converting enzyme inhibitors becomes a valid study subject. To this end, we examined simultaneously in hypertensive patients the acute effects of enalaprilat, an active diacid of enalapril,7J on the brachial artery
May 1, 1988
section and wall rigidity and on the hormones related to the circulating renin-angiotensin pathway.
THE AMERICAN
TABLE Control
JOURNAL
OF CARDIOLOGY
61
1057
I Clinical, Vascular and Hormonal Characterlstlcs and Enalaprllat Groups Before Adminlstratlon’ Control Group (n = 14)
Methods Patients: Twenty-six ambulatory patients with mild to moderate systemic hypertension participated in this study [Table I). Ages ranged from 27 to 60 years. Diastolic BP was 95 to 114 mm Hg (Korotkoff phase V, average of 3 successive supine measurements on at least 2 separate outpatient visits while the patients were not under treatment for at least 1 month). The complete diagnosis included patient history, physical examination and appropriate laboratory tests.5 All patients had essential hypertension without cardiac, neurologic or renal involvement and without arteritis of the legs. Consent was given by each patient after a detailed description of the procedures. Study design: The patients were randomly assigned in a double-blind fashion to 1 of 2 groups. Those in the enalaprilat group received a bolus intravenous injection of 5 ml of saline serum with 2.5 mg of enalaprilat and those in the control group received intravenous saline serum without enalaprilat. Injections and blood withdrawal were performed in the left antecubital vein. All patients were hospitalized for 1 day. Injections were given at 9 A.M and hemodynamic and hormonal measurements were performed 15 minutes before injection (to), 20 to 40 minutes (mean 27.1 f 0.91 after injection (tl) and 80 to 100 minutes (mean 90.2 f 1) after injection (ta). Hemodynamic and biochemical measurements: Patients were placed in the recumbent position with the right arm supported at the midthoracic level in a controlled environment of 20 f 1°C. Systemic BP was measured at the left arm with a noninvasive device (Dinamap type).g Mean BP was calculated as diastolic BP plus one-third of the difference between systolic and diastolic BP. The brachial artery section was studied by a bidimensional pulsed Doppler velocimeter (Echovar Doppler Pulse, Alvar Electronic].10 Its dominant feature was a range-gated time system of reception that enabled us, with a sample volume moving across the brachial lumen, to determine the arterial diameter. The reproducibility of the method was 7 f 2%.l” Assuming a cylindrical model, brachial artery section was calculated and expressed in cm2. Pulse wave velocity from the brachial to the radial arteries was determined using 2 transcutaneous strain gauge transducers (VR 12 Simultrace, Electronics for Medicine) affixed to the skin over the most prominent part of the brachial and radial arteries.” The pulse transducer was connected to a preamplifier optimized to respond to frequencies in the range of 0.1 to 50 Hz. The foot-to-foot arterial wave velocity was calculated as the ratio of the distance separating the 2 transducers and the time interval separating the feet of the brachial and radial waves, recorded simultaneously with a paper speed of 150 mm/s. The length of the arterial segment between the brachial and radial sites was taken as the distance separating the 2 skin marks of the transducers.‘* This interval was measured in at least 10 pairs of pulses and their mean value was used to de-
Volume
M/F ratio Age Ws) Weight (kg) Height (cm) Mean blood pressure (mm Hg) Brachial artery section (cm’) Pulse wave velocity (m/s) Angiotensin converting enzyme activity (mU/ml) Plasma renin activity (nghr/ml) Plasma aldosterone concentration (ng/lOOml) * Mean f + p <0.05.
