Adrenal Medullary Secretion of Epinephrine and
Norepinephrine in Dogs Subjected to
Hemorrhagic Hypotension
By VINCENT V. GLAVIANO, PH.D., NOEL BASS/ B.S., AND
FLORIAN NYKIEL, M.S.
I
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ported that an increase in both epinephrine
and norephiuephrine levels occurred in the
adrenal vein blood of dogs subjected to short
periods of hemorrhagic hypotension. Manger
et al,10 and Watts and Bragg11 reported significant increases in leA'els of epinephrine in
peripheral blood of dogs in hemorrhagic shock.
With the assumption that these high peripheral blood levels of epinephrine reflected a
depression of normal enzymatic processes for
deactivating catechol amines, we decided to
investigate directly the adrenal medullary
secretion to IOAV blood pressure leA'els for A'arying periods of time. Answers to this problem
were sought by studying the following: (1)
the relationship existing between mean blood
pressure and adrenal bloodfloAv,(2) the relationship of the adrenal blood flow to the
gland's output of epinephrine and norepinephrine, and (3) the adrenal blood flow and
adrenal plasma content of epinephrine and
norepinephrine in dogs in hemorrhagic irreA'ersible shock. The report that follows Avill
describe experiments which haA'e made us conclude that regardless of the duration or level
of hemorrhagic hypotension induced, increased peripheral blood levels of catechol
amines, as reported by other laboratories, resulted in part from adrenal medullary stimulation.
T IS generally accepted that the adrenal
medullary hormones of a normal animal
do not play a role in the maintenance of blood
pressure.1' 2 On the other hand, the response
of the adrenal medulla to abnormally low
levels of blood pressure has been extensively
studied. In animals with vena cava pockets for
collecting adrenal vein blood or Avith denerA'ated hearts for indicating circulating epinephrine, the induction of hypotension was accompanied by an increase in the adrenal secretion of epinephrine.3"5 Saito,6 in a brilliant
series of experiments, demonstrated that the
secretion of epinephrine in the adrenal vein
blood of unanesthetized dogs subjected to
hemorrhage was in proportion to the decrease
in blood volume. PreA'iously, Tournade and
Chabrol" had described the elevated adrenal
secretion of epinephrine in hemorrhagic hypotension as an efferent component of a generalized sympathetic response. More specifically,
Heymans8 experimentally demonstrated that
a fall in blood pressure causes baroreceptors
located in the wall of the carotid sinus to initiate nervous reflexes that lead to the secretion of epinephrine by the adrenals and peripheral vasoconstriction.
Eecently, improved biologic and chemical
methods for the analysis of catechol amines
have once again focused interest on the response of the adrenal medulla to hypotension.
Lund,0 with his own fluorometric technic, re-
Methods
Fifteen randomly selected male mongrel dogs
were employed for this study. The animals Averc
anesthetized Avith the intravenous administration
of 10 ml./Kg. of 1 per cent chloralose solution.
From a midline nock incision, a, tracheotomy Avas
performed and the right common carotid artery
was cannulated for recording mean blood pressure.
Blood pressure Avas continuously recorded from a
Statham pressure transducer connected to a Brush
ink Avritinar recorder. The loft femoral arterv and
From the Department of Physiology, University
of Illinois College of Medicine, Chicago, 111.
Results of this work were presented to the Federation of American Societies for Experimental Biology
at Philadelphia, Pa. on April 17th, 1958. A preliminary report appeared in Federation Proceedings 17:
55, 1958.
Received for publication January 4, 1960.
564
Circulation Research, Volume VIII, May 1960
ADRENAL MEDULLARY SECRETION IN HYPOTENSION
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vein were cannulated for bleeding and for reinfusion of blood, respectively. The abdomen was incised in midline to permit exposure of the left
adrenal vein and its branches. After a polyethelene
tube of maximal size was introduced into the
adrenal vein and tied with its opening several millimeters from the gland, the vein was ligated at the
point where it enters the inferior vena ^va. All
branches noted to enter the adrenal vein from the
lumbar wall of the animal were tied off. Blood from
the left adrenal was diverted to a cannulated left
external jugular vein (fig. 1). The adrenal-jugular
circuit established was interrupted by a 3-way
stopcock, permitting the collection and timing of
the adrenal blood flow. Timing and collection of
adrenal venous samples were accomplished with a
stopwatch and a long, graduated glass cylinder
of 10 ml. capacity, immersed in an ice bath. Serial
measurements of blood flow by this method yielded
an average error of less than 1 per cent. Heparin,
in an initial dose of 5 mg./Kg. by vein, was employed as the anticoagulant. In the course of the
experiment, one-half of the initial dose of heparin
was administered every 45 minutes.
