Treatment of Hypertension
With Spironolactone
Double-Blind
Robert L. Wolf, MD, Milton Mendlowitz, MD, Julia Roboz, George P.
Peter Kornfeld, MD, and Alfred Weigl, MD
A double-blind study of patients with essential hyper-
tension was performed in order to determine which dosage
of spironolactone (25 mg, 100 mg, or 200 mg daily), with
or without hydrochlorothiazide, had the optimum hypo-
tensive effect. The data were analyzed by two different
statistical methods, in each of which multivariate analysis
of variance was used. Both methods led to the conclusion
that the most efficacious treatment regimen tested was
spironolactone at a daily dosage of 100 mg, without
hydrochlorothiazide.
Spironolactone (3-(3-oxo-7 a-acetylthio-17/3-hy-
droxy-4-androsten-17a-yl)
lactone)—either alone
propionic acid-y-
or in combinations with
hy¬
drochlorothiazide and other antihypertensive drugs
—has been used by Hollander et al and others17
to reduce the blood pressure of patients with pri¬
mary or essential hypertension. The effects of al-
dosterone and desoxycorticosterone are inhibited
by spironolactone, an aldosterone antagonist, re¬
sulting in increased sodium excretion, reduced po¬
tassium excretion, weight loss, and hypotension
in patients on a restricted sodium intake.8 The
progressive administration of desoxycorticosterone
in animals has reversed the metabolic effects of
spironolactone, implying that these substances
compete for the same renal receptor sites. The
spirolactone group located at the 17 position in
spironolactone is structurally similar to the con¬
figuration of aldosterone at the same site and is
the probable basis for the competitive blocking
of the renal effects of aldosterone by spironolac¬
tone.
The natriuretic effect of spironolactone is modest
From the Circulatory Physiology Laboratory and Hypertension
Clinic, Department of Medicine, and the Andre Meyer Department
of Physics, Mount Sinai Hospital School of Medicine and Mount
Sinai Hospital, and the Department of Mathematical Statistics,
Columbia University, New York.
Reprint requests to 20 E 74th St, New York 10021 (Dr. Wolf).
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Study
H. Styan, MA,
compared to that of chlorothiazide and the mer¬
curial diuretics.1'3 The diuretic action of either the
thiazide or the mercurial diuretics may be poten¬
tiated by the concomitant administration of
spironolactone.1 "°
The mechanism whereby spironolactone admin¬
istration produces hypotension has not been re¬
solved. It is not due solely to the depletion of
total body sodium or contraction of the plasma
volume since the hypotensive effect persists despite
the experimental correction or overcorrection of
these situations.1'38 The magnitude of the anti-
hypertensive action of spironolactone is approxi¬
mately equal to that of the thiazide diuretics.6,9,10
An exhaustive search of the literature has re¬
vealed conflicting reports about the hypotensive
effects of hydrochlorothiazide and spironolactone.
Studies have shown that spironolactone (1) en¬
hances the antihypertensive effect of the thiazide
diuretics and other antihypertensive drugs1'3,5,6;
(2) does not cause a significant decrease in either
systolic or diastolic blood pressure when compared
to placebo7; (3) has no effect on the blood pressure
taken with patients in the reclining position and
does not enhance the hypotensive effect of reser-
pine or guanethidine4; and (4) does enhance the
hypotensive effect of reserpine.7
In order to resolve some of these conflicting ob¬
servations, we have performed a double-blind study
in which the antihypertensive effects of spiron¬
olactone in low (25 mg daily), medium (100 mg
daily), and high (200 mg daily) dosages, both
alone and in combination with hydrochlorothia¬
zide (100 mg daily), were compared. Our main
objective, however, was to find the optimum dos¬
age of spironolactone (with or without hydro¬
chlorothiazide), ie, the dosage that would reduce
blood pressure by the greatest amount. The data
collected were analyzed by multivariate inference
procedures.11
 Methods
Clinical Methods.—Twenty-four cases of benign,
essential hypertension12 were studied. All the pa¬
