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Effects of atenolol and hydrochlorothiazide on blood pressure and plasma catecholamines in
essential hypertension.
M G Myers and J de Champlain
Hypertension. 1983;5:591-596
doi: 10.1161/01.HYP.5.4.591
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Effects of Atenolol and Hydrochlorothiazide on
Blood Pressure and Plasma Catecholamines
in Essential Hypertension
MARTIN
G.
MYERS,
M.D., F.R.C.P.(c),
AND JACQUES DE CHAMPLAIN, M.D.,
PH.D.
SUMMARY The antihypertensive effects of atenolol and hydrochlorothiazide were compared with
placebo in a randomized, double-blind crossover study, with the blood pressure responses related to
sympathetic nervous system activity. Twelve patients with essential hypertension were given atenolol
(100 mg), hydrochlorothiazide (50 mg), and placebo as single daily doses, each for 6 weeks. Mean
supine, standing, and post-exercise blood pressures (mm Hg) on atenolol (155/94, 152/95, 177/93,
respectively) and hydrochlorothiazide (154/99, 150/103, 172/96) were lower (p < 0.01) than corresponding placebo values (172/109, 166/113, 204/111) at 6 weeks. The role of the sympathetic nervous
system in the antihypertensive actions of atenolol and hydrochlorothiazide was examined. The supine
plasma norepinephrine on placebo was used as an index of sympathetic activity to categorize each
patient's "adrenergic status." The six "hyperadrenergic" patients with high resting norepinephrine
values (mean, 302 pg/ml) exhibited a greater (p = 0.05) decrease in BP (— 30/ — 20 mm Hg) on atenolol
compared with the BP fall of - 9/ - 1 1 mm Hg observed in the lower norepinephrine group (mean, 211
pg/ml). Resting plasma norepinephrine values did not predict the BP fall on hydrochlorothiazide. The
"adrenergic status" of each patient as measured by the plasma norepinephrine concentration tended
to be relatively constant regardless of therapy or the state of activity. In this study, atenolol was an
effective antihypertensive agent comparable to hydrochlorothiazide in potency. Adrenergic status
tended to predict the BP response to atenolol and was a relatively constant feature of the patients in all
treatment phases. (Hypertension 5: 591-596, 1983)
KEY WORDS
•
atenolol
hypertension treatment
• sympathetic activity
adrenergic receptors
A
dosage range of 50-100 mg daily has been confirmed.
The elimination half-life of atenolol (6-9 hours)4"6 and
the relatively long duration of its antihypertensive action have made once daily dosing feasible.7
During the past decade there has been considerable
study and speculation on the importance of the sympathetic nervous system in the depressor effects of betablockers, including atenolol. Actions of these drugs on
both the central and peripheral components of sympathetic function have been described and possible
mechanisms postulated. One group8-9 has proposed
that hypertensive patients with high levels of sympathetic activity as characterized by elevated resting plasma norepinephrine concentrations respond better to
beta-blocker therapy. In the present study, we have
examined this hypothesis as part of a double-blind
crossover comparison study of the antihypertensive
effects of atenolol and hydrochlorothiazide compared
with placebo in patients with essential hypertension.
TENOLOL is a cardioselective beta-adrenoceptor antagonist that has been shown to be
an effective antihypertensive agent in patients with essential hypertension.'-2 Initial studies2-3
suggested that the drug had a relatively horizontal
dose-response curve and subsequently an effective
From the Division of Cardiology, Sunnybrook Hospital, Toronto, Ontario (Dr. Myers) and Department of Physiology, Universite
de Montreal, Montreal, Quebec (Dr. dc Champlain).
This study was supported in part by ICI-Pharma.
Dr. Myers is an Ontario Heart Foundation Senior Research Fellow. Dr. de Champlain is the recipient of a J. Edward Professorship
in Cardiovascular Research and is supported by the Medical Research Council of Canada and the Quebec Heart Foundation.
Address for reprints: Dr. Martin G. Myers, Division of Cardiology, Sunnybrook Hospital, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5.
Received September 3, 1982; revision accepted February 17,
1983.
