Interaction of the Sympathetic Nervous System
with Vasopressin and Renin in the
Maintenance of Blood Pressure
HARALAMBOS GAVRAS, M.D.,
PETER HATZINIKOLAOU, M.D.,
WILLIAM G. N O R T H , P H . D . ,
MARGARET BRESNAHAN, D . S C , A N D IRENE GAVRAS,
M.D.
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
SUMMARY To evaluate the partial contributions and interaction of three vasopressor systems in blood
pressure maintenance, nephrectomized rats and rats with intact kidneys were submitted sequentially to
catecholamine depletion, elimination of vasopressin's vasoconstrictor action, and (for those with kidneys in
situ) angiotensin blockade. Catecholamine depletion decreased blood pressure and stimulated vasopressin
levels in all rats, but significantly more so in the anephric ones. Subsequent injection of an antagonist to the
vasopressor effect of vasopressin produced a lasting fall of blood pressure in anephric rats, but only transient
fall in those with intact kidneys. Infusion of teprotide — an angiotensin converting enzyme inhibitor — in the
latter animals also produced transient blood pressure fall, but if this were followed by injection of the vasopressin antagonist, the pressure remained low for several hours. Blood pressure levels were closely correlated
with those of plasma catecholamines throughout these maneuvers. Catecholamine levels were inversely correlated with those of plasma vasopressin, which were far greater in anephric rats through both stimulation and
accumulation. Plasma renin activity was increasingly stimulated by falling blood pressure after each maneuver
in rats with intact kidneys. Thus, it appears that in the resting state the sympathetic nervous system is more involved in the maintenance of blood pressure, whereas vasopressin and renin are important backup mechanisms.
(Hypertension 4: 400-405, 1982)
KEY WORDS
•
catecholamines
renin-angiotensin system
• arginine vasopressin <
1
sympathetic nervous system
blood pressure regulation
M
measurement of plasma catecholamines and plasma
vasopressin, further enhancing research in these vasopressor hormones. Interest in the cardiovascular
effects of vasopressin was revived recently1 and was
particularly stimulated by the development of
chemical analogs that selectively antagonize the vasoconstrictor effects of the hormone without affecting its
renal tubular actions.2-3
The present experiments were designed to evaluate
the contribution of each one of these three vasopressor systems to the maintenance of normal blood
pressure. Catecholamine depletion and bilateral
nephrectomy were intended to produce conditions
comparable — albeit extreme — to those likely to be
encountered in the therapy of human hypertension,
e.g., treatment with sympatholytic agents and advanced renal failure. Under these conditions, we
studied the interaction and relationships of catecholamines, vasopressin, and the renin-angiotensin system.
A I N T E N A N C E of blood pressure at a certain level is the end result of interplay between various vasoactive hormones. In
hypertension research over the past few years, greatest
emphasis has been placed on the renin-angiotensin
system, probably because assays for measurement of
its components and specific inhibitors for several of
these components became widely available. More
recently, methodology was developed for accurate
From the Thorndike Memorial Laboratories, Boston City
Hospital, and Department of Medicine, Boston University School
of Medicine, Boston, Massachusetts, and the Department of
Physiology, Dartmouth Medical School, Hanover, New
Hampshire.
Supported in part by USPHS Grant HL-18318.
Address for reprints: Dr. Haralambos Gavras, 80 East Concord
Street, Boston, Massachusetts 02118.
Received August 11, 1981; revision accepted October 15, 1981.
400
VASOPRESSOR SYSTEMS IN BLOOD PRESSURE MAINTENANCE/Gawos et al.
Methods
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
Fifty-two male Wistar rats (Charles River Breeding Laboratories) weighing 275-320 g were housed in
a temperature- and humidity-controlled environment
with automatic lighting in 12-hour cycles; they were
maintained on Purina rat chow and tap water ad
libitum. Of the 52 rats, 23 underwent uninephrectomy
under ether anesthesia 1 week prior to the experiment. On the day of the experiment, they were again
anesthetized with ether and had the remaining kidney
removed. Subsequently, a PE-50 catheter was inserted
in the right external iliac artery and a PE-10 catheter
in the right femoral vein. Both catheters contained a
heparinized dextrose 5% solution. Upon awakening,
the animals were maintained in a semirestrained position on a light mesh screen for 60-90 minutes until
their blood pressure gradually rose to a steady
baseline.