tients were ambulatory, and the observations were
recorded in the Hypertension Out-Patient Clinic.
The blood pressure readings were systolic and dia-
stolic, taken with patients in the reclining and in the
erect positions.
Seven treatment regimens, one a placebo and
the others as shown below, administered
were
daily in two divided doses.
Hydrochlorothiazide
Present
Spironolactone Absent 100 mg Daily
25 mg daily Lo S Lo S + H
100 mg daily Med S Med S + H
200 mg Hi S
daily Hi S + H
(The abbreviations used in the tabulation will be
used hereafter to designate the treatment regi¬
mens.)
The plan of the study called for each patient
to receive each treatment regimen, denoted "drug"
in the sequel, for three consecutive fortnightly
visits. Thus a patient would be on a particular
regimen for six weeks. The whole study covered
42 weeks. The drugs were administered in a ran¬
dom, double-blind fashion to each patient in order
to eliminate any sequencing effects.
No significant changes were observed during
the course of the study in results of the following
laboratory tests: complete blood count; urinalysis;
sedimentation rate; blood urea nitrogen, fasting
blood glucose, sodium, potassium, chloride, carbon
dioxide, bilirubin, serum glutamic oxaloacetic
transaminase, and alkaline phophatase determina¬
tions; chest roentgenogram; and electrocardiogram.
Statistical Methods.—The blood pressure ob¬
served for each patient constitutes a composite
or set of four measurements, systolic and diastolic
taken with the patient in the reclining and in the
erect position. We call these measurements "sys¬
tolic reclining," "diastolic reclining," "systolic
erect," and "diastolic erect." We are interested in
the effect of the drugs on these blood pressures as
a whole, eg, we would like to lower all four mea¬
surements simultaneously and obtain a measure
for this decrease on the four as a group. We are
also interested in examining the effects of the
drugs on the four pairs of blood pressures formed
by the sets of both systolic, both diastolic, both
reclining, and both erect measurements. Our in¬
ference procedures are, therefore, based on multi-
variate analysis.'1,13
Unfortunately, each patient did not receive each
drug. This undoubtedly was because the subjects
were hospital clinic outpatients and because the
duration of the study was ten months. Of the 24
patients in the study, eight received all seven drugs.
Several patients missed one out of the three
visits to the clinic which they were expected to
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make while receiving each drug. The data, there¬
fore, were unbalanced.
It is known that hydrochlorothiazide produces
carry-over effects of only short duration.14 How¬
ever, two weeks elapsed between observations and
six weeks between treatment regimens. Further¬
more, despite the fact that the drugs were admin¬
istered in random order, it might be expected
that time may affect the values of the observations.
To resolve these two points, nonparametric pro¬
cedures for serial correlation were performed, and
these yielded no evidence to indicate either carry¬
over effects or effects due to time of observation.
Since 24 patients received at least one pair of
drugs, and since 8 patients received all seven
drugs, it is possible to proceed with the statistical
analysis by two different methods. In the first we
considered the 21 possible pairs of drugs, with the
maximum number of patients for each pair. This
has the advantage of producing exhaustive paired
comparisons between drugs but the disadvantage
of using different patients for each drug-pair com¬
parison. In the second we considered the eight
patients only and set up a cross-classified model in
which the effects of spironolactone, hydrochloro¬
thiazide, and their interaction could be estimated
in the form of dose-response relationships. This
has the advantage of using the same patients
throughout the analysis but the disadvantage that
the number of patients is small. Two different
methods of analysis, however, certainly enhance
any possible conclusions that may be found from
