effects of atenolol and hydrochlorothiazide on blood...
TRANSCRIPT
Effects of Atenolol and Hydrochlorothiazide onBlood Pressure and Plasma Catecholamines
in Essential Hypertension
MARTIN G. MYERS, M.D., F.R.C.P.(c),
AND JACQUES DE CHAMPLAIN, M.D., P H . D .
SUMMARY The antihypertensive effects of atenolol and hydrochlorothiazide were compared withplacebo in a randomized, double-blind crossover study, with the blood pressure responses related tosympathetic 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. Meansupine, 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 corre-sponding placebo values (172/109, 166/113, 204/111) at 6 weeks. The role of the sympathetic nervoussystem in the antihypertensive actions of atenolol and hydrochlorothiazide was examined. The supineplasma norepinephrine on placebo was used as an index of sympathetic activity to categorize eachpatient's "adrenergic status." The six "hyperadrenergic" patients with high resting norepinephrinevalues (mean, 302 pg/ml) exhibited a greater (p = 0.05) decrease in BP (— 30/ — 20 mm Hg) on atenololcompared with the BP fall of - 9/ - 1 1 mm Hg observed in the lower norepinephrine group (mean, 211pg/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 tendedto be relatively constant regardless of therapy or the state of activity. In this study, atenolol was aneffective antihypertensive agent comparable to hydrochlorothiazide in potency. Adrenergic statustended to predict the BP response to atenolol and was a relatively constant feature of the patients in alltreatment phases. (Hypertension 5: 591-596, 1983)
KEY WORDS • atenololadrenergic receptors
hypertension treatment • sympathetic activity
ATENOLOL is a cardioselective beta-adreno-ceptor antagonist that has been shown to bean effective antihypertensive agent in pa-
tients with essential hypertension.'-2 Initial studies2-3
suggested that the drug had a relatively horizontaldose-response curve and subsequently an effective
From the Division of Cardiology, Sunnybrook Hospital, Toron-to, Ontario (Dr. Myers) and Department of Physiology, Universitede Montreal, Montreal, Quebec (Dr. dc Champlain).
This study was supported in part by ICI-Pharma.Dr. Myers is an Ontario Heart Foundation Senior Research Fel-
low. Dr. de Champlain is the recipient of a J. Edward Professorshipin Cardiovascular Research and is supported by the Medical Re-search Council of Canada and the Quebec Heart Foundation.
Address for reprints: Dr. Martin G. Myers, Division of Cardiolo-gy, Sunnybrook Hospital, 2075 Bayview Avenue, Toronto, Ontar-io, M4N 3M5.
Received September 3, 1982; revision accepted February 17,1983.
dosage range of 50-100 mg daily has been confirmed.The elimination half-life of atenolol (6-9 hours)4"6 andthe relatively long duration of its antihypertensive ac-tion have made once daily dosing feasible.7
During the past decade there has been considerablestudy and speculation on the importance of the sympa-thetic nervous system in the depressor effects of beta-blockers, including atenolol. Actions of these drugs onboth the central and peripheral components of sympa-thetic function have been described and possiblemechanisms postulated. One group8-9 has proposedthat hypertensive patients with high levels of sympa-thetic activity as characterized by elevated resting plas-ma norepinephrine concentrations respond better tobeta-blocker therapy. In the present study, we haveexamined this hypothesis as part of a double-blindcrossover comparison study of the antihypertensiveeffects of atenolol and hydrochlorothiazide comparedwith placebo in patients with essential hypertension.
591
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592 HYPERTENSION VOL 5, No 4, JULY-AUGUST 1983
MethodsThe study population consisted of 12 patients with
essential hypertension who successfully completed thefull protocol. Three additional patients were enteredbut had to be withdrawn because of a variety of reasonsunrelated to atenolol therapy. The mean age of the 12participants was 52.8 years; eight were men. Secon-dary causes of the hypertension were excluded follow-ing routine clinical, biochemical, and radiologic eval-uations including renal arteriography, if indicated.Entry criteria were as follows: diastolic blood pressure= 100 mm Hg or greater (mean of two readings on twoseparate occasions; no evidence of accelerated or ma-lignant hypertension; absence of second- or third-de-gree heart block; and no history of hepatic or renaldisease, diabetes, alcoholism, asthma, myocardial in-farction, stroke, congestive heart failure, or anginapectoris. Patients with a resting heart rate under 50bpm were also excluded as were individuals needingother medications known to affect blood pressure orsympathetic nervous function.