Twenty-nine animals with intact kidneys were also
catheterized in the same manner under light ether
anesthesia and then maintained in the semirestrained
position. In all animals, arterial pressure was continuously monitored with a Statham transducer and
recorded on a Hewlett Packard recorder (model
7702B). Mean blood pressure and heart rate were recorded directly during the experiment on this recorder.
"Chemical sympathectomy" was induced by intraperitoneal injection of reserpine (Serpasil, CIBA) at a
dose of 0.1 mg/100 g body weight. Four hours later, a
first dose of metyrosine 2.5 mg/100 g (Merck, Sharp
and Dohme) was given intraperitoneally. The animals
were maintained overnight with an intravenous (i.v.)
infusion of 5% dextrose administered by a Harvard
pump at a rate of 0.006 ml/min for a total of approximately 5 ml. Thirteen hours later a second dose of
metyrosine 2.5 mg/100 g was injected intraperitoneally. Suspension of metyrosine for injection was
prepared from 25 mg metyrosine in 1.2 ml of 0.5M
sodium phosphate buffer with pH of 7.4 and 0.8 ml of
5% methyl cellulose (Fisher Scientific Company).
The peptide [l-(/8-mercapto-/3, ^-cyclopentamethylene propionic acid, 2-(0-methyl) tyrosine] arginine vasopressin, which is an analog and competitive
antagonist of arginine vasopressin (AVP) at the
vascular receptor level2-' was used as an inhibitor of
the vasoconstrictor effects of AVP. A 2 mg amount of
this compound was dissolved in a solution made from
10 ml 0.9% NaCl, 10 mg bovine serum albumin, 3 jtl
acetic acid, brought to a pH of 6.4 with NaOH. A
dose of 0.15 ml of this solution containing 30 fig of the
AVP antagonist was administered i.v.
The angiotensin converting enzyme inhibitor
teprotide (SQ2O.881, Squibb) was used as inhibitor of
the renin-angiotensin system. A dose of 0.2 mg/100 g
was dissolved in 0.9% NaCl and infused intravenously
by a Harvard pump over a 90-minute period at a rate
of 0.018 ml/min for a total of 1.6 ml.
The animals were divided in seven groups: Group 1
(n = 8) included nephrectomized animals submitted to
chemical sympathectomy. Three hours after the sec-
401
ond dose of metyrosine they received injection of the
AVP antagonist and 1 hour later they had 0.4 ml of
blood drawn for measurement of plasma catecholamine levels.
Group 2 (n = 7) consisted of nephrectomized and
chemically sympathectomized animals. Three hours
after the second metyrosine injection they had two
samples of blood (2 and 0.4 ml) drawn for determination of plasma AVP and plasma catecholamine levels
respectively.
Group 3 (n = 7) consisted of nephrectomized
animals with sympathetic system intact. They were
catheterized and maintained overnight with a dextrose 5% infusion and at approximately 20 hours after
the nephrectomy they had blood samples drawn as
above for determination of plasma catecholamines
and AVP to be used as controls in the anephric state.
Group 4 (n = 7) consisted of rats with intact
kidneys, submitted to chemical sympathectomy.
Three hours after the second metyrosine dose they
received an injection of the AVP antagonist. One hour
later two blood samples (0.4 and 1 ml) were drawn for
determination of plasma catecholamines and plasma
renin activity (PRA) respectively.
Group 5 (n = 7) consisted of rats with intact
kidneys submitted to chemical sympathectomy. Three
hours after the second dose of metyrosine the teprotide infusion was started. One half hour later, when
blood pressure had reached approximately pre-teprotide levels, the AVP antagonist was injected i.v. At 1
hour later, a 0.4 ml blood sample was drawn for catecholamine determination.
Group 6 (n = 9) consisted of rats with intact
kidneys submitted to chemical sympathectomy. Three
hours after the second metyrosine injection they had
three samples (0.4, 1, and 2 ml) of blood drawn for
determination of plasma catecholamines, PRA, and
AVP.