just one, provided that they are corroboratory.
Method A: Paired Comparisons With Max¬
imum Numbers of Patients.—We consider the
following model for each drug pair:
Ym =£=a*+Pi + ßa+eijk, [1]
where y,,;.=the blood pressure observation of pa¬
tient j with drug i during visit k; ju = the overall
average blood pressure of hypertensive patients;
a, = the effect of drug i ( = 1,2 in each pair); p,= the
effect of patient ; ( = 1,2 . .
, with upper limit
.
differing from each pair) ; ßu = the interaction of drug
i and patient j, as measured by the additional re¬
sponse of patient / to drug i, compared with the
average response of all patients to drug /; and
e,7;, = the random error between measurements from
patient ; with drug i during visit k ( = 1,2,3).
Each underlined quantity is a vector with four
components corresponding to the four blood pres¬
sure measurements observed. The drug effect is
fixed, while the patient effect is random (we are
interested in making inferences for all hypertensive
patients, not just those in this study). The model
is, therefore, called "mized."15 The random error
vector is assumed to follow a multivariate normal
distribution11 with zero mean vector and constant
covariance matrix independent of drug i, patient
j, or visit k.
Method B: Dose-Response Relationships
 With Eight Patients.—We consider the following
model :
y¡;fc = /i+«z¡+Pi + AiZ¡+e,7ft, [2]
where y4//c = the blood pressure observation of pa¬
tient j with spironolactone dosage indexed by i dur¬
ing visit k; ju, = the overall average blood pressure
of hypertensive patients; z, = the dosage of spiro¬
nolactone (we consider two situations, the first
where this is the logarithm of the daily dosage and
the second where this is the composite of the dos¬
age and its square for the purpose of estimating
a parabola), indexed by i (=0,1,2,3); a=the
average amount of dependence of z¡ (eg, the slope) ;
P;=the effect of patient j ( = 1,2 ,8); /?,, = the
. . .
particular amount of dependence of patient j on
the dosage indexed by i; eijk = the random error
between measurements on patient ; with dosage i
during visit k ( = 1,2,3). Similar assumptions ap¬
ply here as in method A regarding the nature of
the vectors involved. The model [2] can be ex¬
panded to include the effect of hydrochlorothiazide,
but this model was not found to be suitable. The
model with z¡ denoting logarithms of spironolac¬
tone dosages was fitted to observations with hydro¬
chlorothiazide, while the model with z, denoting
the straight dosage and its square was fitted to
observations without hydrochlorothiazide. Model
[1] was used also to compare selected dosages with
the eight patients of model [2] in order to confirm
the validity of method A.
Results
In the univariate and bivariate cases F-statistics
were used to test hypotheses about the parameters
in models [1] and [2], In the quadrivariate case
(all four responses considered as a group) an F-ap-
proximation to Anderson's (7-statistic11 provided
by Rao16 was used. In testing the effects of the
drugs, we based15 the denominators used in the
F-statistics (and (7-statistics) on the patient-drug
interactions rather than on the pure errors (resi¬
duals), since the patient effects are random and
the drug effects are fixed. All computations were
performed on the IBM 7094 computer with the
aid of a specially developed program.'7
The results of the analysis by method A are pre¬
sented in Table 1 and illustrated in Fig 1. All
four blood pressures are seen to be lower on the
average for any concentration of spironolactone,
with or without hydrochlorothiazide, than for
placebo. The decrease is not significant (P > 0.05)
for the low dosage, 25 mg, but it is significant
(P < 0.05) at the medium dosage, 100 mg. The
high dosage, 200 mg, is no more effective than the
medium dosage in most situations and is signifi¬
cantly different from placebo in fewer instances
than the medium dosage. The addition of hydro¬
chlorothiazide does not enhance the hypotensive ef¬
fect of spironolactone but rather tends to de¬
crease the blood pressure less.
Considering the significance of the decrease of