591
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592
HYPERTENSION
Methods
The study population consisted of 12 patients with
essential hypertension who successfully completed the
full protocol. Three additional patients were entered
but had to be withdrawn because of a variety of reasons
unrelated to atenolol therapy. The mean age of the 12
participants was 52.8 years; eight were men. Secondary causes of the hypertension were excluded following routine clinical, biochemical, and radiologic evaluations including renal arteriography, if indicated.
Entry criteria were as follows: diastolic blood pressure
= 100 mm Hg or greater (mean of two readings on two
separate occasions; no evidence of accelerated or malignant hypertension; absence of second- or third-degree heart block; and no history of hepatic or renal
disease, diabetes, alcoholism, asthma, myocardial infarction, stroke, congestive heart failure, or angina
pectoris. Patients with a resting heart rate under 50
bpm were also excluded as were individuals needing
other medications known to affect blood pressure or
sympathetic nervous function.
The study design was a double-blind crossover comparison between atenolol 100 mg daily, hydrochlorothiazide 50 mg daily, and placebo. Tablets were administered using a "double dummy" technique so that
each patient received two tablets daily in the following
combinations: placebo atenolol + active hydrochlorothiazide, active atenolol + placebo hydrochlorothiazide, and both placebo. Adherence to therapy was estimated by counting the number of returned tablets on
each visit. Each treatment phase consisted of 6 weeks,
with the patients attending at three weekly intervals.
Prior to entry, each subject underwent a complete history and physical examination. A standard 12 lead
VOL 5, No
4, JULY-AUGUST
electrocardiogram was performed as were the following biochemical tests: complete blood count, serum
electrolytes, creatinine, bilirubin, cholesterol, uric
acid, alkaline phosphatase, SGOT, BUN, urinalysis
and microscopic examination. These parameters were
repeated at the end of each 6-week treatment period.
At each visit, the blood pressure and heart rate were
recorded in duplicate after 5 minutes' supine and 2
minutes' erect using a Random Zero sphygmomanometer (Gelman Hawksley Ltd, Sussex, United Kingdom) and ECG monitor, respectively. Any adverse
effects volunteered by the patient or other medication
given since the previous visit were recorded. After 6
weeks on each treatment, the patient underwent treadmill exercise, achieving 80% of their predicted maximum heart rate using the Bruce protocol. Blood pressure was recorded immediately following the exercise.
An indwelling intravenous heparin lock device was
used to obtain plasma samples for norepinephrine and
epinephrine following 30 minutes of supine rest, 10
minutes erect, and after treadmill exercise at the end of
each 6-week treatment period. Norepinephrine and
epinephrine concentrations were determined according
to the method of Peuler and Johnson.10 "
Differences in blood pressure, heart rate, and plasma catecholamines among the three periods were evaluated by means of analysis of variance. The blood
pressure response to atenolol and hydrochlorothiazide
was examined in patients with either high or normal
adrenergic tone as determined by the supine norepinephrine value during the placebo period. In the absence of a control population, the median value of the
plasma norepinephrine data was arbitrarily used to separate the "high" from "normal" adrenergic status.
TABLE 1. Clinical Aspects of Patients on Entry Including Plasma Norepinephrine Concentrations while Supine on
Placebo
Pretreatment blood pressure (mm Hg)
Patient
1
2
3
4
5
6
7
8
9
10
11
12
Mean ± SEM
Sex
M
M
M
F
F
F
M
F
M
M
M
M
Age
(yrs)
58
58
Pretreatment supine
BP (mm Hg)
193/108
158/107
172/106
168/111
166/101
225/107
174/111
170/99
159/100
181/115
169/101
149/100
53±2
174 ±6/106 ±2
51
35
45
58
56
55
46
48
59
64
1983
BP (mm Hg)
HR (bpm)
Supine plasma
norepinephrine
on placebo
(pg/ml)
209/117
154/92
171/116
173/116
159/109
208/111
168/112
180/119
159/103
178/111
161/108
156/93
80
72
80
84
70
74
72
88
60
110
76
68
293*
219
186
346*
312*
198
164
292*
241
285*
255
286*
173 ±5/109 ± 3
78±4
256 ±16
After 6 wk placebo
supine
•Denotes the "hyperadrenergic" patients.
