THE RESPONSE TO THE ADMINISTRATION OF AN ISOTONIC
SODIUM CHLORIDE-LACTATE SOLUTION IN PATIENTS
WITH ESSENTIAL HYPERTENSION
By SOLOMON PAPPER,* JOSEPH L. BELSKY AND KENNETH H. BLEIFER t
(Fronit the Medical Service and the Research Laboratory, Veterans Admlinlistration Hospital,
anzd the Departments of Medicine, Boston University School of Medicinie and
Tufts University School of Medicine, Boston, Mass.)
(Submitted for publication December 21, 1959; accepted January 8, 1960)
Many studies indicate that patients with essential hypertension have a greater natriuretic response to rapidly administered sodium chloride
solutions than have normotensive individuals
(1-7). However, in most instances other factors known to influence the rate of sodium excretion in the normal subject such as diet, posture, and time of day have not been rigidly controlled (8, 9). Dietary control is of particular
importance in view of observations suggesting that
patients with hypertension may habitually ingest
more salt than do normotensive individuals (1011). If this is indeed the case it might well be
responsible for the enhanced response of the hypertensive patient to administered salt.
The present report is concerned with a comparison of the response of hypertensive and normotensive individuals to the intravenous administration of an "isotonic-balanced" salt solution under
rigidly controlled conditions and at three different levels of dietary salt ingestion. The results indicate that patients with essential hypertension excrete the infused sodium load more
rapidly than do normotensive individuals at each
level of salt consumption.
METHODS
Four niormal Caucasian males aged 29 to 36 and 6
Caucasian patients aged 24 to 63 with essential hypertension were studied. The patients were selected on the
basis of their maintaining a resting diastolic blood pressure of at least 100 mm Hg while hospitalized and consuming a diet containing approximately 10 mEq of sodium daily. Five of the 6 subjects were observed in this
manner for 13 to 47 days prior to study, while Patient 8
received the low salt diet for 8 days prior to study. No
patient had congestive heart failure, although no. 5 had
Present address:
Richmond, Va.
*
t USAF (MC).
Medical College of Virginia,
had a myocardial infarct 6 years earlier. All 6 had electrocardiographic evidence of left ventricular strain, but
were free of gross cardiomegaly on radiographic examination. Three patients had a history of mild hemiparesis 3 months to 10 years before study; Patients 5
and 8 made complete recovery while Patient 9 had mild
neurological residua. Ocular fundi varied from normal
to Grade 2 1 arteriolar narrowing without hemorrhage,
exudate or papilledema. Renal function (including endogenous creatinine clearance, phenolsulfonephthalein
(PSP) excretion, intravenous pyelogram and concentration test) was normal except in Patients 9 and 10
who had modest reduction in creatinine clearance.
Three of the 4 normal subjects and 5 hypertensive patients were provided a diet containing 10 to 15 mEq of
sodium daily (low salt diet). After equilibrium was
established (i.e., a minimum of 4 days of dieting and 2
consecutive days during which time the 24 hour urinary
sodium excretion did not exceed 15 mEq) the following
two studies were done within a period of 3 days.
1. "Blank Day." The subject had his usual breakfast
including 500 ml of water. At 8 a.m. he assumed the
recumbent position and remained so until 3 p.m. except
to void. From 10 a.m. to 2 p.m. each subject drank 100
ml of water hourly and ingested 5 g of carbohydrate
each half hour. Spontaneously voided urine was collected at one-half hour intervals. Venous blood was
collected at least twice (10 a.m. and 2 p.m.).
2. "Infusion Day." The protocol was essentially the
same as on Blank Day except that 2,000 ml of a solution containing 130 mEq per L of sodium, 105 mEq per
L of chloride and 25 mEq per L of lactate was administered intravenously from 10 to 11:30 a.m., and hourly
drinking commenced at 12 noon. Venous blood samples
were collected immediately prior to and at the end of
the infusion period and again at 2 p.m. An additional
normal subject (no. 4) and one hypertensive patient (no.
10) were studied as described for Infusion Day without
a prior Blank Day.
1 The grading system employed is that recommended
to the American Ophthalmological Society by the committee on Classification of Hypertensive Disease of the
Retina: Wagener, H. P., Clay, G. E., and Gipner, J. F.
Classification of retinal lesions in the presence of vascular hypertension. Trans. Amer. Ophthal. Soc. 1947,
45, 57.
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RESPONSES TO INFUSION OF ISOTONIC "BALANCED" SOLUTION IN HYPERTENSION
Three normal subjects and three hypertensive patients
similarly studied after equilibrium was established
while taking the same 10 mEq sodium diet with approximately 35 mEq of sodium chloride (non-enteric
coated tablets) added to each meal and again at bedtime for a total of 150 mEq sodium intake daily (medium
salt diet). On both Blank Day and Infusion Day each
subject ate his usual breakfast and 35 mEq of additional
salt in tablet form. At the end of the Blank Day experimental period, the subjects were given sufficient food
and sodium to maintain caloric intake and the 150 mEq
daily quantity of sodium.