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all four blood pressures simultaneously (Table 1),
it is apparent that Med S is most significant, with
Hi S and Med S + H not quite as significant. The
other three dosages are not significantly different
from placebo, not only for all four blood pressures
in a group, but also for all the four pairs considered
and the four blood pressures taken individually.
The remaining 15 paired comparisons showed no
significant differences except between Hi S and
Hi S + H and between Lo S and Med S, for the
systolic erect response only. The former difference
favored Hi S + H, despite the indication that
Hi S differed from placebo more than Hi S + H.
This anomaly occurred because a different subset
of the 24 patients was considered for each paired
comparison and some extreme values were record¬
ed for the patients in the placebo/Hi S + H com¬
parison not included in method B. The two dif¬
ferences were found tó be as shown below:
Mean SE P
(Hi S + H) Hi S
-
-4.56 1.29 0.008
Med S Lo S
-
-13.19 4.03 0.007
The values for the other 13 comparisons are not
reported. (SE denotes standard error of the mean.)
We do not report results of the between-patients
effects, nearly all of which were found to be sig¬
nificant. This finding is not unusual since differ¬
ences among the patients' blood pressures may
be due to their age, sex, race, etc. These factors do
not bias the tests of drug effects because the meth¬
ods of analyses compared the performances of
drugs within individual patients rather than be¬
tween separate groups of patients. Many patient-
drug interactions were also found to be significant
in method A.
The results of the analysis by method B are pre¬
sented in Tables 2 and 3 and illustrated in Fig 2.
Again, all four blood pressures are seen to be low¬
er on the average for any concentration of spirono¬
lactone, with or without hydrochlorothiazide, than
for placebo. The dose-response relationships appear
different according to whether or not hydrochloro¬
thiazide is included in the dose. With hydro¬
chlorothiazide, increasing the dosage of spirono¬
lactone enhances the lowering of the four blood
pressures, though the decrease falls off with in¬
creasing dosage of spironolactone. A logarithmic
dose-response curve seems indicated. Without
hydrochlorothiazide, increasing the dosage of spiro¬
nolactone enhances the lowering of the blood pres¬
sures up to the medium concentration of 100
mg
and then deters it. It seems then that a parabola
with a minimum near 100 mg would be a good
fit, ie, there is a unimodal dose-response relation¬
ship with a peak at the middle dose. The descent
without hydrochlorothiazide is steeper than that
with hydrochlorothiazide, up to the medium dos¬
age, beyond which the descent continues only with
hydrochlorothiazide. The medium dosage, however,
appears to be better than Hi S + H.
It seems that the data generated by the extra
 Table 1.—Blood Pressure Differences Between Placebo and Each of Six Drug Regimens
Daily Spironolactone Dose
Without Hydrochlorothiazide With Hydrochlorothiazide
25 mg 100 mg 200 mg 25 mg 100 mg 200 mg
No. of patients 21 16 17 17 14 11
No. of observations 56 45 45 40 40 29
Systolic reclining, mm Hg
Mean differences -10.50 -19.86 -21.50 -9.00 -19.14 -16.18
SE of mean differences 5.70 7.34 7.43 6.19 7.85 10.91
0.088 0.016 0.011 0.161 0.027 0.169
Diastolic reclining, mm Hg
Mean differences -3.74 -9.43 -9.23 -4.10 -7.96 -4.00
SE of mean differences 3.00 4.00 2.98 3.33 3.11 4.16
0.235 0.031 0.007 0.233 0.021 0.359
Systolic erect, mm Hg
Mean differences -9.90 -23.08 -20.13 -9.33 -19.25 -16.64
SE of mean differences 5.74 6.29 7.69 6.36 6.92 9.62
0.108 0.002 0.019 0.158 0.013 0.114
Diastolic erect, mm Hg
Mean differences -2.43 -7.16 -6.21 -3.73 -7.33 -5.30
SE of mean differences 2.80 3.54 2.95 2.94 2.43 3.26
0.401 0.060 0.053 0.219 0.008 0.134
Both systolic responses, P 0.242 0.002 0.041 0.376 0.040 0.224
Both diastolic responses, P 0.442 0.103 0.012 0.477 0.034 0.197
Both reclining responses, P 0.218 0.057 0.027 0.385 0.063 0.387
Both erect responses, P 0.234 0.005 0.072 0.374 0.030 0.277
All four responses, P 0.310 0.012 0.046 0.748 0.072 0.324