The collected samples of adrenal blood were immediately centrifuged in a refrigerated centrifuge,
and the plasma separated and frozen for biologic
assay at a later date. A differential assay method
was employed for determining the concentration
of plasma epinephrine and norepinephrine. The
epinephrine content was determined from its action
on the rectal caecum of a hen.12 The caecum was
suspended in a 20 ml. chamber containing Tyrode's
solution, maintained at a constant temperature of
38 C, and aerated with a fine stream of air. Norepinephrine content was determined from its pressor effect on the blood pressure of a eat anesthetized with 35 mg./Kg. of sodium pentobarbital.13
For the purpose of reducing reflex vasodilation
and bradyeardia to the plasma samples, the anesthetized cat was treated with 1 mg./Kg. of atropine
sulfate and 3 mg./Kg. of hexamethonium by vein.
Furthermore, it was found advantageous to lower
blood pressure with hexamethonium to a level of
approximately 60 mm. Hg, since this provided a
much wider and more sensitive blood pressure
range for assaying the pressor amines. It was observed that the administration of hexamethonium
as a ganglionic blocking drug did not alter the
value of "q" (activity ratio of epinephrine to norepinephrine). In more than 150 determinations of
the "q" value in 15 cats, the ratio ranged from 0.1
to 0.4, and averaged 0.3. In both bioassay preparations, unknown samples were preceded and followed by aqueous standard solutions of epinephrine
(Adrenaline Chloride, Parke, Davis & Co., free of
norepinephrine and containing 1 mg. of synthetic
epinephrine per ml.), and norepinephrine (LevoCirculation Research, Volume VIII, May I960
565
Figure 1
Scheme of circulation established for the timing
and collection of venous Mood from the left adrenal
gland.
phed, Winthrop Laboratories, 1 mg. of norepinephrine base per ml.) in concentrations approximately expected to occur in the unknowns. The
reliability of the combined assay method was tested
by the administration of mixtures containing epinephrine and norepinephrine in inactivated dog
plasma. The mean recovery of epinephrine (0.1 to
10.0 /xg.) was 90 per cent (S.E. ± 0.16); for norepinephrine (0.1 to 5.0 /xg.) the recovery was 80
per cent (S.E. ± 0.20).
Essentially 3 groups of experiments were performed to study the response of the adrenal medulla to hemorrhagic hypotension. The level of
hypotension in all dogs was maintained by withdrawing or reinfusing small volumes of the animal's blood. The first group consisted of 4 dogs
(group 1), in which hypotension was maintained
for a period of 15 minutes. The level of hypotension was varied for each member of this group.
The second group, consisting of 4 dogs (group 2),
was made hypotensive for either 45 or 90 minutes.
The level of blood pressure for this group was
maintained at a level of about 70 mm. Hg. Blood
pressure was purposely maintained at this level,
because the object of this group of experiments
was to study a moderate degree of hypotension
without the development of an irreversible state
of hemorrhagic shock. A third group, made up of
3 dogs (group 3), was studied with the specific
purpose of quantitating the secretion of adrenal
epinephrine and norepinephrine during the course
of inducing irreversible hemorrhagic shock. The
principle of inducing shock was essentially that
of Wiggers.14 Sufficient blood was withdrawn by
arterial bleeding to decrease blood pressure to a
level of approximately 50 mm. Hg. The animals
were maintained at this pressure level for a period
of 45 minutes, after which blood pressure was further reduced to 40 mm. Hg and kept at this level
GLAVIANO, BASS, NYKIEL
566
Table 1
Summary of Data on Adrenal Medulla's Response to Hemorrhagic Hypotension
Control
1
Blood samples
Group 1
Dog 1
wt. 23.0 K g .
Dog 2
wt. 19.0 K g .
Dog 3
wt. 14.5 K g .
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Dog 4
wt. 20.0 K g .
Group 2
Dog 5
wt. 20.5 Kg.
