Download Renal Response to Amino Acid Infusion in Essential Hypertension

1-225
Renal Response to Amino Acid Infusion
in Essential Hypertension
Luis Juncos, Juan Carlos Cornejo, Encaraacion Pamies-Andreu, Juan Carlos Romero
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Abstract In the present study, we evaluated the renal
response to a 4-hour infusion of amino acids in essential
hypertensive patients, as well as the effects that dietary sodium
restriction and enalapril (a converting enzyme inhibitor) had
on this renal response. During normal sodium intake, amino
acid infusion significantly increased renal plasma flow from
383±58 to 478±51 mL/min and glomerular filtration rate from
82±8 to 100±13 mL/min. All these effects were abolished
when the patients received a low sodium diet (40 mmol/d) for
3 days before the amino acid infusion. The administration of
enalapril to the patients during sodium restriction restored the
amino acid-induced increment in renal plasma flow (from
388±35 to 537±48 mL/min) and glomerular filtration rate
(from 88±9 to 103±10 mL/min). Mean arterial pressure
remained unaltered under all experimental conditions. The
results show that in patients with essential hypertension dietary sodium restriction prevents amino acid-induced increments in glomerular filtration rate and renal plasma flow and
that this effect is restored during the simultaneous administration of enalapril. (Hypertension. 1994;23 [suppl I]:I-225-I-230.)
I
amino acid infusion? (2) Is the response modified by
sodium dietary restriction? and (3) Would the latter be
changed by inhibition of the renin-angiotensin system?
These observations could have considerable clinical implications concerning the possible effects of a high-protein
diet in patients with essential hypertension.
t is well known1'2 that a high protein intake produces
a significant increase in both renal plasma flow
(RPF) and glomerular filtration rate (GFR). These
effects have been held responsible for accelerating glomerular damage, mainly in patients with preexisting renal
insufficiency.3 However, it is not known if similar deleterious effects are exerted by high-protein diets in patients
with essential hypertension. Intravenous administration of
an amino acid combination used in parenteral nutrition
therapy increases RPF and GFR4 in normotensive volunteers. In these normotensive individuals, dietary sodium
restriction inhibits the renal responses to amino acid
infusion; however, administration of a converting enzyme
inhibitor during sodium restriction restores the vasodilator
renal response.4
A similar renal response should not be assumed for
patients with essential hypertension. In these patients
the kidney endures higher sympathetic tone5 and higher
renal vascular reactivity.6 Likewise, angiotensin II (Ang
II) may contribute to the renal vasoconstriction of
hypertension.7 Hence, renal vasoconstriction is a frequent if not constant finding in essential hypertension.
We speculated that these pressor stimuli, seen in hypertensive but not in normotensive individuals, could restrict a protein-induced renal vasodilation. Furthermore, we felt the basis for such a notion could lie in the
activity of the renin-angiotensin system.
This study was designed to answer the following questions: (1) Is the kidney of patients with essential hypertension able to increase RPF and GFR in response to an
From Institute) Privado de Especialidades Medicas and National
University of Cordoba, Argentina (LJ., J.C.C., E.P.-A.), and the
Department of Physiology, Division of Hypertension, Mayo Clinic,
Rochester, Minn (J.C.R.).
This manuscript from the Mayo dink: was sent to Gerald F.
DiBona, Editor-in-Chief, for review by expert referees, for editorial decision, and for final disposition.
Reprint requests to J.C. Romero, MD, Department of Physiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Key Words • angiotensin converting enzyme inhibitors •
enalapril • diet, sodium-restricted • dietary proteins •
aldosterone • renin
Methods
Nine patients (seven women, two men; age range, 43 to 69
years) with essential hypertension were studied. All patients
had diastolic blood pressure measurements in excess of 90
mm Hg on at least three occasions and a history of hypertension for at least 12 months before the study. Secondary
hypertension was excluded by a clinical medical examination,
urinafysis, serum creatinine, creatinine clearance, serum electrolytes, plasma aldosterone (PA), and 24-hour urinary excretion of vanillylmandelic acid and catecholamines. Renal hypertension was excluded by rapid-sequence intravenous
pyelography in all patients. In some patients, radioisotopic
renogram or renal arteriography was performed to exclude
renal arterial disease. All antihypertensive medications were
discontinued for at least 3 weeks before the study. Patients
then began an isocaloric diet containing 150 mmol sodium,
0.50 g/kg body wt proteins, and free water intake. Urine urea
nitrogen was determined as Urinary Urea x 0.466. Nonprotein
nitrogen excretion was calculated as 29 mg nitrogen/kg per
day. Total nitrogen excretion was obtained from the sum of
urine urea nitrogen and nonprotein nitrogen. The protein
ingestion in grams per day was calculated as the product of
total nitrogen excretion and 6.25.