Table 2.—Mean and SE of Mean Blood Pressure Measurements for Eight Patients Who Received All Drug Regimens
Daily Spironolactone Dose
Without Hydrochlorothiazide With Hydrochlorothiazide
Placebo 25 mg 100 mg 200 mg 25 mg 100 mg 200 mg
No. of observations 24 23 21 24 23 23 21
Systolic reclining, mm Hg
Means 172.71 152.26 139.14 147.38 152.48 142.70 137.86
SE of means 7.26 5.21 4.32 2.68 4.03 3.70 2.58
Diastolic reclining, mm Hg
Means 104.08 96.61 88.81 95.13 98.00 94.91 93.62
SE of means 3.35 1.76 1.89 2.54 :.69 2.09 1.97
Systolic erect, mm Hg
Means 166.17 147.22 132.14 139.88 143.35 138.09 133.57
SE of means 6.89 4.15 3.56 2.55 3.66 3.50 2.70
Diastolic erect, mm Hg
Means 103.17 96.43 96.63 97.87 95.65 94.14
SE of means 3.10 2.30 2.10 2.53 1.39 1.85

Table 3.—P-Values for Selected Hypotheses for Eight Patients Who Received All Drug Regimens
Med S Compared With"
Quadratic
Blood Pressure Med S + H Hi S Hi S + H Logarithmic Fitt Fitt
Systolic reclining 0.697 0.048 0.679 0.027 0.008
Diastolic reclining .042 .098 .078 .077 .011
Systolic erect .355 .112 .624 .029 .005
Diastolic erect .011 .133 .173 .080 .035
Both systolic responses .451 .166 .452 .104 .013
Both diastolic responses .028 .256 .220 .234 .058
Both reclining responses .107 .057 .135 .105 .040
Both erect responses .022 .086 .297 .112 .020
All four responses 0.040 0.324 0.180 Ü.415 0.049
;::Drug dosages in the comparison are Med S, 100 mg of spironolactone daily; Med S -f H, 100 mg of spironolactone and 100 mg of hydrochloro¬
thiazide daily; Hi S, 200 mg of spironolactone daily; Hi S + H, 200 mg of spironolactone and 100 mg of hydrochlorothiazide daily.
tThe logarithmic curve is determined for the regimens that included hydrochlorothiazide.
tThe quadratic curve is determined for the regimens that excluded hydrochlorothiazide.