Group 7 (n = 6) consisted of intact rats catheterized and maintained overnight in the semirestrained
position with an i.v. dextrose infusion. Twenty hours
later they had three blood samples (0.4, 1, and 2 ml)
drawn for determination of plasma catecholamines,
PRA, and AVP respectively, to be used as controls for
comparison with the manipulated groups.
Plasma AVP levels4-5 were determined by radioimmunoassay. The minimum detectable level of AVP
is 0.2 pg/ml with this method, the range of measurement is from 0.2 to 8 pg/ml, and a 50% displacement
of iodinated AVP is regularly produced by 2 pg of the
peptide. Reserpine and metyrosine in solutions of 0.1
mg/100 ml and 2.5 mg/100 ml saline, respectively,
were found not to affect the standard displacement
curve.
PRA levels were also determined by radioimmunoassay,6 and plasma catecholamines were measured by
radioenzymatic assay.7 Results are reported as means
± SEM. Statistical evaluation was made with Student's
t test for paired or nonpaired comparisons as appropriate. Correlations were calculated by the Spearman rank correlation method. Results were considered to be significant if p < 0.05.
402
HYPERTENSION
Results
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
Changes in blood pressure during the various
manipulations in anephric rats and rats with intact
kidneys are illustrated in figure 1. Reserpine alone
produced a small but significant fall in pressure in all
animals, and metyrosine caused a further drop in
pressure. At 20 hours after the beginning of the experiment, injection of the AVP antagonist produced an
abrupt major fall in blood pressure of both nephrectomized animals (Panel A) and those with intact
kidneys (Panel B), indicating that AVP contributed to
a major extent to the maintenance of blood pressure in
these chemically sympathectomized animals. However, rats with intact kidneys showed a rapid gradual
increase in pressure toward levels similar to those
preceding the injection of AVP antagonist, whereas
blood pressure of anephric rats remained depressed
for the next 4 hours of observation. In rats with intact
kidneys who at 3 hours after the second metyrosine injection received infusion of the converting enzyme inhibitor teprotide (Panel C), blood pressure decreased
abruptly, but transiently, despite continuing teprotide
infusion. When blood pressure in these animals again
reached the pre-teprotide levels, injection of AVP antagonist caused the blood pressure to fall further and
stay at that level for the remaining period of observation (at least 1 hour and as long as 4 hours).
Blood pressures and hormone levels for each group
of animals are shown in table 1. Groups 3 and 7 are
VOL 4, No 3, MAY-JUNE
1982
nonmanipulated animals used to provide baseline hormone values for anephric and intact animals respectively. It is apparent that levels of AVP and epinephrine were significantly higher (p < 0.001 andp < 0.05
respectively) in anephric animals, whereas norepinephrine also tended to be higher but not significantly
so. After reserpine and metyrosine injections, catecholamines were markedly depleted in all groups so
treated: both norepinephrine and epinephrine were
significantly lower (p < 0.01 and p < 0.001 respectively) from control values in the anephric animals and
in the animals with intact kidneys (p < 0.001 for
both), compared with the control values of each
group. Although norepinephrine tended to be somewhat higher in the chemically sympathectomized
anephric rats (Groups 1 and 2) than their counterparts with kidneys in situ (Groups 4, 5, and 6), the
differences were not significant.
Chemical sympathectomy produced variable but in
all cases concomitant degrees of depletion of plasma
levels of both norepinephrine and epinephrine. The
levels of the two catecholamines were always closely
correlated. In anephric rats (Groups 1, 2 and 3) the
correlation coefficient between them was r = 0.818,
p < 0.001; in rats with intact kidneys it was r = 0.928,
p < 0.001.
Plasma levels of AVP were already higher in
anephric controls than in normal rats (p < 0.001).
