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Rapid identification of patients with essential hypertension sensitive to acebutolol (a new cardioselective beta-blocker)
Rapid Identification of Patients with Essential Hypertension Sensitive to Acebutolol (A New Cardioselective
Beta-Blocker)
JOEL MENARD, M.D. XAVIER BERTAGNA, M.D. PHAN TAM N’GUYEN, M.D. PATRICE DEGOULET, M.D. PIERRE CORVOL, M.D. Paris, France
From the Service D’HypertensionArterielle et de Medecine, lnterne Hbpital Saint-Joseph, 75014 Paris, France, and the Clinique Medicale Propedeutique (Pr. Milliez), Mpital Broussais, 75014 Paris, France. This work has been supported by grants from DGRST and INSERM. Requests for reprints should be addressed to Dr. Joel Menard, Service D’Hypertension Arterielle et de Medecine, lnterne Hbpital Saint-Joseph, 75014 Paris, France.
888
May 31, 1978
Acebutolol, a new cardioselectlve beta-blocking agent, was administered for 48 hours to 44 patients wlth essential hypertension at a total dosage of 2.0 g (2,000 mg). The slowing down of their pulse rate and the decrease In blood pressure were highly slgnlflcant, whereas eight subjects treated wlth placebos had no change In either the pulse rate or blood pressure. Plasma renln activity decreased from 2.28 f 2.11 ng/ml/hour to 0.87 f 1.04 ng/ml/hour. The decrease In blood pressure was correlated with the inltlal plasma renln actlvlty and with the decrease In plasma renln activity. These results demonstrate that a rapid decrease In blood pressure can be obtained in patients with essential hypertension treated with acebutolol and that the decrease in blood pressure is related to the initial state of the renln-angiotensln system. Since the observation by Prichard that pronethalol was able to decrease blood pressure in hypertensive patients with angina pectoris [ 11, numerous beta- blocking agents have been reported to have an antihypertensive action [2-71 despite differences in their other pharmacologic characteristics. The present study was undertaken to investigate the effects of a new cardioselective betablocking agent, acebutolol, on the pulse rate, blood pressure and plasma renin activity in 44 hospitalized patients with essential hypertension. In less than 48 hours, a significant decrease in blood pressure was obtained in patients in the recumbent and upright posture. The magnitude -of the antihypertensive effect was correlated to the initial level of plasma renin activity in the upright posture and to the importance of the decrease in plasma renin activity induced by the treatment. MATERIAL AND METHODS Patients. Subjects were 44 hypertensive patients, 26 male and 18 female. Mean body weight was 69.0 f 12.5 kg (SE) and mean age 44.6 f 10.5 years. The diagnosis of essential hypertension was made after careful clinical evaluation, laboratory studies including serum electrolytes, serum creatinine, urinary excretion of vanylmandelic acid, rapid sequence intravenous pyelogram and, when necessary, renal arteriogram.
The American Journal of Medfclne
Volume 80
ACEBUTOLOL IN IDENTIFICATION OF ESSENTIAL HYPERTENSION-MENARD
TABLE I
Influence of Two Days’ Acebutolol Treatment on Pulse Rate and Blood Pressure in Hospitalized Patients with Essential Hypertension Mean Arterial _ Position
Treatment Placebo (81 Acebutolol
NOTE:
ET AL.
(44)
Figures in parentheses
Recumbent Ubright Recumbent Upright indicate
Before 129 131 127 128
+ r + +
Blood Pressure (mm Hg) ---
19 23 18 19
PulseRate (per min)
__-
After
Before
129 I21 132224 11ot20 llO+ 19
79+ 13 86+- 12 82+ 12 93+ 12
After
_______
71 81 70 74
_--
t a ? 13 + 7 t 9
the number of patients.
All patients had mild hypertension as judged by grade 0 to 2 fundi, normal serum creaiinilie and abienee of left ventricular hypertrophy as estlrnat$d by ,roentgenogram and electrocardiogram. Patients either had never been treated or antihyperthnsive therapy hsid been withdrawn for at least one month before the study. The study was performed during 5 Constant sodium, pbtassium and caloric diet, each patient taking two pills three tiines a day from ttie second to the sixth hospital day. The placebo was giveri on the second, third and fourth day. Acebutolol was introduced on the fourth hospital day, 200 mg at 12 AM and 8 PM, 400 mg three times on the fifth day and 400 rng at 8 AM on the sixth day. According to the same protocol eight other hypertensive subjects (6 female and 2 male, mean age 44.1 years, mean body weight 60.3 kg) were given a placebo during the entire study. Analytical Methods. Blood pressure was measured with mercury manometers attached to a 14 cm wide cuff with the patient in two positions: recumbent after 10 minutes of rest, standing 1 minute after assumption of the upright posture. Pulse rates were measured 30 seconds before blood pressure readings with the patients in the recumbent and upright positions. Two to four readings were made between 9 and 1 i AM on day 4 (control) and day 6 (treatment). dean blood pressure was calculated according to the formula: diastolic blood pressure + one-third pulse pressure. Plasma renin activity was measured by radioimmunoassay of generated angiotensin I [8,9], at 9 AM, after 1 hour’s ambulatiorl. Normal values measured under the same conditions in 20 normal voluntet%rs,aged 25 to 55, ranged from 0.7 to 3 ng/ml/hour with a mean natrluresis of 99.5 f 21.8 meq/24 hours. Statistical Methods. Statistical methods included Student’s test for group differences and paired data analysis, Wilcoxon’s test and standard methods for calculation of correlation and regression coefficients [lo].