Dog G
wt. 20.0 Kg.
Dog 7
wt. 24.5 Kg.
Dog 8
wt. 19.0 K g .
Group 3
Dog 9
wt. 19.0 Kg.
Dog 10
wt. 1S.1 K g .
MBP*
ABF
PE
PN
MBP
ABF
PE
PN
MBP
ABF
PE
PN
MBP
Dog 11
wt. 18.0 K g .
(400)f
(250)f
0.5
ABF
PE
PX
MBP
ABF
PE
PX
MBP
ABF
PE
PX
MBP
ABF
PE
PX
MBP
ABF
PE
PN
150
(5.5
0.3
0.0
110
5.3
0.1
0.3
150
9.2
0.1
0.1
140
5.0
0.2
0.1
MBP
ABF
PE
PN
MBP
ABF
125
2.6
2.0
0.0
90
3.1
1.3
0.0
160
22
MBP
ABF
PE
PN
Hypotensive period
3
4
(300)t
175
3.5
0.5
0.0
130
1.0
0.0
0.0
160
1.1
0.7
140
2.1
0.2
0.5
PE
PX
Bleeding
response
2
o!i
0.0
(390)t
(425)f
9.0
0.3
0.0
1.4
1.3
0.5
1.4
11.7
0.0
4.4
0.7
0.2
(345)t
(450)t
(425)f
(470)f
2.0
3.2
0.0
1.8
12.0
0.0
2.1
0.5
0.1
(350)f
(370)t
Postinfusion period
.120
* 2.8
0.9
0.2
80
0.6
0.5
0.8
70
0.6
2.1
0.4
45
1.0
9.3
0.0
170
3.1
0.4
0.0
125
1.6
0.0
0.0
140
2.2
0.7
0.2
130
2.4
1.1
0.3.
90
3.5
0.9
0.0
GO
2.1
1.3
0.1
50
1.1
13.0
0.0
90
3.2
5.9
0.0
12.0
0.0
80
2.S
6.4
0.0
160
6.4
0.6
0.0
90
5.3
0.2
0.7
125
9.3
0.3
0.3
1.32
3.4
0.9
0.4
155
—
—
—
90
—
—
—
130
—
—
—
132
4.6
0.8
0.6
40
0.3
23.6
3.2
40
0.9
12.8
1.2
42
0.2
4.0
3.0
120
1.9
3.9
0.6
90
1.6
9.4
0.0
125
1.8
0.6
0.1
64
0.6
1.0
2.6
30
0.8
12.2
0.0
75
1.0
2.6
1.0
50
0.3
9.5
0.0
50
1.4
12.0
2.4
5S
0.4
2.2
0.0
60
2.2
0.8
0.5
60
1.0
30
—
—
—
20
—
—
—
34
0.1
5.2
0.0
* M B P = A v . mean blood pressure (mm. H g ) during collection of adrenal blood sample;
A B F = L e f t adrenal blood flow in ml. per min.; PE=Epinepliriiie in micrograms per ml. of
plasma; P N = N o r e p i n e p h i i n e in micrograms per ml. of plasma.
flnitiul volume of blood (ml.) removed to produce level of hypotension present during
collection of blood sample no. 3.
for an additional 45-minute period. The hypotensive period in this group of dogs was then followed
by the complete reinfusioii of the bled volume. The
animals were observed up to the time their blood
pressure decreased to 30 mm. Hg. In addition to
the decline of blood pressure in the postinfusion
period, heart rate, rectal temperature, respiratory
rate, and hcmatocrits were measured as additional
criteria for establishing irreversible shock. Heniatocrits were determined by centrifuging an aliquot
of the adrenal vein blood in a Wintrobe tube for
30 minutes at 1,500 X g.
The procedure adopted for collecting all adrenal
blood samples was to time and collect 10 ml. of
Circulation Research, Volume VIII, Mail
ADRENAL MEDULLARY SECRETION IN HYPOTENSION
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blood during the continuous recording of blood
pressure. Immediately after the control sample
(no. 1) was collected, the adrenal secretion to a
rapid hemorrhagic (50 ml./min.) was measured
(sample no. 2), for dogs in groups 2 and 3. In
these 2 groups, the duration of hypotension varied
from 45 to 90 minutes, during which time sample
nos. 3 and 4 were taken respectively. At the end
of the predetermined period of hypotension for
each dog, blood, previously withdrawn from the
animal and maintained at 37 C, was gently stirred
and reinfused at a rate of 40 ml./min. Ten minutes following the completion of the reinfusion,
adrenal blood flow and its content of catechol
amines were measured (sample no. 5). All samples
were then collected at the end of 1 hour after reinfusion (sample no. 6), except in the case of 1
dog, where 2 hours elapsed (sample no. 7).