They were greatly stimulated after catecholamine depletion in both the anephric rats and the ones with ina Intact
& Anephric
o Sympathectomized
• Anephric Sympathex
B
r=0.725
p<0.001
• Anephric
oIntact
p-<O.O1 " < 0 . 0 O 1
from baseline
Plasma Norepinephrine pg/ml
p#<0.01 ##<0.0O1
from sympathectomy
o
o
t
.
t
.(
Reserpnne Metyrosine
0 1 2 3 4
"17
SQ2O881
Infusion
19
Time in Hours
FIGURE 1. Time sequence and blood pressure effects of
catecholamine depletion, injection of the vasopressin antagonist, and infusion of the angiotensin converting enzyme
inhibitor in anephric rats and rats with intact kidneys.
r=0.810
p<0.001
200
300
400
600
600
Plasma Epinephrine pg/ml
FIGURE 2. Correlation between blood pressure levels and
plasma levels of norepinephrine and epinephrine in anephric
rats and rats with kidneys in situ, with intact sympathetic
system, or catecholamine-depleted.
VASOPRESSOR SYSTEMS IN BLOOD PRESSURE MAINTENANCE/Gavray et al.
403
TABLE 1. Blood Pressure and Hormone Levels in Seven Groups of Rats
Blood pressures (mm Hg)
Baseline
Reserpine
Metyrosine
109 ± 1.5
98 ± 1.7
85 ± 5.2
107 ± 2.5
93 ± 4.3
80 ± 4.3
Group
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
1 (n = 8)
anephric
2 (n = 7)
anephric
3 (n = 7)
anephric
4 (n = 7)
kidneys
in situ
5 (n = 7)
kidneys
in situ
6 (n = 9)
kidneys
in situ
7 (n = 6)
kidneys
in situ
Teprotide
Hormone levels (pg/ml)
PRA
(ng/ml/hr)
AVP
antag
AVP
97 ± 2.1
71 ± 1.6
110 ±1.4
92 ±1.6
74 ±4.0
114 ± 2.3
98 ± 3.2
74 ± 3.6
a) 56 ± 3.0
b) 66 ± 2.5
Dopa
129±22
73±20
<50
467±90
151 ±39
94±35
<50
10.7 ± 1.1
528 ± 83 600 ± 110 76 ± 19
a) 63 ± 4.0
b) 73 ± 4.0
35 ± 6.7
52 ± 3.3
111 ±3.1
tact kidneys (p < 0.001 from their respective controls). Furthermore, the anephric rats with chemical
sympathectomy (Group 2) had significantly higher
AVP levels (p < 0.01) than their counterparts with intact kidneys (Group 6). Thus, the anephric state and
depletion of catecholamines independently led to increase in plasma AVP levels and their combined effect
caused excessive stimulation and accumulation of
AVP. Dopamine levels were below the method's sensitivity in most of the catecholamine depleted animals.
1OOO
Epi
44 ± 2.2
115 ± 1.8
110 ± 2.4
Norepi
•
E
76 ±14
<50
111 ±18
94 ± 14
<50
2.5 ±0.4
2.2 ±0.5
438 ±32 375 ±56
67 ± 9
A Intact
A Anephric
O Sympathectomized
« Anephric Sympathex
•
r=-0.748
p<0.001
o
o
•
87 ±16
100 ±52
° o
100
< 50
There was a highly significant correlation between
blood pressure levels and those of norepinephrine (r =
0.925, p < 0.001) and epinephrine (r = 0.810, p <
0.001) when data from animals of the four groups who
received no AVP antagonist or teprotide were pooled
together (Groups 2, 3, 6, and 7), as shown in figure 2.
There was also a significant inverse correlation between levels of AVP and those of norepinephrine (r =
-0.724, p < 0.001) and epinephrine (r = -0.748, p <
0.001) in the same four groups, as shown in figure 3.
r-0.724
p<0.001
_
75 ± 7
17.9 ±2.1
•
.•
" «
500
96 ± 9
•
•
o
0
50 --O
-O
o
o
a.
<
o
o o
o
a
10
a.
A
o
a
O
A
>
10
A
A
*
A
A
5a
A
a
1
I
1
A
1
IA
i
100 200 300 400 500 600 800
Plasma Norepinephrine pg/ml
1
1
A
IA
I
1
1
100 200 300 400 5OO 600 700 800
Plasma Epinephrine pg/ml
FIGURE 3. Correlation between plasma levels of vasopressin and plasma levels of norepinephrine and epinephrine in anephric rats and rats with kidneys in situ, with intact sympathetic system, or catecholaminedepleted.
HYPERTENSION
404
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
When all the anephric animals and all those with
kidneys in situ were analyzed as two separate groups,
the correlations between blood pressure and plasma
catecholamines and vasopressin remained the same.