The study design was a double-blind crossover com-parison between atenolol 100 mg daily, hydrochloro-thiazide 50 mg daily, and placebo. Tablets were ad-ministered using a "double dummy" technique so thateach patient received two tablets daily in the followingcombinations: placebo atenolol + active hydrochloro-thiazide, active atenolol + placebo hydrochlorothia-zide, and both placebo. Adherence to therapy was esti-mated by counting the number of returned tablets oneach visit. Each treatment phase consisted of 6 weeks,with the patients attending at three weekly intervals.Prior to entry, each subject underwent a complete his-tory and physical examination. A standard 12 lead
electrocardiogram was performed as were the follow-ing biochemical tests: complete blood count, serumelectrolytes, creatinine, bilirubin, cholesterol, uricacid, alkaline phosphatase, SGOT, BUN, urinalysisand microscopic examination. These parameters wererepeated at the end of each 6-week treatment period.
At each visit, the blood pressure and heart rate wererecorded in duplicate after 5 minutes' supine and 2minutes' erect using a Random Zero sphygmomanom-eter (Gelman Hawksley Ltd, Sussex, United King-dom) and ECG monitor, respectively. Any adverseeffects volunteered by the patient or other medicationgiven since the previous visit were recorded. After 6weeks on each treatment, the patient underwent tread-mill exercise, achieving 80% of their predicted maxi-mum heart rate using the Bruce protocol. Blood pres-sure was recorded immediately following the exercise.
An indwelling intravenous heparin lock device wasused to obtain plasma samples for norepinephrine andepinephrine following 30 minutes of supine rest, 10minutes erect, and after treadmill exercise at the end ofeach 6-week treatment period. Norepinephrine andepinephrine concentrations were determined accordingto the method of Peuler and Johnson.10 "
Differences in blood pressure, heart rate, and plas-ma catecholamines among the three periods were eval-uated by means of analysis of variance. The bloodpressure response to atenolol and hydrochlorothiazidewas examined in patients with either high or normaladrenergic tone as determined by the supine norepi-nephrine value during the placebo period. In the ab-sence of a control population, the median value of theplasma norepinephrine data was arbitrarily used to sep-arate the "high" from "normal" adrenergic status.
TABLE 1. Clinical Aspects of Patients on Entry Including Plasma Norepinephrine Concentrations while Supine onPlacebo
Patient
1
2
34
5
6
7
8
9
10
11
12
Mean ± SEM
Sex
M
M
MF
F
F
M
F
M
M
M
M
Age(yrs)
51
35
4558
56
55
46
48
59
64
58
58
53±2
Pretreatment blood pressure (mm Hg)
Pretreatment supineBP (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
174 ±6/106 ±2
After 6 wk placebosupine
BP (mm Hg)
209/117
154/92
171/116
173/116
159/109
208/111
168/112
180/119
159/103
178/111
161/108
156/93
173 ±5/109 ±3
HR (bpm)
80
72
8084
70
74
72
88
60
110
76
68
78±4
Supine plasmanorepinephrine
on placebo(pg/ml)
293*
219
186
346*
312*
198
164
292*
241
285*
255
286*
256 ±16
•Denotes the "hyperadrenergic" patients.