standard
error
1212 47 f 75 f 172f 115f3 0.161 f 9.9 f 31 f3 0.92 f 12.1 f
2 3 2 0.009 0.5
In the
Enalaprilat Group (n = 12) 1072 45 f 73 f 172f2 118f4 0.168 f 9 9 f 28 f
0.21 16
1.97 f 13.0 f
3 2
0.016 0.2 2 0 41’ 16
of the mean
TABLE II Matrix of Correlation Coefflclents Between Values Hemodynamlc and Hormonal Parameters Measured at Times and t2 After Injection In the Control Group
BAS PWV ACEA PRA APC
MBP 0.40’ 0.10 -0.39 -0.36 0.26
BAS 0.10 0.24 0.02 0.17
PWV 0.14 -0.28 -0.20
ACEA -0.03 -0.22
of 11
PRA 0 05
* p <0.05. ACEA = angiotensin converting enzyme activity in plasma; APC = aldosterone plasma concentration; BAS = brachial artery section: EPC = enalaprilat PRA = plasma renin plasma concentration; MBP = mean blood pressure; activity; PWV = pulse wave velocity
fine pulse wave velocity in meters/second. Reproducibility of the method was 8 f 5% .ll Biochemical determinations of hormones were performed in plasma. Plasma renin activity was measured by radioimmunoassay and expressed in ng hour/ml? Angiotensin converting enzyme activity was measured by an enzymatic assay and expressed in mU/ml.13 Plasma aldosterone concentrations were also determined and expressed in ng/lOO ml. l4 Enalaprilat concentrations were measured in plasma by a specific radioimmunoassay and expressed in ng/ml.15 Statistical analyses: Data were reported as mean f standard error of the mean. Serial measurements in the enalaprilat group were compared to serial measurements in the control group by a profile analysis of repeated measurements using the SYSTAT computer program of Wilkinson. 16.17Linear correlation was performed by the least-squares method. Mean values between the 2 groups were compared by the Student t test (independent samples).
Results Comparison of enalaprilat and saline effects: Fourteen patients (12 men and 2 women) were randomly assigned to saline vehicle injection and 12 (10 men and 2 women) to enalaprilat injection, The 2 groups had basically the same age, sex ratio, weight,
BRACHIAL
1058
ARTERY
AND
ACUTE
CONVERTING
ENZYME
INHIBITION
height, preinjection hemodynamics and hormonal status [Table I). Notice, however, that basal plasma renin activity in the enalaprilat group was somewhat higher (O.OZ
Postinjection correlations in the control and enalaprilat groups: When the measurements at time t1 and tz were pooled together in the control group (Table II), no correlation existed between arterial and hormonal parameters measured after injecting the saline vehicle, except for the brachial artery section and mean BP, which were positively related (r = 0.40,p
Enalaprilat ‘i
Mean
blood
pressure
1
plasma concentration
(rig/ml)
mean;-
(mmHg) ) p
100 I to Brachial
artery
(cm21
} p
to
t1
Plasma renin activity
-14
Pulse wave velocity
t1
to vehicle
(m/set)
Plasma aldosterone
0
t1 periods *
FIGURE 1. Mean blood pressure, wave velocity after Intravenous vehicle (to, 11 and tl deslgnate ment).
to
t2
1
1
. saline
t2
(mg.h/ml)
v
I
1 to
6
t2 (mu /ml)
1 t2
t1 section
to t1 conver Ung enzyme activity
t2 of measure enalaprilat
brachlal artery section and pulse Injection of enalaprllat or saline the different periods of measure-
t1 concentration
15 r
T
10
\q------!
-
t2 (mg/ 1 OOml) T
) P
5 1 to
t1 periods
. saline vehicle
t2
of measure * enalaprilat
FIGURE 2. Enalaprllat plasma concentration, plasma anglotensln converting enzyme actlvlty, plasma renln actlvlty and plasma aldosterone concentration after Intravenous lnjectlon of enalaprllat or saline vehicle (to, t, and t2 deslgnate the different periods of measurement).
May
period (r = -0.75, p
Discussion The brachial artery, taken as a model of peripheral large arteries,ll was investigated by means of its section (measured by pulsed Doppler technique)lO and its wall rigidity [assessed by pulse wave velocity).*l Compared with the vehicle, enalaprilat reduced BP even at the low doses used18 and increased the brachial artery section, although it did not modify the arterial wall stiffness. The increase in section was due to a direct dilatory effect of the drug on the arterial walls because, without such a direct effect, the systemic BP fall induced by enalaprilat would reduce the mechanical stretch on the arterial walls and decrease the arterial section.1g In the same line, a decrease in pulse wave velocity, taken as an index of arterial wall rigidity,*lJg could be expected as a result of BP reduction. However, the pulse wave velocity remained unchanged,
1, 1988
THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
61
1059
probably because the drug-induced increase in arterial section had annihilated the BP fall effect on the arterial walls by enhancing arterial wall distensibility. The explanation was supported by the positive relation found between pulse wave velocity and arterial section in the enalaprilat group. Compared with the saline vehicle, enalaprilat reduced plasma angiotensin converting enzyme activity, decreased plasma aldosterone concentration and increased plasma renin activity?O A close relation was observed between plasma enalaprilat concentration and plasma converting enzyme activity. Regarding the connection between circulating hormones and hemodynamics, no correlation was observed after injecting the vehicle in the control group, which indicated that the circulating renin-angiotensin system did not influence directly the control of the vascular parameters measured in steady state. After the injection of enalaprilat, a negative relation was found between transient levels of mean BP and plasma renin activity. Thus, the inhibition of the circulating renin-angiotensin system participated in the regu-
0
135 Q g aJ
0
130 125
4
I
0 r = 0 42, 4
a
75..