Results and Discussion
Data collected in 11 of 15 experiments have
been summarized in table 1. Because of errors
committed in the assay procedure, or because
of kinks or clots found in the adrenal vein
cannula at the end of an experiment, data on
4 experiments have been omitted. The control
mean blood pressure (MBP) average for 11
successful experiments was 139 mm.Hg. For
the same period, the blood flow of the left
adrenal gland (ABF) ranged from 1.0 to 9.2
ml./min., an average flow of 3.8 ml./min. The
resting secretion (control) of adrenal plasma
epinephrine ( A P E ) averaged 0.6 /xg./ml.
Adrenal plasma norepinephrine (APNE),
which was detected in only 5 of 11 dogs,
averaged to 0.1 ftg./ml.
The state of hemorrhagic hypotension in all
dogs, regardless of duration or level of hypotension, was accompanied by an adrenal secretion of epinephrine many times the level found
in the control period. On the other hand, the
presence of APNE was found to be variable
and unpredictable. In group 1 dogs, a 15
minute period of hypotension produced more
than a 5-fold increase in the average control
level of A P E . APNE was found in 3 of the 4
dogs (1, 2, 3), with only dog 2 having an
increase above the resting secretion. Lund 9
reported that the adrenal vein blood of dogs
subjected to short periods (approximately 10
minutes) of hemorrhagic hypotension contained APNE in concentrations equal to about
one-half of the epinephrine level. In none of
Circulation Research, Volume VIII, May I960
140
567
Hemorrhoge (5OccAnin.)
it
Reinfusion (425cc)
--—
Epinephrine
Norepinephrine
Time (min.)
Figure 2
Average mean blood pressure, adrenal blood flow,
and adrenal plasma epinephrine and norepinephrine in a dog subjected to a moderate degree of
hemorrhagic hypotension.
our experiments were we able to generally apply this observation. However, we cannot omit
the possibility that norepinephrine could
have been present in our samples at a concentration below the sensitivity (0.1 to 0.2 /ug.)
detectable by the cat assay method. Furthermore, Gaddum15 has recently pointed out the
impossibility of detecting, by the cat assay,
norepinephrine in concentrations of less than
5 per cent in mixtures containing large quantities of epinephrine. Our findings on APNE
during periods of hypotension are in agreement with those of Manger and co-workers.10
Their data indicate that blood norepinephrine
levels do not correlate consistently with the
level or duration of hemorrhagic hypotension
in clogs. This agreement can only be considered
valid if Ave accept peripheral blood levels as
a quantitative measure of the adrenal's output
of catechol amines.
Figure 2 represents the typical changes in
mean blood pressure, adrenal blood flow, APE,
and APNE of a dog with a moderate degree
GLAVIANO, BASS, NYKTEL
568
Hemorrhoge (50cc/min.)
Reinfusion (37Occ)
Av. mean B. P.
Sh. dog II
Wt. 18 kg. (f
Epinephrine
Norepinephrine
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0
60
120
Time(min.)
Figure 3
Average mean blood pressure, adrenal blood flow,
and adrenal plasma epinephrine and norepinephrine during the course of inducing irreversible
liemorrhagic shock.
of hypotension for an approximate period of
90 minutes. These same parameters were altered to a similar extent in the remaining 3
dogs (5, 6, 7) of group 2. It can be noted from
figure 2, that the response of the adrenal
medulla to a relatively short period of rapid
arterial bleeding caused more than a 3-fold
increase in APE, while the rate of adrenal
blood flow during the same period decreased
by only 12 per cent. For that matter, the secretion of APE, in response to a rapid hemorrhage for dogs in both groups 2 and 3, was
elevated with concurrent small reductions in
adrenal blood flow. The average increase in
APE was 3.7 ng./m\., which represents a 6fold increase above the resting secretion, while
adrenal blood flow decreased by only 35 per
cent. The small reduction in adrenal blood
flow accompaning a rapid hemorrhage indicates that a large quantity of APE could enter
the peripheral circulation in a short period of
time. The magnitude of this immediate response by the adrenal medulla could not have
been ascertained from the analysis of epineph-
rine in peripheral blood. Aside from a dilution factor, peripheral levels of epinephrine
cannot serve as an absolute measure of the
adrenal's production of this hormone, since
peripheral concentrations will represent a
level resulting from its rate of production and
inactivation.