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EFPECTS OF ATENOLOL AND HYDROCHLOROTHIAZIDE/Afyers and de Champlain 593
TABLE 2. Effect of Atenolol, Hydrochlorothiazide, and Placebo on Blood Pressure (mm Hg) Heart Rate (bpm), PlasmaNorepinephrine and Epinephrine Concentrations (pg/ml) in 12 Patients Completing the Three Crossover Phases
Atenolol Hydrochlorothiazide Placebotreatment period (wk) treatment period (wk) treatment period (wk)
Supine
BP
HR
Norepinephrine
Epinephrine
Standing
BP
HR
Norepinephrine
Epinephrine
Exercise
BP
HR
Norepinephrine
Epinephrine
3
153/94t
61*
—
—
150/96*
65
—
—
—
—
—
—
6
155/94t
62*
251
52
152/95t
63
422
88
177/93t
101*
1351*
144t
3
156/101*
83
—
—
152/105*
93
—
—
—
—
—
—
6
154/99t
79
327*
63
150/103*
91
489
72
172/96*
132
951
89
3
172/108
81
—
—
169/112
89
—
—
—
—
—
—
6
173/109
79
256
55
166/113
87
402
68
204/111
134
813
93
Statistical significance of difference from corresponding placebo value: *p < 0.05; tp < 0.01; %p < 0.001.
ResultsThe mean value for the pre-entry supine blood pres-
sure was 174/106 mm Hg and on standing 164/108 mmHg (table 1). These recordings were consistent withpressure measurements taken after 6 weeks of placebowhen the mean supine and erect values were 173/109and 166/113 mm Hg, respectively (table 2). Both aten-olol 100 mg daily and hydrochlorothiazide 50 mg dailyproduced a significant reduction in blood pressure inboth the supine and erect positions after 3 and 6 weeksof therapy (table 2). Blood pressure readings takenimmediately after treadmill exercise were also signifi-cantly reduced by both of these drugs. Diastolic pres-sures on atenolol tended to be slightly lower than thoserecorded during hydrochlorothiazide therapy but thedifferences were small and significant (p < 0.05) onlyat 6 weeks in the erect position. Atenolol producedsignificant reductions in mean supine, erect, and exer-cise heart rates compared to both placebo and hydro-chlorothiazide values.
Plasma norepinephrine concentrations were signifi-cantly higher when measured in the supine positionwhile on hydrochlorothiazide and after exercise onatenolol compared with corresponding placebo values(table 2). Similarly, mean epinephrine concentrationswere significantly elevated after exercise on atenololtherapy.
The "adrenergic status" of each patient was con-stant regardless of the treatment phase or activity (table3). For example, patients with high plasma norepi-nephrine concentrations while supine had relativelyhigh values while erect or after exercise. The supinenorepinephrine concentrations on placebo also corre-lated significantly with the corresponding values after
exercise on atenolol (p < 0.01) and hydrochlorothia-zide (p < 0.001).
The supine norepinephrine value on placebo wasused to characterize the adrenergic status of the pa-tients. The six individuals who were classified as hy-peradrenergic (plasma norepinephrine 285 pg/ml orgreater) had a mean concentration of 302 pg/ml com-pared with a mean value of 211 pg/ml in the "normaladrenergic" group. The "hyperadrenergic" patientsexhibited a fall in blood pressure of — 30/ — 20 mm Hgon atenolol whereas the "normal adrenergic" grouphad a BP reduction of only —9/— 11 mm Hg.
The "adrenergic" status did not predict the re-sponse to hydrochlorothiazide and patients with higher
TABLE 3. Coefficients of Correlation for Norepinephrine andEpinephrine Values in the 12 Subjects While Supine, Erect, andAfter Exercise
Norepinephrine
supine vs erect
supine vs exercise
erect vs exercise
Epinephrine
supine vs erect
supine vs exercise
erect vs exercise
Coefficient of correlation (r)
Placebo
0.679*
0.718t
0.602*
0.80510.583*
0.566
Atenolol
0.762t0.879*
0.534
0.758t
0.736t0.829*
Hydrochloro-thiazide
0.740t0.853*
0.816t
0.758t
0.736t
0.830*
*p < 0.05; tp < 0.01; *p < 0.001.
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594 HYPERTENSION VOL 5, No 4, JULY-AUGUST 1983
epinephrine values did not exhibit greater depressoreffects with either drug. In the "hyperadrenergic" pa-tients, the mean supine plasma norepinephrine concen-trations on placebo (302 pg/ml) was reduced slightly to292 pg/ml (p > 0.05) during atenolol therapy. Themean ( ± SEM) supine heart rate on placebo at 6 weekswas 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 statisticallysignificant.