In anephric rats, the blood pressure was highly correlated with norepinephrine (r = 0.932,/? < 0.001) and
epinephrine (r = 0.904, p < 0.001). In those with intact kidneys blood pressure was also highly correlated
with norepinephrine (r = 0.822, p < 0.001) and epinephrine (r = 0.818, /? < 0.001). Blood pressure was
also significantly correlated with AVP levels in the
two groups of anephric rats (Groups 2 and 3; r =
0.715, p < 0.001) as well as those with intact kidneys
(Groups 6 and 7; r = 0.776, p < 0.001). The plasma
AVP levels were also inversely correlated with the
plasma levels of norepinephrine and epinephrine (r =
0.653, p < 0.001 and r = -0.679, p < 0.01 respectively) in the anephric rats of Groups 3 and 4; in rats
with intact kidneys (Groups 6 and 7) these correlations were even closer (r = —0.825, p < 0.001 and r =
-0.795, p < 0.001 respectively).
Plasma renin activity was measured in all rats with
intact kidneys except for those of Group 5 who
received teprotide. It was significantly higher than
normal in those who had chemical sympathectomy
only and even more in those who received in addition
the AVP antagonist (p < 0.001 for both). In fact,
there was a significant negative correlation between
blood pressure levels obtained after removal of the
sympathetic system and vasopressin sequentially and
corresponding PRA levels (r = -0.667, p < 0.02), indicating an attempt of the renin system to maintain
normal blood pressure, which was decreasing after
each maneuver.
Discussion
These experiments attempt to define the participation and interrelation of three vasopressor systems:
the sympathetic nervous system, renin-angiotensin
system, and arginine vasopressin (AVP) in blood
pressure maintenance. We chose two rat models, one
anephric, because in previous experiments we found
that the plasma levels and pressor effects of catecholamines and AVP seemed to be very pronounced in
nephrectomized animals,8 and one with intact kidneys
for comparison. Indeed, our present data indicate that
levels of AVP were significantly higher in the anephric
rats than in those with kidneys in situ (Groups 2 and 3
vs Groups 6 and 7 in table 1), which is compatible with
knowledge of the kidney's participation in the
clearance of AVP. 9 Catecholamines also tended to be
higher in anephric rats than in their counterparts with
intact kidneys, but only the levels of epinephrine were
significantly higher in the anephric model with intact
sympathetic system.
Treatment with combination of reserpine and
metyrosine was chosen as an effective and rapid way
to eliminate catecholamines. The former interferes
with uptake and storage of catecholamines by
adrenergic neurons, thus inducing catecholamine depletion which is maximal by 24 hours after ad-
VOL 4, No 3, MAY-JUNE
1982
ministration. The latter inhibits tyrosine hydroxylase,
the enzyme catalyzing the conversion of tyrosine to
dihydroxyphenyl alanine (DOPA), which is the first
step in catecholamine biosynthesis. Effectiveness of
this treatment was shown by significant depletion of
all catecholamines in all groups so treated.
This "chemical sympathectomy" was accompanied
by gradual fall of blood pressure and corresponding
levels of catecholamines in all groups, as shown by
figure 2, indicating the degree of contribution of the
sympathetic system to maintenance of blood pressure
levels. Depletion of catecholamines was associated
with a marked stimulation of AVP levels in an effort
to maintain blood pressure. There was a significant inverse correlation between AVP levels and those of epinephrine and norepinephrine (figure 3), indicating that
the more pronounced the depletion of catecholamines, the more the release of AVP was stimulated.
This could partly be attributed to hypotension per se
acting as a stimulus for secretion of AVP 10 and partly
to removal of the attenuating or inhibitory influence of
catecholamines on the secretion of AVP. 8 ' n~13 In the
anephric model, the participation of AVP in maintaining blood pressure after chemical sympathectomy
was far more important, as shown by both the excessively high plasma AVP levels and the magnitude of
blood pressure fall (average 40 mm Hg) after injection of the AVP antagonist (fig. 1 A and table 1,
Group 1). Moreover, blood pressure remained at that
low level for several hours. Remarkably, these animals tolerated pressures ranging between 35-55 mm
Hg very well, since they appeared to be alert and in no
distress during the period of observation.