Adrenal blood samples (nos. 3 and 4), taken
during the period of hypotension in figure 2,
had APE levels that averaged more than 30
times the concentration present in the control
sample. These peak concentrations of APE
can be regarded as illustrating the classical
relationship existing between the level of mean
blood pressure and its influence on the adrenal
medulla through nervous reflexes.8 On the
other hand, the adrenal output of epinephrine
in hemorrhage cannot solely be considered on
the basis of reflexes from baroreceptors. The
state of hypokinetic anoxia in our hypotensive
animals must have surely initiated reflexes
from the carotid and aortic chemoreceptors,
as well as from higher centers of the central
nervous system.16 Further study of our experimental findings reveals that the adrenal blood
flow to a major extent is determined hy the
level of mean blood pressure, a relationship
which has been found not always in strict
proportion. For example, in figure 2, the decrease in adrenal blood flow that occurred
during the collection of sample no. 3 was 36
per cent, while the decrease in mean blood
pressure was also 36 per cent. The dependency
of the former on the latter can be further
emphasized Avhen it is considered that the
average decrease for mean blood pressure during the collection of sample no. 3 in all dogs
was 50 per cent, while the average decrease
for adrenal bloodflowwas 61 per cent. Despite
this decrease in adrenal blood flow, the rate
of APE secretion from the adrenal for this
period was 5.5 jug./ml./min., as compared with
a control rate of 1.52.
The reinfusion of blood in the experiment
of figure 2, illustrates that, with the return of
mean blood pressure to near control levels,
the APE secretion remained more than 4
times above the control level. The average
Circulation Research, Volume VIII, May I960
ADEENAL MEDULLARY SECRETION IN HYPOTENSION
569
Table 2
Additional Parameters Measured for Establishing Irreversible Hemorrhagic Shock in
Dog 11
Blood samples
Mean blood pressure (nun. Hg.)
Heart rate
Hematocrit (per cent)
Eespiratory rate (per min.)
Rectal temperature (°C)
l
2
3
4
5
6
7
ieo
140
180
58
198
42
186
125
138
75
186
34
15G
186
45.8
45.0
40.0
39.6
51.0
52.4
52.5
24
26
30
28
24
38
32
38.5
38.5
38.5
38.0
37.5
36.0
36.0
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adrenal blood flow for all dogs during tlie
collection of the postinfusion sample (no. 5)
averaged 3.5 ml./inin. (control was 3.8), while
the APE averaged 1.6 /xg./ml.; more than 2 ^
times the control concentration. With the
restoration of mean blood pressure in the postinfusion period, we considered it doubtful
that the adrenal's secretion of epinephrine is
being governed by reflex mechanisms involving blood pressure regulation, or that it resulted from a gradual deterioration of our
experimental animal, since the resting secretion of catechol amines in anesthetized dogs
with adrenal vein cannulation was found not
to vary significantly in periods of time including our longest experiment.17 The return of
blood pressure to near control levels, and the
maintenance of a high secretory rate by the
adrenals, represents, most likely, in addition
to other factors, a direct form of stimulation
by a humoral substance. If this be the case,
stimulation by humoral agents must have required a period of hypotension of more than
15 minutes, since in 3 of 4 dogs in group 1
(sample no. 5), epinephrine content did not
increase above control levels. A humoral substance which could act directly on the adrenal
medulla of our dogs is potassium,38 an ion
which has been generally reported to increase
in the blood of shocked dogs.14 Another possible explanation for the origin of these
humoral substances might well be the metabolic by-products of an accelerated adrenal
metabolism. While the low adrenal blood flow
in hypotension can be expected to cause a
local state of adrenal hypoxia, there is no
evidence that such a mechanism will elevate
adrenal production of catechol amines.