occurred on going from the recumbent to the upright PO& ture (10.9 f 10.2) before treatment, 4.36 f 4.29, after treatment, P < 0.001). The antihyp6rtehsive effect was not accoinpanied by a change in body weight, or in natriuresis, which was 123 f 34 meq/day before the administration of acebutolol and 1 i2 f 38 meq/day after. The decrease in blood pressure was independent of age, initial blood pressure level, initial pulse rate in recumbent and upright positions. The decrease in blood pressure was not correlated to the slowing of pulse rate. Effect of Aceblatolol on Piastia keriin Activity. In all but two cases, acebutolol lowered plasma renin activity. The mean change for the entiie group was from 2.26 f 2.11 ng/mllhour to 0.87 f 1.04 ng/ml/hour. Ih placebo-treated subjects, plasma renin activity was unchanged from 1.75 f 1.15 to 2.38 f 2.24 ng/ml/hour. Initial plasma renin activity valuds were negatively correlated with age (r = -0.417, p < 0.001). Relation of Changes 61 kean Arterial Blood Pressure to Plasma kenin Activity. The decrease in mean arterial blood presstire was significantly correlated with the initial PLASMA RENIN AtilVITY i ng/ml/ hr 10 1
5
’ 1
2
’ .5
.3 0
A
0
.
I
0
0
RESULTS Effect of Acebutolol on Blood Pressure and Pulse Rate. All the blood pressure and puls’e rate measurements are given in Table I. No significant change in blood pressure or in pulse rate was observed among the eight placebo-treated patients. In acebutolol-treated subjects, the decrease in systolic and diastolic blood pressure was highly significant (p < 0.001) in both positions. Resting pulse rate was decreased as was the acceleration which
r =0.498 pc=-001
Fig& 1. Correlation between the initial plasma renin activity values with patients in upright posture and the percentage of d&crease in mean arterial blood pressure (MAW) in upright posture.
May 31, 1976
The American Journal of
Yediclne
Volume 60
887
ACEBUTOLOL IN IDENTIFICATION OF ESSENTIAL HYPERTENSION-MENARD
TABLE II
Influence of Acebutolol on Recumbent and Upright Mean Arterial Blood Pressure, According to the Initial PRA Values &crease in Mean Arterial Blood Pressure (mm Hg) Patient Recumbent
PlasmaRenin Activity
-6.8 t 15.7 -17 k 12 -29.7 2 10.0
1.437 6.983 8.889
Figures in parentheses
indicate
Low (1 I) Normal (24) High (9) NOTE:
Patient Upright
t
-9.3 -16? -32.9
NUMBER 11 AGE 49 PULSERATE 82
f 16.3 11.1 + 14.0
1.888 7.123 7.023
number of patients.
NORMAL RENIN
HIGH RENIN
24 48.3
9 37.3
82
77
mmHg
110.
90.
r Differences in the response to acebutolol treatment according to plasma renin activity.
Figure 2.
888
May
31, 1978
blood pressure was lower in patients with high renin activity than in patients with normal renin activity (p < 0.01) whose mean arterial blood pressure was lower than in subjects with low renin activity (p < 0.05). Pulse rate and body weight were identical in the three subgroups, but the patients with high renin activity were younger than the others.