Compliance with therapy was excellent with over90% of the prescribed tablets being consumed. Twelveof the 15 patients entering the study completed all threetreatment phases. One patient was withdrawn becauseof persisting severe hypertension during the initial twophases (atenolol and hydrochlorothiazide). Another in-dividual was removed from the trial after 3 weeks onthe request of his family doctor. The third withdrawaloccurred when the patient developed a recurrence ofher chronic anxiety state as a result of her participationin the research study.
Mean serum concentrations of potassium (mEq/li-ter), uric acid (mg/dl) and bicarbonate (mmol/liter) onplacebo (3.9, 5.5 and 24.3 respectively) were signifi-cantly altered by hydrochlorothiazide therapy (3.6, 7.0and 28.5). Differences in individual patient valueswere not likely of any clinical importance. No signifi-cant alterations in values of biochemical tests weredetected during atenolol therapy.
DiscussionAtenolol appears to be an effective antihypertensive
agent of at least equal potency to usual doses of hy-drochlorothiazide. In the present study, these drugswere well tolerated by patients and each reduced themean blood pressure substantially in the supine anderect positions and after treadmill exercise. Atenolollowered the diastolic blood pressures somewhat morethan hydrochlorothiazide. This finding is consistentwith previous reports which showed a greater diastolicblood pressure fall on atenolol compared with chlor-thalidone 25 mg'2 and bendrofluazide 5 mg daily.13 It islikely that the preferential effect of atenolol on thediastolic blood pressure resulted from differences inthe mechanisms of action of the two classes of drugs.The magnitude of the depressor response to atenololwas comparable to findings from other studies' 2-l2 "as was the degree of beta-blocker induced bradycardia.
Previous reports have demonstrated variable effectsof beta-blockers on sympathetic activity as measuredby plasma norepinephrine concentrations. For in-stance, propranolol caused significant increases in su-pine and post-exercise plasma norepinephrine in oneseries14 but only increased the supine concentration inanother,15 with the latter report showing a significantfall in exercise norepinephrine. In a series of "hyper-adrenergic" hypertensives, metoprolol and proprano-lol reduced both the supine and erect plasma norepi-nephrine values.8 A beta-adrenoceptor antagonist withintrinsic sympathomimetic activity, pindolol, has beenreported16 to lower plasma norepinephrine significant-
ly in patients supine, erect, and post-exercise. Pre-vious studies with atenolol have shown relatively con-sistent norepinephrine data with increases in supineand post-exercise values reported by Distler et al ." andWiner et al.18 in hypertensive and normotensive sub-jects respectively. Data from the present study showedonly the exercise norepinephrine values to be increasedon atenolol. The variable effects of these beta-blockerson plasma norepinephrine may be due to differentpharmacologic properties of the drugs (e.g., intrinsicsympathomimetic activity, presynaptic beta-receptorblockade, central nervous system penetration), envi-ronmental conditions, types of subjects studied (nor-mal or hyperadrenergic) or possibly the result of inad-equate group sizes.
Thiazide diuretics also appear to affect plasma nor-epinephrine values. Lake et al.19 have reported signifi-cant increases in both the supine and erect positionsfollowing hydrochlorothiazide therapy. In the presentstudy, hydrochlorothiazide increased plasma norepi-nephrine in the supine and erect post-exercise statesalthough only the supine data were significantly differ-ent from control. As suggested by Lake et al. '9 this risein the plasma norepinephrine may be secondary to abaroreceptor-mediated reflex increase in sympatheticactivity in response to the blood pressure loweringeffects of hydrochlorothiazide.