p < 065
4 I 0 35
7.0 0 05
0.10
0.15
0.20
0.25
0.30
Brachial artery section km 2,
2
l t1 FIGURE 3: Relation between pulse wave velocity and brachlal artery section afler enalaprllat injection (1, and t2 designate the measurement periods after the lnjectlon).
4
7r
6
8
Plasma renin activity
ot2
10
12
(mg.h/ml)
l t1
FIGURE 5. Relation between mean activity after enalaprllat Injection measurement periods).
0’2 blood pressure and plasma renln (t, and t2 are the posinjection
0 11.5,
-2 2 3 a 2 a, +-
11 0 105 t 10.0~. 95.. 9.0 . .
d$
8.9 . .
%
8.0 ..
01.. 20
40
60
Enalaprilat
80
100
120
140
160
plasma concentration
200 7.0 J 20
40
60
80
100
120
140
Enalaprilat concentration
t1
0 t2 FIGURE 4. Ftelatlon between plasma anglotensln zyme activity and enalaprllat plasma concentration lnjectlon (the measurement periods after injections and tr). l
180
(mg/ml)
converting enafter enalaprilat are shown as 1,
FIGURE 6. Relation plasma concentration jectlon measurement
160
180
1 200
(rig/ml)
l ‘l 0’2 between pulse wave velocity and enalaprilat afler enalaprilat Injection (1, and t2: postlnperiods).
1060
BRACHIAL
ARTERY
AND
ACUTE
CONVERTING
ENZYME
INHIBITION
TABLE III Matrix of Correlation CoeH lclents Between Values Hemodynamlc and Hormonal Parameters and of Enalaprllat Plasma Concentration Measured at 1, and t2 After Admlnlstratlon In the Enalaprllat Group
BAS PWV ACEA PRA EPC APC
MBP 0.40 0.20 -0.15 -0.46‘ -0.10 -0.03
BAS 0.42t 0.04 0.05 -0.01 0.22
PWV 0.34 -0.04 -0.50 -0.06
of
Acknowledgment: We thank Muriel Lefort, Christine Beretti, Caroline PCtrBs, T. Tam Guyene and Christine Beuzet for technical and secretarial assistance.
References ACEA -0.33 -0.725 -0.15
PRA -0.10 0.06
EPC 0.21
l p <0.02; t b <0.05; t p
lation of BP in acute conditions. No correlation was bbserved after qnalaprilat between circulating hormones and brachial arteiy properties, suggesting that the inhibition of the circulating renin-angiotensin system did not influence the brachial artery changes after drug administration. A direct action of enalaprilat on the brachial artery was attested to by the existence of a negative telation between pulse wave velocity and plasma enalaprilat concentration: the higher the enalaprilat concentration, the lower the pulse wave velocity, i.e., the higher the distensibility of the brachial artery. The interpretation of such a relation merits 2 remarks. First, the lack of correlation between pulse wave velocity and circulating hormones suggests that enalaprilat action on arterial stiffness was mediated by mechanisms other than the inhibition of the circulating renin-angiotensin system. Second, the relation between pulse wave velocity and enalaprilat concentration in plasma was significant at measurement times tI and t2 and the sldpe of this relation was higher at t2 that at tl. Thus, the action of enalaprilat on pulse wave velocity was time-dependent and more efficient when the time of measurement after drug injection was delayed. That a time delay from the moment of injection improved the efficiency of plasma enalaprilat on pulse wave velocity constituted an additional argument in favor of the inhibition of angiotensin converting enzyme in a compartment other than plasma and of such a compartment possibly being the arterial tissue.1-4
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