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593
EFPECTS OF ATENOLOL AND HYDROCHLOROTHIAZIDE/Afyers and de Champlain
TABLE 2. Effect ofAtenolol, Hydrochlorothiazide, and Placebo on Blood Pressure (mm Hg) Heart Rate (bpm), Plasma
Norepinephrine and Epinephrine Concentrations (pg/ml) in 12 Patients Completing the Three Crossover Phases
Atenolol
treatment period (wk)
6
3
Supine
BP
HR
Norepinephrine
Epinephrine
Standing
BP
HR
Norepinephrine
Epinephrine
Exercise
BP
HR
Norepinephrine
Epinephrine
Hydrochlorothiazide
treatment period (wk)
3
6
Placebo
treatment period (wk)
6
3
153/94t
61*
—
—
155/94t
62*
251
52
156/101*
83
—
—
154/99t
79
327*
63
172/108
81
—
—
173/109
79
256
55
150/96*
65
—
—
152/95t
63
422
88
152/105*
93
—
—
150/103*
91
489
72
169/112
89
—
—
166/113
87
402
68
—
—
—
—
177/93t
101*
1351*
—
—
—
172/96*
132
951
89
—
—
—
204/111
134
813
93
144t
—
—
Statistical significance of difference from corresponding placebo value: *p < 0.05; tp < 0.01; %p < 0.001.
Results
The mean value for the pre-entry supine blood pressure was 174/106 mm Hg and on standing 164/108 mm
Hg (table 1). These recordings were consistent with
pressure measurements taken after 6 weeks of placebo
when the mean supine and erect values were 173/109
and 166/113 mm Hg, respectively (table 2). Both atenolol 100 mg daily and hydrochlorothiazide 50 mg daily
produced a significant reduction in blood pressure in
both the supine and erect positions after 3 and 6 weeks
of therapy (table 2). Blood pressure readings taken
immediately after treadmill exercise were also significantly reduced by both of these drugs. Diastolic pressures on atenolol tended to be slightly lower than those
recorded during hydrochlorothiazide therapy but the
differences were small and significant (p < 0.05) only
at 6 weeks in the erect position. Atenolol produced
significant reductions in mean supine, erect, and exercise heart rates compared to both placebo and hydrochlorothiazide values.
Plasma norepinephrine concentrations were significantly higher when measured in the supine position
while on hydrochlorothiazide and after exercise on
atenolol compared with corresponding placebo values
(table 2). Similarly, mean epinephrine concentrations
were significantly elevated after exercise on atenolol
therapy.
The "adrenergic status" of each patient was constant regardless of the treatment phase or activity (table
3). For example, patients with high plasma norepinephrine concentrations while supine had relatively
high values while erect or after exercise. The supine
norepinephrine concentrations on placebo also correlated significantly with the corresponding values after
exercise on atenolol (p < 0.01) and hydrochlorothiazide (p < 0.001).
The supine norepinephrine value on placebo was
used to characterize the adrenergic status of the patients. The six individuals who were classified as hyperadrenergic (plasma norepinephrine 285 pg/ml or
greater) had a mean concentration of 302 pg/ml compared with a mean value of 211 pg/ml in the "normal
adrenergic" group. The "hyperadrenergic" patients
exhibited a fall in blood pressure of — 30/ — 20 mm Hg
on atenolol whereas the "normal adrenergic" group
had a BP reduction of only —9/— 11 mm Hg.
The "adrenergic" status did not predict the response to hydrochlorothiazide and patients with higher
TABLE 3. Coefficients of Correlation for Norepinephrine and
Epinephrine Values in the 12 Subjects While Supine, Erect, and
After Exercise
Coefficient of correlation (r)
Hydrochlorothiazide
Placebo
Atenolol
Norepinephrine
supine vs erect
supine vs exercise
erect vs exercise
0.679*
0.718t
0.602*
0.762t
0.879*
0.534
0.740t
0.853*
Epinephrine
supine vs erect
supine vs exercise
erect vs exercise
0.8051
0.583*
0.566
0.758t
0.736t
0.829*
0.758t
0.736t
0.830*
*p < 0.05; tp < 0.01; *p < 0.001.