Circulation Research,
Volume VIII, May 1960
Figure 3 is representative of our group 3
experiments, where the level of hypotension
was of a sufficient duration to induce a state
of irreversible shock. In addition to the characteristic decline of mean blood pressure in
the postinfusion period, changes in heart rate,
respiration, hematocrit, and body temperature, as given in table 2, are in agreement
with accepted criteria for establishing irreversible hemorrhagic shock.14 With little variation in heart rate and respiratory rate, dogs
JIOS. 9 and 10 demonstrated essentially the
same changes for these parameters. The
adrenal responses observed during the period
of marked hypotension in this group of experiments were found to be similar to those observed for dogs in group 2. Despite the marked
decrease in adrenal blood flow during hypotension, the output of APE remained significantly above the resting secretion (table
1). Our data on adrenal catechol amines
secreted in hemorrhagic shock have several interesting interpretations. One of these observations is concerned with the adrenals remaining functional to the point where the animal
is within minutes away from complete cardiorespiratory collapse. This observation implies
that the neurogenic control of blood pressure,
of which the adrenals are an integral component, will remain functional in the terminal
state of shock. We can also conclude from
these experiments, as well as from the results
of experiments alreadjr described, that the
high levels of epinephrine in peripheral blood
do not result, at least to a large degree, from
a depression of physiologic processes for deactivation. On the contrary, the adrenals consistently demonstrated an amazing capacity
GLAVIANO, BASS, NYKIEL
570
to continuously secrete pressor hormones under the severe stress of progressing circulatory
failure. The maintenance of a high secretory
rate of adrenal epinephrine in animals in
reversible and irreversible hemorrhagic shock
has led us to consider the possibility that
epinephrine is entering tissues in significant
concentrations. It follows that epiuephrine
may be responsible for causing some of the
metabolic and hemodynamic alterations of the
animal in shock. We are at present actively
pursuing this line of investigation.
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Summary
The response of the adrenal medulla in
anesthetized dogs to hemorrhagic hypotension of a varied level and duration was observed to be primarily accompanied by a
highly significant increase in adrenal plasma
epinephrine. On the other hand, the secretion
of norepinephrine had an unpredictable occurrence in adrenal blood samples collected
in periods of hypotension. The essential determinant of adrenal blood flow was observed
to be the level of mean blood pressure. While
this relationship was not in strict proportion,
changes in mean blood pressure were invariably followed by changes in adrenal blood flow
in the same direction. The adrenal medulla
of dogs in hemorrhagic irreversible shock was
observed to continue to secrete epinephrine at
very low levels of mean blood pressure, characteristic of terminal shock. Keports by other
groups of investigators on elevated peripheral
blood levels of epinephrine in hemorrhagic
shock have been found to result mainly from
an actively secreting adrenal medulla.
Summario in Interlingua
In anosthesiate canes, le responsa del medulla adrenal a hypotension hemorrhagic de varie intensitates
o durationes so monstrava aceompaniate primarimente
de mi significativissime augmento do epinephrina in
la plasma adrenal. Del altere latere, le secretion de
norepinophrina occurreva in non-predicibile forrnas in
specimens de sanguine adrenal colligite durante periodos de hypotension. Esseva constatate quo le determinante essential del fluxo de sanguine adrenal esseva
le nivello del tension medie del sanguine. Durante
que isto relation non se exprimeva in un proportion
strictomente uniforme, alterationos del tension medie
del sanguine esseva sequite invariabilemente sequite
de alterationcs isodirectional in le fluxo del sanguine
adrenal. Essova trovate quo lc medulla adrenal de
canes in non-reversibile ehoe hemorrhagic continuava
socerner epinephrina a bassissime nivellos medio del
tension de sanguine, i.e. a nivellos characteristic de
choc terminal. Le elevate nivellos de epinephrina
roportate per altere gruppos de investigatores coino
characteristic;! del sanguine pcripheric in choc post
heniorrhagia result a, seeundo lc presente investigationes, principalmonte del secretion active del medulla
adrenal.
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3. BEDFORD, E. A., AND JACKSON, H. C.: Epineph-
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Effets
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Adrenal Medullary Secretion of Epinephrine and Norepinephrine in Dogs Subjected to
Hemorrhagic Hypotension
VINCENT V. GLAVIANO, NOEL BASS and FLORIAN NYKIEL
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Circ Res. 1960;8:564-571
doi: 10.1161/01.RES.8.3.564
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