After giving written informed consent, the patients were
admitted to the hospital, weighed, and heart rate and blood
pressure measured. All patients fasted from 8 PM the night
before the experiment until completion of the study on the
following day. During this time water was allowed ad libitum.
All the procedures and written consents were approved by the
local Institutional Review Committee.
Experimental Protocol
At the beginning of each experiment, a urethral catheter
was placed for the collection of urine, and the patients reclined
in the supine position and remained in this position for the
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Supplement I Hypertension
Vol 23, No 1 January 1994
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duration of the experiment. The clearances of inulin (for
determination of GFR) and /wra-aminohippurate (PAH) for
calculation of RPF were measured during diuresis, which was
elicited by the oral ingestion of 20 mL water/kg body wt during
each clearance period. Priming boluses of inulin (50 mg/kg)
and PAH (8 mg/kg) were administered (both diluted in 5%
dextrose) over 5 minutes. This was followed by continuous
infusions of inulin (0.5 mg/kg per minute) and PAH (0.25
mg/kg per minute) at a total constant rate of 24.66 mL/h by an
infusion pump (Harvard Apparatus, South Natick, Mass).
After a 45 -minute equilibration period, the bladder was emptied, and two consecutive 30-minute control clearances were
obtained. Urine volume (UV) and sodium, PAH, and inulin
concentrations were measured during each clearance period.
Blood samples were obtained at the midpoint of each clearance period from the contralateral arm vein for measurement
of plasma inulin, PAH, sodium, potassium, renin activity
(PRA), and PA. The values for these two periods were
averaged. After the control clearances, a 10% amino acid
solution commonly used for parenteral nutrition was infused at
a rate of 0.70 mL/kg per hour. The amino acid composition of
this solution is shown in Table 1. Because the volume infused
each minute varied between 0.72 (patient 4) and 1.07 mL
(patient 1), no correction was made in the osmolality of the
solution. It was assumed that such small volumes diluted in the
much larger extracellular fluid volume did not change plasma
osmolality. The amino acid infusion was continued for 4 hours,
and urine and plasma variables were measured during the last
30 minutes of each hour.
TABLE 1. Composition of the 10% Amino Acid Solution
Amount, mg
L-lsoleudne
720
L-Leucine
940
L-Lyslne L-glutamate
720
L-Methlonine
400
L-Phenylalanine
440
L-Threonine
520
L-Tryptophan
160
L-Valine
800
L-Arginine
980
L-Hlstidine
300
L-Alanine
1280
L-Prollne
860
Serlne
420
Tyrosine
Glycine
Osmolality
44
1280
lOOOmOsm/L
NaiEDTA
Water for Injection
Baseline Studies
The control studies were conducted after the patients were
allowed 3 days of free sodium intake. Twenty-four-hour
urinary sodium excretion (UN,V) was measured the day before
the amino acid infusion.
Studies During Low Sodium Diet
Negative sodium balance verified by urinary sodium concentration was achieved by an oral dose of furosemide (80 mg)
followed by 3 days of a 40-mmol/d sodium and 60-mmol/d
potassium diet. Twenty-four-hour Un,V was measured on the
third day, and on the fourth day the amino acid infusion was
repeated.
Studies During Low Sodium Diet and Treatment
With Enalapril
After the completion of the study on the low sodium diet,
enalapril (10 mg) was administered orally beginning at 8 PM on
that same day and every night for the next 3 days. During this
period, the patients were kept on the low sodium diet (40
mmol/d). Another 24-hour UN,V was measured on the third
day of enalapril administration, and the infusion study was
repeated the following day.