t
plasma renin activity (Figure 1) and with the decrease in plasma renin activity both in the recumbent (r = 0.485, p < 0.001) and upright position (r = 0.495, p < 0.001). By comparison with the norClasslflcatlon of Patients. mal values, 11 patients exhibited a low plasma renin activity (less than 0.7 ng/ml/hour), nine a high plasma renin activity (more than 3 ng/ml/hour) and 24 a normal plasma renin‘activity (Table II). In the patients with low renin, the decrease in mean arterial blood pressure was not significant in both positions. In the patients with high renin, the decrease in mean arterial biood pressure was much larger and statistically significant. Patients with a normal renin activity had a decrease in blood pressure which was intermedlary between the decrease observed in the patients with low and high renin activity (Figure 2). Whereas blood pressure was identical in the three subgroups before treatment; after acebutolol administration, mean arterial
LOW RENIN
ET AL,
The American Journal of Yedlclne
COMMENTS
These results clearly show that acebutolol, a new cardioselective beta-blocker, exerts a clear cut antihypertensive effect. The influence of acebutolol on the heart is shown in this study by the slowing of the heart rate and by the inhibitlon of tachycardia on standing. Acebutolol, at the dosage used in this study, is remarkable for its speed of action on the blood pressure, which was apparent in less than 48 hours. Rest in bed in hospital between the fourth and sixth days of the study could not account for the decrease in blood pressure, as the eight hypertensive patients who received the placebo showed no change in their blood pressures. The speed of the decrease in the blood pressure contrasts with the long delay in effect which has been reported on several occasions with orally administered propranolol [2]. However, a rapid decrease in blood pressure with propranolol has already been recorded by Waal [ 1 l], Hansson [ 121 and Buhler et al. [ 133. The delay in hypotensive effect of orally administered betablockers is perhaps dependent on the size of the initial dosage. These dosages are difficult to define, for the same dose of propranolol can vary in its betablocking action from one person to another [ 141, and it is equally difficult to make a comparison in dosage of two beta-blockers. On the basis that a single oral dose of 300 mg of acebutolol is comparable to 40 mg of propranolol in the inhibition of isoprenaline-induced tachycardia [ 161, the average dosage of acebutolol used in this study would be equivalent to 2 mg/kg/day of propranolol. However, this dosage of acebutolol administered repeatedly is probably higher than the equivalent dosage of propranolol. The metabolism of the two products is quite different and the plasma half-life of acebutolol is approximately three times that of propranolol [ 161. The effect on blood pressure varied from one patient to another. Of the 44 subjects, 19 showed either no decrease in blood pressure or an average decrease of below 10 per cent; on the other hand, 13 patients showed a considerable decrease, more than 20 per cent of the initial mean arterial pressure. This observation, that results can be variable in hypertensive subjects after only 48 hours of acebutolol therapy, may have important practical implications, It might be possible to select those who are sensitive
Volume 80
ACEBUTOLOL
or resistant and
quick
to beta-blockers therapeutic
test
on the basis of a simple if the
long-term
IN IDENTIFICATION
OF ESSENTIAL
When the results
results
as those
parallel those of the short-term, which has already been shown to be so with propranolol [ 131 but which has not yet been studied for acebutolol. At the same time, as regards its antihypertensive activity, acebutolol can lower the plasma renin activity by 60 per cent in 48 hours. In a recent study, two cardioselective beta-blockers, practolol and metoprolol, inhibited the chronotropic action of isoproterenol without preventing its stimulatory effect on plasma renin activity [ 171. The marked influence of acebutolol on plasma renin activity can be interpretated in two different ways. Since evidence from animal work has suggested that acebutolol is cardioselective [ 181, the effect on plasma renin activity of beta-blockers would not be dependent upon their affinity for beta-2 receptors. On the contrary, the effect of acebutolol on plasma renin activity would be another argument against its cardioselectivity, since in man, acebutolol, unlike practolol, affects peripheral vasculature and airways as well as the heart [ 191. What are the connecting links, if any, between the decrease in blood pressure brought about by the beta-blocker, the renin-angiotensin system and the effect of the beta-blocker in the heart? A number of clinical and laboratory measurements have been used to try to predict the antihypertensive action of beta-blockers [ 7,12,13]. Buhler et al. were the first to report that subjects with a high plasma renin activity showed a greater decrease in blood pressure after treatment with propranolol for a period averaging three to five months than subjects with a normal plasma renin activity who were themselves more responsive than those with a low plasma renin activity [ 131. Hansson [ 121, using propranolol, Eistel and Nestel, with practolol [6], and Merkers et al. with I.C.I. 66,082 [7], were unable to confirm these observations. Our results agree with those of Buhler et al. and the decrease in blood pressure after 48 hours of treatment with acebutolol correlated in a very significant manner with the initial level of plasma renin activity measured after 1 hour in the upright position in subjects on a normal sodium intake. Among those treated with acebutolol, there was before treatment, a very significant negative corretation between plasma renin activity and age as in normotensive subjects [20]. This observation increases interest in the correlation between plasma renin activity and the decrease in blood pressure induced by acebutolol, since this hypotensive effect is independent of age. Furthermore, neither the initial level of blood pressure nor the initial heart rate can predict the hypotensive response.