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0.816t
594
HYPERTENSION
epinephrine values did not exhibit greater depressor
effects with either drug. In the "hyperadrenergic" patients, the mean supine plasma norepinephrine concentrations on placebo (302 pg/ml) was reduced slightly to
292 pg/ml (p > 0.05) during atenolol therapy. The
mean ( ± SEM) supine heart rate on placebo at 6 weeks
was higher in the "hyperadrenergic" patients (83.3 ±
6.2 bpm) than in the "normoadrenergic" group (72.3
± 2.8 bpm) but the difference was not statistically
significant.
Compliance with therapy was excellent with over
90% of the prescribed tablets being consumed. Twelve
of the 15 patients entering the study completed all three
treatment phases. One patient was withdrawn because
of persisting severe hypertension during the initial two
phases (atenolol and hydrochlorothiazide). Another individual was removed from the trial after 3 weeks on
the request of his family doctor. The third withdrawal
occurred when the patient developed a recurrence of
her chronic anxiety state as a result of her participation
in the research study.
Mean serum concentrations of potassium (mEq/liter), uric acid (mg/dl) and bicarbonate (mmol/liter) on
placebo (3.9, 5.5 and 24.3 respectively) were significantly altered by hydrochlorothiazide therapy (3.6, 7.0
and 28.5). Differences in individual patient values
were not likely of any clinical importance. No significant alterations in values of biochemical tests were
detected during atenolol therapy.
Discussion
Atenolol appears to be an effective antihypertensive
agent of at least equal potency to usual doses of hydrochlorothiazide. In the present study, these drugs
were well tolerated by patients and each reduced the
mean blood pressure substantially in the supine and
erect positions and after treadmill exercise. Atenolol
lowered the diastolic blood pressures somewhat more
than hydrochlorothiazide. This finding is consistent
with previous reports which showed a greater diastolic
blood pressure fall on atenolol compared with chlorthalidone 25 mg' 2 and bendrofluazide 5 mg daily.13 It is
likely that the preferential effect of atenolol on the
diastolic blood pressure resulted from differences in
the mechanisms of action of the two classes of drugs.
The magnitude of the depressor response to atenolol
was comparable to findings from other studies' 2-l2 "
as was the degree of beta-blocker induced bradycardia.
Previous reports have demonstrated variable effects
of beta-blockers on sympathetic activity as measured
by plasma norepinephrine concentrations. For instance, propranolol caused significant increases in supine and post-exercise plasma norepinephrine in one
series14 but only increased the supine concentration in
another,15 with the latter report showing a significant
fall in exercise norepinephrine. In a series of "hyperadrenergic" hypertensives, metoprolol and propranolol reduced both the supine and erect plasma norepinephrine values.8 A beta-adrenoceptor antagonist with
intrinsic sympathomimetic activity, pindolol, has been
reported16 to lower plasma norepinephrine significant-
VOL 5, No 4, JULY-AUGUST
1983
ly in patients supine, erect, and post-exercise. Previous studies with atenolol have shown relatively consistent norepinephrine data with increases in supine
and post-exercise values reported by Distler et al." and
Winer et al.18 in hypertensive and normotensive subjects respectively. Data from the present study showed
only the exercise norepinephrine values to be increased
on atenolol. The variable effects of these beta-blockers
on plasma norepinephrine may be due to different
pharmacologic properties of the drugs (e.g., intrinsic
sympathomimetic activity, presynaptic beta-receptor
blockade, central nervous system penetration), environmental conditions, types of subjects studied (normal or hyperadrenergic) or possibly the result of inadequate group sizes.
Thiazide diuretics also appear to affect plasma norepinephrine values. Lake et al.19 have reported significant increases in both the supine and erect positions
following hydrochlorothiazide therapy. In the present
study, hydrochlorothiazide increased plasma norepinephrine in the supine and erect post-exercise states
although only the supine data were significantly different from control. As suggested by Lake et al. '9 this rise
in the plasma norepinephrine may be secondary to a
baroreceptor-mediated reflex increase in sympathetic
activity in response to the blood pressure lowering
effects of hydrochlorothiazide.
In relating changes in plasma catecholamines to the
antihypertensive actions of drugs, it is important to
consider possible limitations of plasma norepinephrine
as a measure of sympathetic nervous system activity.