Analysis
Urinary and plasma PAH and inulin were measured by a
photocokjrimetric method. Urinary and plasma sodium and
potassium concentrations were determined by flame photometry.
PRA was measured by radioimmunoassay using a commercial kit
(Gamma Coat Kit, Baxter Corp, Cambridge, Mass). PA was
measured by solid-phase radioimmunoassay (Coat-A-Count, Diagnostic Products Corp, Los Angeles, Calif).
Statistical Methods
Data are presented as mean±SEM. The significance of the
difference of the recorded values between groups was evaluated with a randomized block analysis of variance and the
Newman-Keuls multiple-range test.
Results
Effects of Amino Acid Infusion During Normal
Sodium Diet
During a normal sodium diet (24-hour UN>V the day
before the study averaged 126.3±11.1 mmol), the infusion
of amino acids induced a progressive increase in RPF that
was significant by the fourth hour (Table 2). These increments in flow from hour 1 to hour 4 averaged approximately 24% above control. Similarly, GFR progressively
increased and became significantly elevated above control
(22%) by the fourth hour of the amino acid infusion.
Fractional excretion of sodium (Fe Nt ), total UNiV, UV,
fractional excretion of potassium (FeK), PRA, and PA
remained unchanged (Table 2). During the infusion,
neither systolic nor diastolic blood pressure experienced
any change of importance. Plasma potassium did not
change and averaged from 4.1 to 4.4 mmol/L during the
experiment.
Amino Acid Infusion During Low Sodium Diet
The procedures adopted to induce a negative balance
of sodium (a single oral dose of 80 mg furosemide
followed by 3 days of 40 mmol sodium per day) were
effective in reducing the 24-hour UN.V to 27.4±1.8
mmol and the total UN,V to 124±16 junol/min (Table
3). GFR was significantly decreased by the low sodium
diet (from 82±8 to 71±8 mL/min). However, no significant changes were observed in RPF (from 383 ±58 to
361 ±45 mlVmin). These changes were accompanied by
an upward trend in PRA and PA that did not achieve
statistical significance. The low sodium diet produced a
significant decrease in basal values of diastolic and
systolic blood pressures. The remaining parameters
were not significantly affected.
Juncos et al Amino Acid Effects in Essential Hypertension
TABLE 2.
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Effects of Amlno Acid Infusion In Hypertensive Patients Receiving a Normal Sodium Diet
Measurement
Control
1 Hour
2 Hours
3 Hours
4 Hours
RPF, (mL/min)/1.73 m*
383±58
435±62
468±60
471 ±58
478±51*
GFR, (mL/min)/1.73 m2
82±8
UV, mUmln
5±0.9
92±11
95+11
102±13
100±13*
4.7±1
4.9±1.3
4.2±1
4.1 ±0.8
208±40
166±20
UN,V, /imol/min
197±32
183±28
170±31
Few.,%
1.8±0.3
1.6±0.3
1.5±0.3
1.7±0.4
1.4±0.3
22.5±1.9
20.9±2.2
18±2.4
21.1 ±7.9
20.7±8.3
2±0.6
1.6±0.5
1.7±0.6
1.4±0.3
1.2±0.2
24.9±7
23.7±6.4
23.6±7.1
19.7±6.1
20.4±5.9
SBP, mm Hg
172±6
167±6
164±5
162±5
161±5
DBP, mm Hg
104±3
104±1
204±1
104±1
103±1
F6K,%
PRA (ng Ang l/mL)/h
PA, ng/dL
, fractional
RPF Indicates renal plasma flow; QFR, gkxnerular filtration rate; UV, urine volume; U^V, urinary sodium excretion rate;
excretion of sodium; FeK, fractional excretion of potassium; PRA, plasma renln activity; Ang I, angiotensin I; PA plasma aldosterone;
SBP, systolic Wood pressure; and DBP, diastolic Wood pressure.
*P<.05 vs control period.
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During dietary sodium restriction, amino acid infusion failed to alter RPF, GFR, or PRA, which remained
fairly stable. In contrast, PA levels decreased to 45% of
the control value by the fourth hour of the infusion.
Amino acid infusion had no effect on UV, Fe Nl , or FeK.