HYPERTENSION-MENARD
are expressed
in the same
of Buhler et al. [ 131 by distinguishing
ET AL.
way three
groups of patients according to their plasma renin activity, our results are very comparable to those of these investigators. The number of cases in the three groups is also the same, although the method of dosage and the conditions of the protocol were not identical. However, the limits of such a classification
must be emphasized.
In our study, the predictive value of plasma renin activity was not absolute, for one subject with a low renin level and six subjects with normal levels had decreases in their blood pressures of over 20 per cent. These divergences at the individual level could be interpreted in different ways: (1) Treatment had perhaps been for too short a period and long-term treatment with acebutolol might not give the same results as short-term treatment. (2) The correlation between the initial plasma renin activity and the decrease in blood pressure might be fortuitous. (3) Lastly, investigation of the renin-angiotensin system by measurement of plasma renin activity in subjects in the upright position and with a normal sodium intake might not always be sufficient to allow assessment of the degree of activity or inactivity of the renin-angiotensin system [21], which might be better explored by other tests which inhibit this system [22,23]. There is one other correlation between the reninangiotensin system and the decrease in blood pressure induced by acebutolol: the greater the decrease in renin, the greater the decrease in blood pressure. Such a finding suggests that the slowing down of renin secretion might contribute to the decrease in blood pressure induced by acebutolol; this is in agreement with the results obtained by Buhler et al. [13] with propranolol and against the findings of Leonetti et al. [24] and Hansson [ 121, who found no relationship between the decrease in blood pressure and that of renin. The slowing down of renin secretion is not, however, the only property of the betablockers which could explain their hypotensive action, since under several circumstances, the two properties are clearly separated [25-271.
In conclusion, our results are in keeping with those of Laragh et al. [25] and suggest that there is a parallel between the decrease in blood pressure brought about by beta-blockade and the initial level and suppression of plasma renin activity. However, more direct evidence is necessary before we can assert that the early response of the blood pressure to treatment with acebutolol is characteristic of renin-dependent hypertension.
May 31, 1976
The American Journal of Medlclne
Volume 60
669
ACEBUTOLOL
IN IDENTIFICATION
OF ESSENTIAL HYPERTENSION-MENARD
ET AL.
REFERENCES 1. 2. 3.
4.
5.
6.
7.
6.
9.
10. 11. 12.
13.
14. 15.
890
Prichard BNC: Hypotensive action of pronethalol. Br Med J 1: 1227, 1964. Prichard BNC, Gillam PMS: Treatment of hypertension with propranolol. Br Med J 1: 7, 1969. Tibblin G, Ablad B: Antihypertensive therapy with alprenoloI, a j%adrenergic receptor antagonist. Acta Med Stand 166: 451, 1969. Morgan TO, Louis WJ. Dawborn JK, Doyle AE: The use of pindolol in the treatment of hypertension. Med J Austral 2: 309, 1972. Lohmoller G, Frohlich ED: A comparison of timolol and propranolol in essential hypertension. Am Heart J 69: 437,1975. Esler MD, Nestel PJ: Evaluation of practolol in hypertension- effects on sympathetic nervous system and renin responsiveness. Br Heart J 35: 469, 1973. Meekers J, Missotten A, Fagard R, et al.: Predictive value of various parameters for the antihypertensive effect of the beta blocker ICI 66,062. Arch Int Pharmacodyn Ther 213: 294, 1975. Menard J, Corvol P, Allegrini J, et al.: Mesure de I’Activite Renine Plasmatique de I’homme par le dosage radioim munologique de I’Angiotensine I. Techniques Radioimmunologiques. Paris lnserm Ed, 1972, p 459. Corvol P, Rodbard D. Drouet J, et al.: Monoiodinated angiotensins: Preparation and characterization by polyarylamide gel electrophoresis and isoelectric focusing. Biochim Biophys Acta 251: 254, 1971. Armitage P: Statistical Methods in Medical Research. New York, John Urley & Sons, 1971. Waal HJ: Hypotensive action of propranolol. Clin Pharmacol Ther 7: 566, 1966. Hansson L: Beta-adrenergic blockade in essential hypertension-Effects of propranolol on hemodynamtc parameters and plasma renin activity. Acta Med Stand 194 (suppl): 550, 1973. Buhler FR, Laragh J, Baer H, et at.: Propranolol inhibition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. N Engl J Med 287: 1209, 1972. Nies AS, Shand DG: Clinical pharmacology of propranolol. Circulation 52: 6, 1975. Cuthbert MF, Owusu-Ankomarch K: Effect of M. and B; 17, 803 A, a new B adrenoceptor blocking agent on the car-
May 31, 1976
The American
Journal of Medicine
16.