On the contrary, rats with intact kidneys seemed to
have at least two more backup mechanisms to maintain blood pressure after catecholamine depletion.
Both PRA and AVP release were significantly stimulated by this maneuver (as shown in Group 6 of table
1). The AVP antagonist produced a blood pressure fall
of only 15 mm Hg, on the average, which within
minutes started increasing again toward preinjection
levels. The high PRA levels at that point suggest that
stimulation of the renin-angiotensin system tended to
offset the hypotensive action of the AVP analog in
these animals (as shown in fig. 1 B and table 1, Group
4). When the catecholamine-depleted model with intact kidneys was submitted to infusion of teprotide,
which eliminated the formation of angiotensin II,
blood pressure again fell temporarily, but soon
returned to preinfusion levels despite continuing infusion of teprotide (fig. 1 C and table 1, Group 5). At
that point, additional administration of AVP antagonist had a marked depressor effect which remained unchanged for up to 4 hours of observation, indicating
that the blood-pressure-maintaining reserves were
now neutralized.
Arginine vasopressin does not seem to play an important role in blood pressure maintenance under normal conditions, unless the subject has suffered
dehydration or hemorrhage which has compromised
effective arterial pressure and volume and increased
plasma osmolality."' " The renin-angiotensin system
VASOPRESSOR SYSTEMS IN BLOOD PRESSURE MAINTENANCE/Gav/us et al.
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
also does not contribute to the blood pressure maintenance unless sodium deprivation, diuretics, tilting,
etc., manipulations act to decrease blood pressure,16"18
in which case a compensatory renin release tends to
restore pressure to normal.
Recently, Andrews and Brenner," using the anesthetized dehydrated rat model, showed that both
angiotensin II and vasopressin assume an important
role in the homeostasis of blood pressure that has been
compromised, but not in the normal state. Our present
experiments also indicate that these two mechanisms
become important when another vasopressor mechanism, the sympathetic system, has been interfered
with. Particularly in the renoprival state, stimulated
vasopressin accumulates to excessive levels and
assumes a major role in the maintenance of blood
pressure.
In conclusion, our findings indicate that in the resting state the sympathetic system is more involved in
the maintenance of normal blood pressure, whereas
vasopressin and the renin-angiotensin system are important backup mechanisms. During sequential interference with, or elimination of, each one of these
systems, the remaining mechanisms are stimulated to
take over the task of preserving the homeostasis of
blood pressure.
These findings produced in an experimental model
with nephrectomy or chemical sympathectomy could
be relevant to the management of clinical hypertension. It is possible that treatment with sympatholytic agents, especially in subjects with various
degrees of renal insufficiency and variable capacity to
stimulate renin secretion, could produce conditions
similar to those observed in the present experiments.
It is well known that the antihypertensive effect of
diuretics may be limited by reactive hyperreninemia.18> 1S It is reasonable to speculate that volume
depletion by diuretics and sympathetic blockade by
various antihypertensive agents may lead to compensatory stimulation of vasopressin as well, thus offsetting the blood-pressure-lowering effect of these agents.
This would be particularly relevant to subjects with
renal insufficiency in whom a sodium and fluid load is
more likely to induce elevation in blood pressure
through AVP release80 and whose AVP clearance may
be impaired so that the hormone's levels can become
excessive. Therefore, AVP antagonists may have an
antihypertensive potential not only in the rare cases of
mineralocorticoid-induced hypertension21 but also as
an adjunct treatment in refractory hypertension of
chronic renal failure treated by sympatholytic agents.
References
1. Editorial: Progress in essential hypertension. Lancet 1: 1066,
1979
405
2. Manning M, LowbridgeJ, StierCT, Haldar J, Sawyer WH: (1Deaminopenicillamine, 4-valine)-8-D-arginine-vasopressin, a
highly potent inhibitor of the vasopressor response to argininevasopressin. J Med Chem 20: 1228, 1977
3. Kruszynski M, Lammek B, Manning M, Seto J, Haldar J,
Sawyer WH: (l-(/S-Mercapto-j9, /S-cyclopentamethylenepropionic acid), 2-(O-methyl tryosine) arginine-vasopressin and
(l-(i8-mercapto-|8, /3-cyclopentamethylenepropionic acid)) arginine-vasopressin, two highly potent antagonists of the vasopressor response to arginine-vasopressin. J Med Chem 23: 364,
1980
4. North WG, LaRochelle FT, Haldar J, Sawyer WH, Valtin H:
Characterization of an antiserum used in a radioimmunoassay
for arginine-vasopressin: implications for reference standards.