No significant changes were observed in systolic or
diastolic blood pressures or in plasma potassium (4.2 to
4.4 mmol/L).
Effect of Amino Acid Infusions in Patients on Low
Sodium Diet Pretreated With Enalapril
Patients treated with enalapril for 3 days simultaneously with the low sodium intake exhibited an average
24-hour UN,V of 34.9±7.6 mmol, which is comparable
to that recorded during the low sodium diet without
enalapril. However, the administration of enalapril increased control values of GFR (88 ±9 mL/min, Table 4)
24% above the control value obtained in the same
patients during sodium-restricted diets without enalapril (71 ±8 mL/min, Table 3). However, these values
were not significantly higher than those recorded during
the control period of a normal sodium intake. Enalapril
did not alter basal values of RPF (388 ±35 versus
361 ±45 mL/min), UN.V, UV, FeNa, or FeK. Similarly,
enalapril produced a significant threefold increase in
the control values of PRA, whereas control PA was
decreased 50%. However, plasma potassium remained
unaltered from 4.4 to 4.1 mmol/L. Enalapril also decreased the control values of systolic blood pressure by
16% (153±4 versus 129±6 mm Hg) without altering the
control values of diastolic blood pressure.
During enalapril treatment, the suppressor effects of
a low sodium diet on amino acid-induced increments in
RPF and GFR were reversed. In fact, as shown in Table
4, RPF and GFR were significantly above the control
level, reaching values comparable to those seen during
amino acid infusion on a normal sodium diet. The mean
rise in RPF at 4 hours was 38.4%, well above the 17.0%
rise in GFR. This is reflected in a mean 3.5% fall in
filtration fraction.
Discussion
Changes in Renal Hemodynamics
This study included nine randomly selected patients
with essential hypertension who exhibited a wide dis-
persion in RPF and GFR values that ranged from
subnormal to normal levels. This finding most probably
reflects the variable renal damage inflicted by variable
periods of hypertensive disease. However, the relatively
low basal values of hemodynamic parameters also could
have been produced by dietary protein restriction imposed 3 days before the study. 810 We performed this
maneuver to standardize the renal response to amino
acid infusions. Within these experimental conditions,
our study demonstrated that amino acid infusions induced increases in RPF and GFR that were inhibited by
sodium restriction. The administration of enalapril during the sodium restriction restored the effects of amino
acid infusion on RPF and GFR.
These results, although analogous to those reported
in healthy individuals, were not expected. Patients with
essential hypertension have different basal renal hemodynamics, and they are under the influence of distinct
pressor effects. Thus, we expected to see resistance to
the vasodilator effects of amino acids. This was not so
and shows that patients with essential hypertension are
exposed to protein-induced hyperfiltration. The mechanisms responsible for these effects are difficult to
identify because the intimate mode of action underlying
the vasodilator effects of amino acids are poorly understood. Early hypotheses on the participation of pituitary
growth hormone,11 as well as liver hormones such as
glomerulopressin,12 were ruled out after amino acids
were shown to produce significant increases in renal
hemodynamics in patients with panhypopituitarism13
and in animals in whom the liver was functionally
excluded from the general circulation.14 Similarly, the
participation of glucagon315 was eliminated mainly because the infusion of this hormone failed to increase
renal hemodynamics.16
More recently, the renal response to amino acid
infusion has been regarded as a manifestation of endothelial modulatory function. Benigni et al17 have shown
that hyperfiltration induced by a high protein intake in
animals with experimental nephrosis was related to a
significant increase in 6-ketoprostaglandin F l o and suppressed by indomethacin, suggesting that prostacyclin
plays a role in the hyperfiltration response to amino acid
infusion. Ruilope et al4 reported that in normotensive
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Supplement I Hypertension
Vol 23, No 1 January 1994
TABLE 3. Effects of Amlno Acid Infusion In Hypertensive Patients on a Low Sodium Diet
Control
1 Hour
2 Hours
3 Hours
4 Hours
361 ±45
372±46
388±42
384±54
411 ±51
71 ±8
71 ±9
73±6
72±8
77±7
4±0.8
3.8±0.7
3.9±0.8
3.1 ±0.7
3.8±0.6
124±16
124±16
140±20
136±17
203±53
1.5±0.3
1.4±0.3
1.6±0.3
1.5±0.2
2±0.5
23.6±3.5
21.4±3.3
21.4±3.6
19.1 ±3.3
18.9±2.8
3.2±0.5
3.5±0.7
3.7±0.8
2.8±0.7
3.1 ±0.7
37.3±8.7
31.5±8.3
25.5±7.6
21.6±3.8
20.2±5*
SBP, mm Hg
153±4
151 ±5
151±5
151±5
151 ±5
DBP, mm Hg
88±4
87±4
86±4
85±4
85±4
(Measurement
RPF, (mL/min)/1.73 m
GFR,
2
(m\Jm\n)r\.73rtf
UV, mL/min
UNJV, fimol/min
FON.,%
FOK, %
PRA, (ng Ang l/mL)/h
PA, ng/dL
RPF Indicates renal plasma flow; GFR, glomerular filtration rate; UV, urine volume; UM.V, urinary sodium excretion rate; Few,, fractional
exaetion of sodium; Fox, fractional excretion of potassium; PRA, plasma renin activity; Ang I, angiotensin I; PA, plasma aldosterone;
SBP, systolic blood pressure; and DBP, dlastolic blood pressure.