17.
18.
19. 20.
21.
22.
23.
24.
25.
26.
27.
26.
Volume 60
diovascular responses to tilting and to isoprenaline in man. Br, J Pharmacol43: 639, 1971. Cuthbert MF, Collins RF: Plasma levels and B-adrenoceptor blockade with acebutolol, practolol and propranolol in man. Br J Clin Pharmacol 2: 49, 1975. Weber MA, Stokes GS, Gain JM: Comparison of the effects on renin release of beta adrenergic antagonists with differing properties. J Clin Invest 54: 1413, 1974. Basil B, Jordan R, Loveless AH, et al.: B-adrenoceptor blocking properties and cardioselectivity of M and B 17, 803 A. Br J Pharmacol48: 198, 1973. Kumana CR, Leighton M, Kaye CM, et al.: Cardiac and pulmonary effects of acebutolol. Lancet 2: 89, 1975. Sambhi P, Crane MG, Genest J: Essential hypertensionNew concepts about mechanisms-. Ann Intern Med 79: 411.1973. Drayer JIM, Kloppenborg PWC, Benraad TJ: Detection of low-renin hypertension; evaluation of outpatient reninstimulating methods. Clin Sci Molec Med 48: 91, 1975. Gavras G, Brunner HR, Laragh JH, et al.: An angiotensin converting-enzyme inhibitor to identify and treat vasoconstrictor and volume factors in hypertensive patients. N Engl J Med 291: 817, 1974. Streeten DHP, Anderson GH, Freiberg M, et al.: Use of an angiotensin II antagonist (Saralasin) in the recognition of angiotensinogenic hypertension. N Engl J Med 292: 657, 1975. Leonetti G, Mayer G, Morganti A, et al.: Hypotensive and renin-suppressing activities of propranolol in hypertensive patients. Clin Sci Molec Med 48: 491, 1975. Bravo EL, Tarazi RC, Dustan HP, et al.: Dissociation between renin and arterial pressure responses to beta-adrenergic blockade in human essential hypertension. Circ Res 36 (suppl I): 241, 1975. Stokes GS, Weber MA, Thornell IR: Beta-blockers and plasma renin activity hypertension. Br Med J 1: 60, 1974. Menard J, Corvol P, Alexandre JM, et al.: Equilibration du traitement des hypertensions arterielles &v&esInter&t du d-l propranolol. Nouv Presse Med 3: 87 1, 1975. Laragh JH, Sealey JE, Buhler FR, et al.: The renin axis and vasoconstriction volume analysis for understanding and treating renovascular and renal hypertension. Am J Med 58: 4, 1975.
Beta-Blocker)
JOEL MENARD, M.D. XAVIER BERTAGNA, M.D. PHAN TAM N’GUYEN, M.D. PATRICE DEGOULET, M.D. PIERRE CORVOL, M.D. Paris, France
From the Service D’HypertensionArterielle et de Medecine, lnterne Hbpital Saint-Joseph, 75014 Paris, France, and the Clinique Medicale Propedeutique (Pr. Milliez), Mpital Broussais, 75014 Paris, France. This work has been supported by grants from DGRST and INSERM. Requests for reprints should be addressed to Dr. Joel Menard, Service D’Hypertension Arterielle et de Medecine, lnterne Hbpital Saint-Joseph, 75014 Paris, France.
888
May 31, 1978
Acebutolol, a new cardioselectlve beta-blocking agent, was administered for 48 hours to 44 patients wlth essential hypertension at a total dosage of 2.0 g (2,000 mg). The slowing down of their pulse rate and the decrease In blood pressure were highly slgnlflcant, whereas eight subjects treated wlth placebos had no change In either the pulse rate or blood pressure. Plasma renln activity decreased from 2.28 f 2.11 ng/ml/hour to 0.87 f 1.04 ng/ml/hour. The decrease In blood pressure was correlated with the inltlal plasma renln actlvlty and with the decrease In plasma renln activity. These results demonstrate that a rapid decrease In blood pressure can be obtained in patients with essential hypertension treated with acebutolol and that the decrease in blood pressure is related to the initial state of the renln-angiotensln system. Since the observation by Prichard that pronethalol was able to decrease blood pressure in hypertensive patients with angina pectoris [ 11, numerous beta- blocking agents have been reported to have an antihypertensive action [2-71 despite differences in their other pharmacologic characteristics. The present study was undertaken to investigate the effects of a new cardioselective betablocking agent, acebutolol, on the pulse rate, blood pressure and plasma renin activity in 44 hospitalized patients with essential hypertension. In less than 48 hours, a significant decrease in blood pressure was obtained in patients in the recumbent and upright posture. The magnitude -of the antihypertensive effect was correlated to the initial level of plasma renin activity in the upright posture and to the importance of the decrease in plasma renin activity induced by the treatment. MATERIAL AND METHODS Patients. Subjects were 44 hypertensive patients, 26 male and 18 female. Mean body weight was 69.0 f 12.5 kg (SE) and mean age 44.6 f 10.5 years. The diagnosis of essential hypertension was made after careful clinical evaluation, laboratory studies including serum electrolytes, serum creatinine, urinary excretion of vanylmandelic acid, rapid sequence intravenous pyelogram and, when necessary, renal arteriogram.