Endocrinology 103: 1976, 1978
5. LaRochelle FT Jr. North WG, Stern P: A new extraction of
arginine-vasopressin from blood: the use of octadecasilylsilica.
Pflugers Archiv 387: 79, 1980
6. Sealey JE, Gerten-Banes J, Laragh JH: The renin system:
variations in man measured by radioimmunoassay or bioassay.
Kidney Int 1: 240, 1972
7. Peuler JD, Johnson GA: Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and
dopamine. Life Sci 21: 625, 1977
8. Hatzinikolaou P, Gavras H, Brunner HR, Gavras I: Role of
vasopressin, catecholamines, and plasma volume in hypertonic
saline-induced hypertension. Am J Physiol 240: H827, 1981
9. Walter R, Simmons WH: Metabolism of neurohypophyseal
hormones: considerations from a molecular viewpoint. In
Neurohypophysis, edited by Moses AM, Share L. Basel: S
Karger, 1977, pp 167
10. Cowley AW Jr, Switzer SJ, Guinn MM: Evidence and quantification of the vasopressin arterial pressure control system in
the dog. Circ Res 46: 58, 1980
11. Fisher DA: Norepinephrine inhibition of vasopressin antidiuresis. J Clin Invest 47: 540, 1968
12. Bed T, Cadnapaphornchai P, Harbottle JA, Schrier RW:
Mechanism of stimulation of vasopressin release during beta
adrenergic stimulation with isoproterenol. J Clin Invest 53:857,
1974
13. Montani JP, Liard JF, Schoun J, Mohring J: Hemodynamic
effects of exogenous and endogenous vasopressin at low plasma
concentrations in conscious dogs. Circ Res 47: 346, 1980
14. Andrews CE Jr, Brenner BM: Relative contributions of
arginine vasopressin and angiotensin II to maintenance of
systemic arterial pressure in the anesthetized water-deprived
rat. Circ Res 48: 254, 1981
15. Aisenbrey GA, Handelman WA, Arnold P, Manning M,
Schrier RW: Vascular effects of arginine vasopressin during
fluid deprivation in the rat. J Clin Invest 67: 961, 1981
16. Haber E, Sancho T, Burton GT, Barger AC: The role of the
renin-angiotensin-aldosterone system in cardiovascular homeostasis in normal man. Clin Sci Mol Med 48 (suppl 2): 49, 1975
17. Posternak L,. Brunner HR, Gavras H, Brunner D: Angiotensin
II blockade in normal man. Interaction of renin and sodium in
maintaining blood pressure. Kidney Int 11: 197, 1977
18. Gavras H, Waeber B, Kershaw GR, Liang CS, Textor S,
Brunner HR, Gavras I: Role of reactive hyperreninemia in the
blood pressure changes induced by sodium depletion in patients
with refractory hypertension. Hypertension 3: 441, 1981
19. Vaughan ED Jr, Carey RM, Peach MJ, Ackerly JA, Ayers CA:
The renin response to diuretic therapy. Circ Res 42: 376, 1978
20. Hatzinikolaou P, Gavras H, Brunner HR, Gavras I: Sodiuminduced elevation of blood pressure in the anephric state.
Science 209: 935, 1980
21. Crofton JT, Share L, Shade RE, Lee-Kwon WJ, Manning M,
Sawyer WH: The importance of vasopressin in the development and maintenance of DOC-salt hypertension in the rat.
Hypertension 1: 31, 1979
Interaction of the sympathetic nervous system with vasopressin and renin in the
maintenance of blood pressure.
H Gavras, P Hatzinikolaou, W G North, M Bresnahan and I Gavras
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
Hypertension. 1982;4:400-405
doi: 10.1161/01.HYP.4.3.400
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1982 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/4/3/400
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/