In relating changes in plasma catecholamines to theantihypertensive actions of drugs, it is important toconsider possible limitations of plasma norepinephrineas a measure of sympathetic nervous system activity.Recent studies have shown that norepinephrine valuesmay be determined not only by spillage form the syn-aptic cleft of the nerve terminal but also by changes innorepinephrine clearance from the plasma. In normo-tensive subjects, Esler et al.20 have reported that nor-epinephrine kinetics are age dependent with older per-sons exhibiting reduced clearance from the plasma.These authors concluded that the decreased norepi-nephrine clearance in the elderly may explain the posi-tive correlation observed between age and the plasmanorepinephrine concentration.21-22 However, othershave not observed such a correlation in hypertensivepatients.8-23
The clearance of norepinephrine from the circula-tion may also depend upon changes in cardiac outputwith resultant alterations in blood flow to the liver andlungs, major sites of norepinephrine elimination.Brown et al.24 have reported that the infusion of isopro-terenol increases norepinephrine elimination whereasothers25-26 have shown that beta-adrenoceptor antago-nism will have the opposite effect. Thus, the higherpost-exercise norepinephrine values on atenolol mayhave resulted from the relatively lower exercise-in-duced augmentation of cardiac output during beta-blockade. Furthermore, atenolol may only cause anapparent increase in sympathetic activity with thehigher norepinephrine values resulting from a fall inclearance rather than an increase norepinephrine spill-age from the synaptic cleft. If true, this phenomenonwould explain the paradox of a drug lowering blood
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EFFECTS OF ATENOLOL AND HYDROCHLOROTHIAZIDE/Afyers and de Champlain 595
pressure while simultaneously appearing to increasesympathetic activity. However, not all studies are inagreement with the observations of Brown et al.24 Inseven normal subjects and ten patients with borderlinehypertension, Vincent et al.27 have recently reportedthat isoproterenol caused an increase in the plasmaconcentration of norepinephrine. These conflicting re-sults must be investigated further before the impor-tance of changes in clearance to the plasma concentra-tion of norepinephrine is fully understood.
The possible role of norepinephrine clearance as adeterminant of the amount of circulating norepineph-rine does not preclude the use of the plasma nor-epinephrine value as a measure of sympathetic ac-tivity. In our group of predominantly middle-agedhypertensive patients under standardized conditions,the plasma norepinephrine concentration was a predic-tor of the blood pressure response to atenolol. Thisfinding is consistent with an earlier observation8 that"hyperadrenergic" patients exhibited greater bloodpressure reductions on either metoprolol or proprano-lol therapy. The detection of a similar relationship foratenolol in this relatively small number of patientssuggests that adrenergic status is likely a major deter-minant of the blood pressure response to beta-blockers. Furthermore, beta-adrenoceptors may them-selves play a more critical role in the maintenance ofhypertension in the "hyperadrenergic" hypertensivepopulation.
Even under conditions where cardiac output andnorepinephrine clearance may change, it may still bepossible for the plasma norepinephrine concentrationto reflect relative levels of sympathetic activity. Forexample, patients with higher supine plasma norepi-nephrine values on placebo in our study tended to haveproportionately higher values while standing and afterexercise. The rank order of norepinephrine status wasalso maintained during atenolol and hydrochlorothia-zide therapy. Furthermore, the supine plasma norepi-nephrine concentration on placebo correlated signifi-cantly with the corresponding post-exercise values onboth atenolol and hydrochlorothiazide. These observa-tions suggest that alterations in cardiac output and oth-er factors affecting norepinephrine clearance may exerta proportionately similar effect on the plasma norepi-nephrine concentrations such that those individualswith higher norepinephrine values on placebo will con-tinue to exhibit relatively high values regardless ofatenolol or hydrochlorothiazide therapy.
The combined results of the present study and earlierreports suggest that all beta-blockers do not exert thesame effect on sympathetic nervous system function asmeasured by plasma norepinephrine. Drugs withoutintrinsic sympathomimetic activity such as proprano-lol, metoprolol and atenolol tend to increase norepi-nephrine values, particularly after exercise. However,certain sub-groups such as "hyperadrenergic" hyper-tensive patients may actually exhibit a fall in plasmacatecholamines coincidental with the pronounced re-duction in blood pressure. One might speculate that"adrenergic" status may be a useful index of respon-
siveness prior to the initiation of antihypertensive ther-apy. Furthermore, the sympathetic profile of patientsappears to be relatively consistent under a variety ofconditions when determined by a single plasma norepi-nephrine sample, regardless of alterations in clear-ance.
AcknowledgmentThe authors thank A. G. McMillan and E. Roberts for technical
and secretarial assistance.
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M G Myers and J de Champlainessential hypertension.
Effects of atenolol and hydrochlorothiazide on blood pressure and plasma catecholamines in
Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 1983 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Hypertension doi: 10.1161/01.HYP.5.4.591
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