The American Journal of Medfclne
Volume 80
ACEBUTOLOL IN IDENTIFICATION OF ESSENTIAL HYPERTENSION-MENARD
TABLE I
Influence of Two Days’ Acebutolol Treatment on Pulse Rate and Blood Pressure in Hospitalized Patients with Essential Hypertension Mean Arterial _ Position
Treatment Placebo (81 Acebutolol
NOTE:
ET AL.
(44)
Figures in parentheses
Recumbent Ubright Recumbent Upright indicate
Before 129 131 127 128
+ r + +
Blood Pressure (mm Hg) ---
19 23 18 19
PulseRate (per min)
__-
After
Before
129 I21 132224 11ot20 llO+ 19
79+ 13 86+- 12 82+ 12 93+ 12
After
_______
71 81 70 74
_--
t a ? 13 + 7 t 9
the number of patients.
All patients had mild hypertension as judged by grade 0 to 2 fundi, normal serum creaiinilie and abienee of left ventricular hypertrophy as estlrnat$d by ,roentgenogram and electrocardiogram. Patients either had never been treated or antihyperthnsive therapy hsid been withdrawn for at least one month before the study. The study was performed during 5 Constant sodium, pbtassium and caloric diet, each patient taking two pills three tiines a day from ttie second to the sixth hospital day. The placebo was giveri on the second, third and fourth day. Acebutolol was introduced on the fourth hospital day, 200 mg at 12 AM and 8 PM, 400 mg three times on the fifth day and 400 rng at 8 AM on the sixth day. According to the same protocol eight other hypertensive subjects (6 female and 2 male, mean age 44.1 years, mean body weight 60.3 kg) were given a placebo during the entire study. Analytical Methods. Blood pressure was measured with mercury manometers attached to a 14 cm wide cuff with the patient in two positions: recumbent after 10 minutes of rest, standing 1 minute after assumption of the upright posture. Pulse rates were measured 30 seconds before blood pressure readings with the patients in the recumbent and upright positions. Two to four readings were made between 9 and 1 i AM on day 4 (control) and day 6 (treatment). dean blood pressure was calculated according to the formula: diastolic blood pressure + one-third pulse pressure. Plasma renin activity was measured by radioimmunoassay of generated angiotensin I [8,9], at 9 AM, after 1 hour’s ambulatiorl. Normal values measured under the same conditions in 20 normal voluntet%rs,aged 25 to 55, ranged from 0.7 to 3 ng/ml/hour with a mean natrluresis of 99.5 f 21.8 meq/24 hours. Statistical Methods. Statistical methods included Student’s test for group differences and paired data analysis, Wilcoxon’s test and standard methods for calculation of correlation and regression coefficients [lo].
occurred on going from the recumbent to the upright PO& ture (10.9 f 10.2) before treatment, 4.36 f 4.29, after treatment, P < 0.001). The antihyp6rtehsive effect was not accoinpanied by a change in body weight, or in natriuresis, which was 123 f 34 meq/day before the administration of acebutolol and 1 i2 f 38 meq/day after. The decrease in blood pressure was independent of age, initial blood pressure level, initial pulse rate in recumbent and upright positions. The decrease in blood pressure was not correlated to the slowing of pulse rate. Effect of Aceblatolol on Piastia keriin Activity. In all but two cases, acebutolol lowered plasma renin activity. The mean change for the entiie group was from 2.26 f 2.11 ng/mllhour to 0.87 f 1.04 ng/ml/hour. Ih placebo-treated subjects, plasma renin activity was unchanged from 1.75 f 1.15 to 2.38 f 2.24 ng/ml/hour. Initial plasma renin activity valuds were negatively correlated with age (r = -0.417, p < 0.001). Relation of Changes 61 kean Arterial Blood Pressure to Plasma kenin Activity. The decrease in mean arterial blood presstire was significantly correlated with the initial PLASMA RENIN AtilVITY i ng/ml/ hr 10 1
5
’ 1
2
’ .5
.3 0
A
0
.