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 patients included in method A dampen the up¬
swing of the dose-response relationship without
hydrochlorothiazide. These extra data, however,
are not as reliable as the data for the eight pa¬
tients common to both methods because several
extreme values recorded.
were
While no significant differences were found be¬
tween the medium and high dosages with method
A, the data from the eight patients common to
both methods yield some significant differences.
These are reported in Table 3 and illustrated
in Fig 2. We find that Med S is superior to Med
S + H for all four blood pressures considered
as a group (P=0.04) while, for systolic reclining
only, Med S is significantly better than Hi S
(P=0.048). Here the high correlations between
the random errors in the four blood pressures re¬
duced this to a nonsignificant effect when all four
were considered together. The correlations found
were systolic reclining/diastolic reclining, 0.85; sys¬
tolic reclining/systolic erect, 0.73; systolic reclin¬
ing/diastolic erect, 0.8; diastolic reclining/systolic
erect, 0.5; diastolic reclining/diastolic erect, 0.89;
and systolic erect/diastolic erect, 0.52. No signifi¬
cant differences were found between Med S and
Hi S + H, as seems indicated by Fig 2 and Table 2.
The conjectured logarithmic dose-response
curve, with hydrochlorothiazide, is significant for
systolic reclining and systolic erect blood pres¬
sures. Here again the correlations between the
random errors in the blood pressures are so great
that this significance is eliminated when they are
considered together or in association as pairs of
blood pressures. The values are reported in Table 3.
The conjecture of a quadratic dose-response
curve, without hydrochlorothiazide, is much more
encouraging. Here the fit is highly significant for
all blood pressures, considered individually or in
groups. From Table 3 we see that systolic reclin¬
ing and systolic erect are, once again, the best fits.
If we let x be dosage of spironolactone divided
by 25 and ignore the patient-spironolactone inter¬
actions (which were generally not significant in
method B), then the estimated four-dimensional
surface is
systolic reclining =169.1 -13.38x+1.34x2,
diastolic reclining = 103.35— 6.28x+0.66x2,
systolic erect = 163.21 13.74x+ 1.36x2,
diastolic erect =102.26- 5.06x+0.55x2.[3]
-
Dosages in milligrams yielding the minimum blood
pressures, rounded to the nearest 10 mg, are,
spectively, 120, 120, 130, and 120.
If the patient-spironolactone interactions are
included in equation [3], a separate "minimum
dosage" can be estimated for each blood pressure
response for each patient. Empirical 95% confi¬
dence intervals for these minimum dosages are in¬
dicated in Fig 2. The values in milligrams, corrected
again to the nearest 10 mg, are systolic reclining,
110, 140; diastolic reclining, 110, 130; systolic
erect, 110, 180; diastolic erect, 100, 140.
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All test statistics would have been much more
significant if the patients' effects had been taken
as fixed and we had, therefore, confined our in¬
ferences only to the patients taking part in this
study.
Comment
Seven treatment regimens ("drugs") were ad¬
ministered to 24 patients making three visits per
drug. Since only eight of the 24 patients received
all the drugs, probably due in part to the length
of the study conducted, two different statistical
analyses have been used to analyze the data col¬
lected. In the first, all possible paired comparisons
between the drugs were considered with no note
taken that they were in reality three different dos¬
ages of one drug, with or without another drug,
plus a placebo. In this analysis we found that Med
S, 100 mg of spironolactone without the addition
of hydrochlorothiazide, differed most significantly
from placebo and that, of the other five drugs,
only Hi S and Med S + H were found to be sig¬
nificantly different from placebo. For systolic erect
only, Hi S + H was significantly superior to Hi S.
Thus, we found all six drugs clustered together,
with the four mentioned furthest from placebo. The
best of these four is Med S.
The second analysis took note of the composi¬
tion of the drugs but included only the eight pa¬
tients who received all seven drugs. The results
were very similar to those of the first analysis, ex¬
cept that now it became apparent that Hi S + H
was almost as good as Med S. In estimating dose-
response curves, we found that a logarithmic rela¬
tionship was marginally significant for the drugs
with hydrochlorothiazide, while, for those without
hydrochlorothiazide, a quadratic relationship was
highly significant. For the latter, even the four-
dimensional surface was found to be significant,
despite high correlations between the blood pres¬
sure responses. The marginal minima of this sur¬
face were estimated to correspond to between 120
and 130 mg of spironolactone. The responses there
were lower than those corresponding to the best
with hydrochlorothiazide, that is, Hi S + H, on
the average. Med S was found to be significantly
better than Med S + H and marginally better
than Hi S for systolic reclining. No significant dif¬
ferences were found between Med S and Hi S + H,
though both analyses showed Med S to be no worse
than Hi S + H, on the average.
re¬ We conclude, therefore, that spironolactone in
its medium dosage (100 mg daily), without hydro¬
chlorothiazide is the best of the treatment regi¬
mens considered in this double-blind study. It is
possible that the high dosage with hydrochloro¬
thiazide might do as well.
The initial blood pressure decline and subse¬
quent rise with increasing dosage of spironolactone
without hydrochlorothiazide seems to be the same
phenomenon that has also been observed for the
thiazide drug group, of which hydrochlorothiazide
 TOTAL DAILY DOSAGE OF TOTAL DAILY DOSAGE OF
SPIRONOLACTONE (mg) SPIRONOLACTONE (mg)
25 100 200 25 100 200
T —I- T T ~r