Three normal subjects and three hypertensive patients
were similarly studied while they were taking approximately 300 mEq of sodium daily (high salt diet).
Blood pressure was determined at one-half hour intervals in the hypertensive patients during both experimental days at each dietary level, and less often in the
normal subj ects.
Serum and urine were analyzed for sodium, potassium,
chloride, creatinine and total solute content by methods
employed in this laboratory and previously described
(12). Serum protein, blood hemoglobin concentration
and hematocrit were also determined.
NORMOTENSIVE
879
HYPERTENSIVE
were
RESULTS
1. On Blank Day there was no significant difference between the normotensive and hypertensive subjects, taking the low sodium diet, in the
quantities of sodium and chloride excreted from
10 a.m. to 3 p.m. In five of six instances, while
provided with medium and high salt intakes, the
hypertensive patients excreted more sodium and
chloride than did the normal individuals from
10 a.m. to 3 p.m. (Tables I and II, Figure 1).
2. On Infusion Day the preinfusion rates of
sodium excretion were no higher in the hypertensive than in the normal group at each dietary
level of sodium ingestion. In fact, the hypertensive patients had slightly lower rates of sodium
excretion prior to infusion while taking the medium salt diet (Tables I and II, Figure 1).
3. In each instance at all levels of salt intake,
the hypertensive patient had a far greater natriuresis after intravenous salt loading than had the
normal. The maximal rates of sodium excretion
after salt loading occurred more promptly in the
hypertensive patient at the low level of salt intake
(Tables I and II, Figures 1 and 2).
4. By the morning after salt loading the hypertensive patients had excreted more sodium than
had the normal subjects at each dietary level.
This difference is attributed to the prompt re-
SODIUM
EXCRETION
mioEq
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WITH
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FIG. 1. SODIUM EXCRETION WITH AND WITHOUT INFUSION IN ONE NORMOTENSIVE( SUBJECT 3) AND ONE
HYPERTENSIVE( SUBJECT 6) WHILE PROVIDED WITH LOW,
MEDIUM ANDH IGH SALT DIETS. The ordinate scale for
the 150 mEq and 300 mEq sodium diets is double and
triple, respectively, the scale for the 10 mEq sodium diet.
sponse (10 a.m. to 3 p.m.) rather than to any
continued difference in sodium excretion throughout the remainder of the day (Table III).
5. Endogenous creatinine clearance generally
increased in both normal and hypertensive subjects when dietary salt was increased from low
to medium salt intake levels. The change in
clearance was less conspicuous between the medium and high salt intakes. It is also apparent
that the 8:30 to 10 a.m. endogenous creatinine
clearance often varied significantly in the two
studies carried out in a single individual on different days. The differences in natriuretic response
observed were not consistently or uniformly correlated with preinfusion differences in endogenous
creatinine clearance or with change in clearance
following infusion (Tables I and II).
6. In nine experiments in patients with hypertension, the infusion of sodium chloride-lactate
solution was not associated with a rise in blood
pressure. In the remaining two experiments a
rise in diastolic blood pressure of 10 to 12 mm Hg
was observed following infusion.
880
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PAPPER, BELSKY AND BLEIFER
882
NORMOTENSIVE
HYPERTENSIVE
ANo
EXCRETION
( peok-conrolm)
nictoEq /min
9. Serum concentration of sodium and chloride
did not change significantly (- 1 to + 3 mEq
per L) following the infusion of the sodium chloride-lactate solution. A small decrease in hematocrit (1 to 4 points) and total protein concentration (0.2 to 1.1 g per 100 ml) was observed
following infusion.
DISCUSSION
Ififusion
The present study confirms other observations
that patients with essential hypertension have a
greater natriuretic response to administered salt
solution than have normal individuals. In addition it establishes the fact that this difference in
sodium excretion is short-lived and is not due to
differences in dietary ingestion of salt prior to the
test. Indeed, the data demonstrate that the exaggerated natriuresis of the hypertensive individual is apparent at all levels of salt intake rangFIG. 2. THE DIFFERENCE IN THE RATE OF SODIUM EX- ing from 10 to 300 mEq daily. Furthermore,
the study suggests that the difference in natriuretic
CRETION BETWEEN THE 60 MINUTE PERIOD OF MAXIMUM
response is probably not due to an alteration in
NATRIURESIS AFTER 10 A.M. AND THE MEAN SODIUM EXCRETION BETWEEN 8:30 AND 10 A.M. (While on a high
diurnal rhythm. Thus, on Blank Days on the
salt diet, Subject 2 had a maximal natriuresis prior to low salt diet, the normal and the hypertensive
the infusion period.)
subjects excreted comparable quantities of sodium.