I
0
0
RESULTS Effect of Acebutolol on Blood Pressure and Pulse Rate. All the blood pressure and puls’e rate measurements are given in Table I. No significant change in blood pressure or in pulse rate was observed among the eight placebo-treated patients. In acebutolol-treated subjects, the decrease in systolic and diastolic blood pressure was highly significant (p < 0.001) in both positions. Resting pulse rate was decreased as was the acceleration which
r =0.498 pc=-001
Fig& 1. Correlation between the initial plasma renin activity values with patients in upright posture and the percentage of d&crease in mean arterial blood pressure (MAW) in upright posture.
May 31, 1976
The American Journal of
Yediclne
Volume 60
887
ACEBUTOLOL IN IDENTIFICATION OF ESSENTIAL HYPERTENSION-MENARD
TABLE II
Influence of Acebutolol on Recumbent and Upright Mean Arterial Blood Pressure, According to the Initial PRA Values &crease in Mean Arterial Blood Pressure (mm Hg) Patient Recumbent
PlasmaRenin Activity
-6.8 t 15.7 -17 k 12 -29.7 2 10.0
1.437 6.983 8.889
Figures in parentheses
indicate
Low (1 I) Normal (24) High (9) NOTE:
Patient Upright
t
-9.3 -16? -32.9
NUMBER 11 AGE 49 PULSERATE 82
f 16.3 11.1 + 14.0
1.888 7.123 7.023
number of patients.
NORMAL RENIN
HIGH RENIN
24 48.3
9 37.3
82
77
mmHg
110.
90.
r Differences in the response to acebutolol treatment according to plasma renin activity.
Figure 2.
888
May
31, 1978
blood pressure was lower in patients with high renin activity than in patients with normal renin activity (p < 0.01) whose mean arterial blood pressure was lower than in subjects with low renin activity (p < 0.05). Pulse rate and body weight were identical in the three subgroups, but the patients with high renin activity were younger than the others.
t
plasma renin activity (Figure 1) and with the decrease in plasma renin activity both in the recumbent (r = 0.485, p < 0.001) and upright position (r = 0.495, p < 0.001). By comparison with the norClasslflcatlon of Patients. mal values, 11 patients exhibited a low plasma renin activity (less than 0.7 ng/ml/hour), nine a high plasma renin activity (more than 3 ng/ml/hour) and 24 a normal plasma renin‘activity (Table II). In the patients with low renin, the decrease in mean arterial blood pressure was not significant in both positions. In the patients with high renin, the decrease in mean arterial biood pressure was much larger and statistically significant. Patients with a normal renin activity had a decrease in blood pressure which was intermedlary between the decrease observed in the patients with low and high renin activity (Figure 2). Whereas blood pressure was identical in the three subgroups before treatment; after acebutolol administration, mean arterial
LOW RENIN
ET AL,
The American Journal of Yedlclne
COMMENTS
These results clearly show that acebutolol, a new cardioselective beta-blocker, exerts a clear cut antihypertensive effect. The influence of acebutolol on the heart is shown in this study by the slowing of the heart rate and by the inhibitlon of tachycardia on standing. Acebutolol, at the dosage used in this study, is remarkable for its speed of action on the blood pressure, which was apparent in less than 48 hours. Rest in bed in hospital between the fourth and sixth days of the study could not account for the decrease in blood pressure, as the eight hypertensive patients who received the placebo showed no change in their blood pressures. The speed of the decrease in the blood pressure contrasts with the long delay in effect which has been reported on several occasions with orally administered propranolol [2]. However, a rapid decrease in blood pressure with propranolol has already been recorded by Waal [ 1 l], Hansson [ 121 and Buhler et al. [ 133. The delay in hypotensive effect of orally administered betablockers is perhaps dependent on the size of the initial dosage. These dosages are difficult to define, for the same dose of propranolol can vary in its betablocking action from one person to another [ 141, and it is equally difficult to make a comparison in dosage of two beta-blockers. On the basis that a single oral dose of 300 mg of acebutolol is comparable to 40 mg of propranolol in the inhibition of isoprenaline-induced tachycardia [ 161, the average dosage of acebutolol used in this study would be equivalent to 2 mg/kg/day of propranolol. However, this dosage of acebutolol administered repeatedly is probably higher than the equivalent dosage of propranolol. The metabolism of the two products is quite different and the plasma half-life of acebutolol is approximately three times that of propranolol [ 161. The effect on blood pressure varied from one patient to another. Of the 44 subjects, 19 showed either no decrease in blood pressure or an average decrease of below 10 per cent; on the other hand, 13 patients showed a considerable decrease, more than 20 per cent of the initial mean arterial pressure. This observation, that results can be variable in hypertensive subjects after only 48 hours of acebutolol therapy, may have important practical implications, It might be possible to select those who are sensitive
Volume 80
ACEBUTOLOL
or resistant and
quick
to beta-blockers therapeutic
test
on the basis of a simple if the
long-term
IN IDENTIFICATION
OF ESSENTIAL
When the results
results
as those