Recent studies have shown that norepinephrine values
may be determined not only by spillage form the synaptic cleft of the nerve terminal but also by changes in
norepinephrine clearance from the plasma. In normotensive subjects, Esler et al.20 have reported that norepinephrine kinetics are age dependent with older persons exhibiting reduced clearance from the plasma.
These authors concluded that the decreased norepinephrine clearance in the elderly may explain the positive correlation observed between age and the plasma
norepinephrine concentration.21-22 However, others
have not observed such a correlation in hypertensive
patients.8-23
The clearance of norepinephrine from the circulation may also depend upon changes in cardiac output
with resultant alterations in blood flow to the liver and
lungs, major sites of norepinephrine elimination.
Brown et al.24 have reported that the infusion of isoproterenol increases norepinephrine elimination whereas
others25-26 have shown that beta-adrenoceptor antagonism will have the opposite effect. Thus, the higher
post-exercise norepinephrine values on atenolol may
have resulted from the relatively lower exercise-induced augmentation of cardiac output during betablockade. Furthermore, atenolol may only cause an
apparent increase in sympathetic activity with the
higher norepinephrine values resulting from a fall in
clearance rather than an increase norepinephrine spillage from the synaptic cleft. If true, this phenomenon
would explain the paradox of a drug lowering blood
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EFFECTS OF ATENOLOL AND HYDROCHLOROTHIAZIDE/Afyers and de Champlain
pressure while simultaneously appearing to increase
sympathetic activity. However, not all studies are in
agreement with the observations of Brown et al.24 In
seven normal subjects and ten patients with borderline
hypertension, Vincent et al.27 have recently reported
that isoproterenol caused an increase in the plasma
concentration of norepinephrine. These conflicting results must be investigated further before the importance of changes in clearance to the plasma concentration of norepinephrine is fully understood.
The possible role of norepinephrine clearance as a
determinant of the amount of circulating norepinephrine does not preclude the use of the plasma norepinephrine value as a measure of sympathetic activity. In our group of predominantly middle-aged
hypertensive patients under standardized conditions,
the plasma norepinephrine concentration was a predictor of the blood pressure response to atenolol. This
finding is consistent with an earlier observation8 that
"hyperadrenergic" patients exhibited greater blood
pressure reductions on either metoprolol or propranolol therapy. The detection of a similar relationship for
atenolol in this relatively small number of patients
suggests that adrenergic status is likely a major determinant of the blood pressure response to betablockers. Furthermore, beta-adrenoceptors may themselves play a more critical role in the maintenance of
hypertension in the "hyperadrenergic" hypertensive
population.
Even under conditions where cardiac output and
norepinephrine clearance may change, it may still be
possible for the plasma norepinephrine concentration
to reflect relative levels of sympathetic activity. For
example, patients with higher supine plasma norepinephrine values on placebo in our study tended to have
proportionately higher values while standing and after
exercise. The rank order of norepinephrine status was
also maintained during atenolol and hydrochlorothiazide therapy. Furthermore, the supine plasma norepinephrine concentration on placebo correlated significantly with the corresponding post-exercise values on
both atenolol and hydrochlorothiazide. These observations suggest that alterations in cardiac output and other factors affecting norepinephrine clearance may exert
a proportionately similar effect on the plasma norepinephrine concentrations such that those individuals
with higher norepinephrine values on placebo will continue to exhibit relatively high values regardless of
atenolol or hydrochlorothiazide therapy.
The combined results of the present study and earlier
reports suggest that all beta-blockers do not exert the
same effect on sympathetic nervous system function as
measured by plasma norepinephrine. Drugs without
intrinsic sympathomimetic activity such as propranolol, metoprolol and atenolol tend to increase norepinephrine values, particularly after exercise. However,
certain sub-groups such as "hyperadrenergic" hypertensive patients may actually exhibit a fall in plasma
catecholamines coincidental with the pronounced reduction in blood pressure. One might speculate that
"adrenergic" status may be a useful index of respon-
595
siveness prior to the initiation of antihypertensive therapy. Furthermore, the sympathetic profile of patients
appears to be relatively consistent under a variety of
conditions when determined by a single plasma norepinephrine sample, regardless of alterations in clearance.
Acknowledgment
The authors thank A. G. McMillan and E. Roberts for technical
and secretarial assistance.
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