*P<.05 vs control period.
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patients pretreated with indomethacin, the renal response to amino acid infusion was inhibited.
Endothelium-derived relaxing factor, namely, nitric
oxide (NO), which is known to be produced from the
nitrogen atom contained in the JV-guanidino group of
L-arginine,18 also has been implicated in the amino acid
response. In rats, amino acid-induced increments in
RPF or GFR are largely prevented by prior administration of an NO inhibitor, 7V°-monomethyl L-arginine.1921
This observation is in agreement with the study of
Premen and Dobbins,22 who have shown that amino
acid combinations of L- but not r>isomers elevated RPF
and GFR, and with Castellino et al,23 who demonstrated
that RPF and GFR were increased by a solution of
gluconeogenic amino acids containing L-arginine. NO
may have taken part in the renal hemodynamic response
to amino acids in our patients during a normal salt diet.
The suppressed response after sodium restriction could
have been caused by depressed NO activity. This notion
is supported by the work of Shultz and Tolins24 showing
that NO activity rises during a high salt intake, thus
suggesting a role of NO in renal adaptation to variations
in sodium intake. An alternative mechanism proposed
by Woods et al25 and DeNicola et al21 is that amino acids
induce an afferent arteriole vasodilatation through a
tubular glomerular feedback mechanism. However, our
results do not allow a distinction among these
possibilities.
The involvement of Ang II in the renal response to
amino acid infusion is strongly advocated by the suppressive effect of sodium dietary restriction and the
restoring action of enalapril. These results are comparable to those reported by Ruilope et al4 in normotensive patients. Moreover, Slomowitz et al26 observed that
captopril enhanced the renal response to amino acids in
normotensive diabetics. Although these patients were
on a normal sodium diet, the results were attributed to
the abnormally elevated Ang II levels in this disease.26
The specific mechanism through which changes in the
formation of Ang II could influence the responses to
amino acid remains unknown. Some investigators have
suggested that Ang II could alter the sensitivity of
tubular glomerular feedback responses.27 However, others have considered that the intrarenal changes in the
TABLE 4. Effects of Amlno Acid Infusion In Hypertensive Patients on a Low Sodium Diet and During the Inhibition of
Converting Enzyme
Measurement
RPF, (mL/mlnyi.TSm
2
GFR, (ml_/min)/1.73 m2
Control
1 Hour
2 Hours
3 Hours
4 Hours
388±35
450±38
467±44
518±53
537±48*
88±9
100±11
99±9
103±10
103±10*
4±0.7
UV, mL/min
3.8±0.8
4.1 ±0.7
3.8±0.7
UM,V, junol/min
144±24
148±20
1.1 ±0.2
157±29
1.2±0.2
168±25
15.2±2.5
15.2±2.5
12.3±2.1
FON.,%
1.3±0.3
154±20
1.2±0.2
FOK.%
18.3±2.2
16.2±1.8
3.3±0.4
1.3±0.2
9.9±3.3
8±3.4
7.5±3.4
6.6±2.9
6.2±3.5
PA, ng/dL
18.8±2.1
16.6±8.3
15.1 ±3.6
14.4±2.5
13.6±3.7
SBP, mm Hg
129±6
126±6
126±6
126±6
126±6
DBP, mm Hg
79±5
80±5
79±5
77±5
77±5
PRA, (ng Ang l/mL)/h
RPF indicates renal plasma flow; GFR, glomerular filtration rate; UV, urine volume; UMV, urinary sodium excretion rate; Fa*,, fractional
excretion of sodium; FBK, fractional excretion of potassium; PRA, plasma renin activity; Ang I, angiotensin I; PA, plasma aldosterone;
SBP, systolic blood pressure; and DBP, diastolic blood pressure.