parallel those of the short-term, which has already been shown to be so with propranolol [ 131 but which has not yet been studied for acebutolol. At the same time, as regards its antihypertensive activity, acebutolol can lower the plasma renin activity by 60 per cent in 48 hours. In a recent study, two cardioselective beta-blockers, practolol and metoprolol, inhibited the chronotropic action of isoproterenol without preventing its stimulatory effect on plasma renin activity [ 171. The marked influence of acebutolol on plasma renin activity can be interpretated in two different ways. Since evidence from animal work has suggested that acebutolol is cardioselective [ 181, the effect on plasma renin activity of beta-blockers would not be dependent upon their affinity for beta-2 receptors. On the contrary, the effect of acebutolol on plasma renin activity would be another argument against its cardioselectivity, since in man, acebutolol, unlike practolol, affects peripheral vasculature and airways as well as the heart [ 191. What are the connecting links, if any, between the decrease in blood pressure brought about by the beta-blocker, the renin-angiotensin system and the effect of the beta-blocker in the heart? A number of clinical and laboratory measurements have been used to try to predict the antihypertensive action of beta-blockers [ 7,12,13]. Buhler et al. were the first to report that subjects with a high plasma renin activity showed a greater decrease in blood pressure after treatment with propranolol for a period averaging three to five months than subjects with a normal plasma renin activity who were themselves more responsive than those with a low plasma renin activity [ 131. Hansson [ 121, using propranolol, Eistel and Nestel, with practolol [6], and Merkers et al. with I.C.I. 66,082 [7], were unable to confirm these observations. Our results agree with those of Buhler et al. and the decrease in blood pressure after 48 hours of treatment with acebutolol correlated in a very significant manner with the initial level of plasma renin activity measured after 1 hour in the upright position in subjects on a normal sodium intake. Among those treated with acebutolol, there was before treatment, a very significant negative corretation between plasma renin activity and age as in normotensive subjects [20]. This observation increases interest in the correlation between plasma renin activity and the decrease in blood pressure induced by acebutolol, since this hypotensive effect is independent of age. Furthermore, neither the initial level of blood pressure nor the initial heart rate can predict the hypotensive response.
HYPERTENSION-MENARD
are expressed
in the same
of Buhler et al. [ 131 by distinguishing
ET AL.
way three
groups of patients according to their plasma renin activity, our results are very comparable to those of these investigators. The number of cases in the three groups is also the same, although the method of dosage and the conditions of the protocol were not identical. However, the limits of such a classification
must be emphasized.
In our study, the predictive value of plasma renin activity was not absolute, for one subject with a low renin level and six subjects with normal levels had decreases in their blood pressures of over 20 per cent. These divergences at the individual level could be interpreted in different ways: (1) Treatment had perhaps been for too short a period and long-term treatment with acebutolol might not give the same results as short-term treatment. (2) The correlation between the initial plasma renin activity and the decrease in blood pressure might be fortuitous. (3) Lastly, investigation of the renin-angiotensin system by measurement of plasma renin activity in subjects in the upright position and with a normal sodium intake might not always be sufficient to allow assessment of the degree of activity or inactivity of the renin-angiotensin system [21], which might be better explored by other tests which inhibit this system [22,23]. There is one other correlation between the reninangiotensin system and the decrease in blood pressure induced by acebutolol: the greater the decrease in renin, the greater the decrease in blood pressure. Such a finding suggests that the slowing down of renin secretion might contribute to the decrease in blood pressure induced by acebutolol; this is in agreement with the results obtained by Buhler et al. [13] with propranolol and against the findings of Leonetti et al. [24] and Hansson [ 121, who found no relationship between the decrease in blood pressure and that of renin. The slowing down of renin secretion is not, however, the only property of the betablockers which could explain their hypotensive action, since under several circumstances, the two properties are clearly separated [25-271.
In conclusion, our results are in keeping with those of Laragh et al. [25] and suggest that there is a parallel between the decrease in blood pressure brought about by beta-blockade and the initial level and suppression of plasma renin activity. However, more direct evidence is necessary before we can assert that the early response of the blood pressure to treatment with acebutolol is characteristic of renin-dependent hypertension.
May 31, 1976
The American Journal of Medlclne
Volume 60
669
ACEBUTOLOL
IN IDENTIFICATION
OF ESSENTIAL HYPERTENSION-MENARD
ET AL.
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