The present data do not provide final proof on
7. Potassium excretion varied considerably but this point since the change in sodium excretion
there was no consistent difference between the hy- (peak minus control) on Blank Days was greater
pertensive and normotensive subjects (Tables I in the patients with hypertension than in the
and II).
normal subjects. This difference seems to be
8. On Infusion Days urine flow and free water related primarily to a generally lower control
clearance (as well as osmolar clearance) were (8:30 to 10 a.m.) rate of sodium excretion in the
greater in the hypertensive patients than in the hypertensive subjects on Blank Days, compared
normal subjects.
with the normal individuals, rather than to a conTABLE III
sistently higher peak excretory rate for sodium.
Sodium excretion* during and after infusion
That this may have been fortuitous is perhaps
suggested by the fact that the preinfusion values
II
III(I +11)
I
10 a.m.-3 p.m. 3 p.m.-7 a.m. 10 a.m.-7 a.m.
on Infusion Days while taking the low salt diet
Normo- Hyper- Normo- Hyper- Normo- Hyperdo
not bear out this difference in control values.
tensive tensive tensive tensive tensive tensive
Clearly, more studies are required to resolve the
42 172
24
41
18 131
1. Low salt
role of diurnal rhythm with complete certainty.
94
74
22
72
48
26
diet
That the hypertensive subject excreted more so245
60
13 185
226
68
28 158
dium than did the normal individual on Blank
379
168
Days at medium and high dietary levels is probII. Mediumsalt 97 211
269 398
186 138
83 260
diet
due to the fact that added salt was taken on
ably
270 330
183 151
87 179
these days at breakfast time and in effect consti409 961
238 634
171 327
III. High salt
tuted a small but effective "salt load." In addi445 544
336 222
109 322
diet
387
265
122 367
tion, the present study makes it quite clear that
the exaggerated natriuretic response is not due to
* Total number of milliequivalents excreted in each time
a difference in baseline rates of sodium excretion
interval.
m
wirm
Infusin
SUBJECT NUMBER
RESPONSES TO INFUSION OF ISOTONIC "BALANCED" SOLUTION IN HYPERTENSION
prior to infusion. Finally, the infusate was such
that serum sodium concentration was not changed
significantly during any experiment, thus precluding the possibility that the exaggerated natriuresis may be related to a peculiarly distorted
response to hypertonic salt solutions in patients
with hypertension.
While the present study documents the existence of abnormal sodium excretion in hypertension under controlled conditions, the data do not
provide an understanding of the mechanisms involved. In these studies, as in others, in which
there is no consistent relationship between endogenous creatinine clearance (or inulin clearance) and sodium excretion, it is virtually impossible to establish or exclude the importance
of small but significant changes in glomerular
filtration rate in determining differences in sodium excretion. From the present studies it
would appear that the exaggerated natriuretic
response is not clearly attributable to increased
glomerular filtration rate either in the basal period or in response to salt administration. Consequently, it seems reasonable to focus attention
on the renal tubular handling of sodium in patients
with hypertension. The possibility exists that the
renal tubular cell itself is abnormal or that a
normal tubular cell is responding normally to abnormal influences or to stimuli that are abnormally
mediated. While a specific tubular "defect" cannot be excluded, there is little evidence in support
of this concept (7). Among the variety of known
and unknown extrarenal factors that might influence renal tubular handling of sodium in the
hypertensive patient are hormonal factors (e.g.,
adrenocortical and adrenomedullary), neurogenic
factors and intrarenal circulatory phenomena (8).
There is little direct evidence to support the causal
role of any of these at the present time. The
amount of sodium in the body, perhaps as expressed in terms of "effective" extracellular fluid
volume, seems to be an important determinant of
sodium excretion in the normal individual (8).
How the kidney is made aware of changes in this
factor is not at all clear. There are data which
suggest increased total body sodium as well as
increased extracellular fluid volume in patients
with essential hypertension, although other data
are not in accord with these findings (13-17).
Nonetheless, no causal relationship between al-
883
terations in extracellular volume or body sodium
content and the observed exaggerated natriuretic
response to administered sodium seems warranted
by the data at this time. The present study does
not clarify the relationship of the disturbances in
sodium excretion to other aspects of the condition
called "essential hypertension," including the elevation of blood pressure.
SUMMARY AND CONCLUSIONS
1. The natriuretic response to the infusion of
an isotonic solution of sodium chloride-lactate
was studied in four normal subjects and in six patients with essential hypertension, under conditions rigidly controlled in respect to the amount of
sodium ingested, posture, and time of day.
2. At each of three levels of daily sodium ingestion (10, 150 and 300 mEq) the patients with
hypertension had a far greater natriuretic response to administered sodium than had the normal individuals.
3. Without infusion, at the low salt dietary
level, there was no difference in the quantity of
sodium excreted between normal subjects and patients with hypertension, suggesting that variations in basic diurnal rhythm probably do not
account for the enhanced rate of sodium excre-
tion.
4. The exaggerated natriuresis is not attributable to differences in preinfusion rates of sodium
excretion or to greater increase in serum sodium
concentration. In addition, the difference in
natriuresis following infusion between the hypertensive and normotensive subjects is not associated with clearly consistent differences in endogenous creatinine clearance or further augmentation in blood pressure.
5. The "abnormal" response to salt administration in patients with essential hypertension remains unexplained.
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