*P<.05 vs control period.
Juncos et al Amino Acid Effects in Essential Hypertension
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formation of Ang II involve reciprocal alterations in the
synthesis of NO in a manner such that the inhibition of
Ang II formation28 or blockade of Ang II receptors29
favors the expression of the effects of NO stimulation.
Recently, DeNicola et al21 showed that pretreatment
with the Ang II receptor antagonist DuP 753 restores
the glomemlar and tubular response to glycine during
NO inhibition, suggesting that NO is a physiological
antagonist of Ang II. These findings support our results
after angiotensin converting enzyme inhibition. It could
therefore be assumed that much of the renal effect
produced by the amino acid-mediated stimulation of
NO was curtailed by the presence of Ang II.
The amino acid infusion during angiotensin converting enzyme inhibition caused a percent rise in RPF
twice as large as that of GFR. Thus, filtration fraction
decreased substantially (3.5%). This predominant effect
on RPF could only indicate a significant reduction in
efferent arteriolar resistance. In other words, blood flow
through an amino acid-dilated afferent arteriole encounters little resistance through the also dilated efferent arteriole. Other reported effects of angiotensin
converting enzyme inhibition on renal hemodynamics,
such as increased K, or afferent vasodilation, could not
explain the drop in filtration fraction during amino acid
infusion.
It should be mentioned that the average increments
in GFR and RPF during amino acid infusion with a
normal sodium diet are within the range reported by
other investigators in a normotensive population.8'26-30-31
Changes in Excretory Function, Plasma Renin
Activity, and Plasma Aldosterone
As reported by others,32 the amino acid infusions
induced a downward trend in PRA during a normal
sodium diet as well as during dietary sodium restriction
with the concomitant administration of a converting
enzyme inhibitor that could be attributed to a stimulation of endothelium-derived relaxing factor.3335 However, this issue deserves further investigation.
Similarly, the administration of amino acids produces
a consistent fall in PA values during a low sodium diet
that appears to be independent of fluctuations in PRA.
These decrements in PA also occurred in the absence of
any significant changes in plasma potassium concentration. The mechanism by which amino acids influence
aldosterone secretion is uncertain.
The observations of this study have important clinical
implications because they indicate that (1) in untreated
essential hypertensive patients, an increase in circulating amino acids is capable of exposing the glomeruli to
the same degree of hyperfiltration as that shown by
other investigators to accelerate glomemlar damage9-36;
(2) such a deleterious effect of amino acids on glomerular function is likely to be ameliorated by negative
sodium balance, a condition routinely obtained by sodium dietary restriction and/or the administration of
diuretics in patients with essential hypertension; and (3)
the protective effects of sodium restriction on glomerular hyperfiltration rate appear to be reversed by the
administration of enalapril. However, because of the
observed fall in filtration fraction, the clinical significance of these acute effects of amino acids should be
carefully evaluated to understand the more prolonged
1-229
beneficial effects that have been reported during longterm treatment with converting enzyme inhibitor.31
Acknowledgments
This study was supported by grant HL-16496 from the
National Institutes of Health and by grants from the Mayo
Foundation. We thank Sandra Baigorria for her excellent
technical assistance.
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Renal response to amino acid infusion in essential hypertension.
L Juncos, J C Cornejo, E Pamies-Andreu and J C Romero
Hypertension. 1994;23:I225
doi: 10.1161/01.HYP.23.1_Suppl.I225
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