DECREASE IN DECREASE IN
SYSTOLIC SYSTOLIC
RECLINING 10 ERECT I0
BLOOD BLOOD
-

PRESSURE PRESSURE
OVER PLACEBO OVER PLACEBO
20 -20

TOTAL DAILY OOSAGE OF TOTAL DAILY OOSAGE OF

SPIRONOLACTONE I mg ) SPIRONOLACTONE (mg)
25 100 200 25 100 200
1. Mean differences between
"7s I-1- placebo and each of the six
other treatment regimens for
DECREASE IN DECREASE IN four blood pressures, as found
DIASTOLIC DIASTOLIC
RECLINING 0 ERECT -10 by method A (paired compari¬
BLOOD sons with maximum numbers
BLOOD
PRESSURE PRESSURE of patients). Solid fine, with
OVER PLACEBO OVER PLACEBO hydrochlorothiazide; broken
-20 -20 fine, without hydrochlorothia¬
zide.

HS DECREASE NOT SIGNIFICANT AT 0 05 LEVEL * /«* DECREASE SIGNIFICANT AT 005/0.01 LEVEL

180
175 2. Means for four blood pres¬
sures with each of the seven
170
treatment regimens as found
165 by method B (including only
SYSTOLIC 160 eight patients who had all the
ERECT drugs), with 95% confidence
8L00D
155 regions for optimum dosages.
PRESSURE 150 Solid line, with hydrochlorothi¬
145
azide; broken /¡ne, without hy¬
drochlorothiazide.
140
135
130
25 100 200 0 25 100 200
TOTAL DAILY DOSAGE OF TOTAL DAILY DOSAGE OF
SPIRONOLACTONE (mg) SPIRONOLACTONE (mg)

105 105

DIASTOLIC
RECLINING
BLOOD
100
k DIASTOLIC
ERECT
BLOOD
100

95 95
PRESSURE PRESSURE

90 \l" 90

85 Jit !.. j_ 85
i-. J_
25 100 200 0 25 100 200
TOTAL DAILY DOSAGE OF TOTAL DAILY DOSAGE OF
SPIRONOLACTONE (mg ) SPIRONOLACTONE (mg)

957. EMPIRICAL CONFIDENCE REGION FOR OPTIMUM DIFFERENCE FOUND SIGNIFICANT

DOSAGE OF SPIRONOLACTONE WITHOUT HYDRO¬ AT 0 05 LEVEL
CHLOROTHIAZIDE, WITH ARROW (|l AT VALUE
ESTIMATED WITH PATIENT-SPIRONOLACTONE
INTERACTION IGNORED

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 is a member. It might be conjectured that the rise
will level off when the daily dosage increases be¬
yond 200 mg.
This investigation was supported by Public Health Service
research grant HE 06546-04 (CV) from the National Heart In¬
stitute.
References
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Antihypertensive Actions of Mercurial, Thiazide, and Spironolac-
tone Diuretics," in Buchborn, E., and Bock, K.D. (eds.): Diuresis
and Diuretics: An International Symposium, Berlin: Springer-
Verlag, 1959, pp 297-312.
2. Hollander, W.; Chobanian, A.V.; and Wilkins, R.W.: "Poten-
tial of the Aldosterone Antagonists in Hypertension," in Bartter,
F.C. (ed.): The Clinical Use of Aldosterone Antagonists, Spring-
field, Ill: Charles C Thomas, Publisher, 1960, pp 169-185.
3. Hollander, W.; Chobanian, A.V.; and Wilkins, R.W.: The
Role of Diuretics in the Management of Hypertension, Ann NY
Acad Sci 88:975-989 (Oct 11) 1960.
4. Georgopoulos, A.J.; Dustan, H.; and Page, I.H.: Spironolac-
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Desoxycorticosterone—Córtate, Decortin, Decosterone, Doca,
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Chlorothiazide—Diuril.
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1966.

THE HEART AS A COMBUSTION ENGINE.-Heart and other muscles

may be said to be engines. They transform the energy of chemical reactions,
"metabolism," into mechanical energy, often into work. The mechanisms where¬
by they accomplish this are much more obscure than those of man-made ma¬
chines. Still, an important part of physiological, biochemical, and biophysical
investigation is aimed at solving this riddle. There is no assurance that such a
solution will ever be obtained, but it is a part of the optimism of science to
keep up the effort.
The metabolic reactions in the living organism have often been compared with
combustion and, in a similar fashion, comparisons have been made between mus¬
cles and combustion engines. In light of this analogy, it is of interest to con¬
sider the mechanism of an automobile motor, both from the "physiological" and
from the "biochemical" standpoint. The ultimate contribution of the biochemist
would be to identify the energy-yielding reaction by some equation describing
the combustion of a mixture of lower hydrocarbons. To the physiologist, this
would appear to be only a very peripheral piece of information, for it would stand
in no relation to the specific performances of the different parts of the machine,
and would not explain how these latter become engaged in a sequence of trans-
locations whereby force and motion are produced.
Would this comparison also imply that the biochemical analysis of the con¬
tractile machinery in myofibrils, which has played such a prominent role during the
last generation, will always stay on the outside of the real fundamental problems?
Not at all, because there is an essential difference.—Mommaerts, W.F.H.M.:
"Heart Muscle," in Circulation of the Blood—Men and Ideas, Fishman,
A.P. and Richards, D.W. (eds.) New York: Oxford University Press, 1964, p 128.

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