Reprinted from Tur JouRNAL oF Ciinicar Investication, Vol. XX XI, No. 3, pp. 273-279, March, 1952
Printed in U.S. A.

THE EFFECTS OF LEPINEPHRINE AND -NOR-EPINEPHRINE
UPON CEREBRAL CIRCULATION AND METABOLISM
IN MAN?

By BENTON D. KING, LOUIS SOKOLOIT, anp RICHARD L. WECHSLER

(From the Departments of Anesthesia, Hospital of the University of Pennsylvania, Physiology
and Pharmacology, Graduate School of Medicine, the Harrison Department of Surgical
Research, University of Pennsylvania, Philadelphia, and the Aviation Medical

Acceleration Laboratory, Jolinsville, Pa.)

(Submitted for publication September 24, 1951; accepted December 27, 1951)

Studies comparing the effects of epinephrine and
nor-epinephrine, the two sympathomimetic amines
which occur naturally in the mammalian body,
show that these two closely related substances dif
fer in many of their pharmacodynamic proper-
ties. The metabolic rate in man has been shown
to increase after epinephrine (1, 2), whereas there
is no significant change produced by nor-epineph-
rine (2). Systemic administration of epinephrine
to man has been shown to result in a decrease in
total peripheral resistance (1, 3), indicating that
vasodilatation has occurred in many portions of
the body; in contrast, nor-epinephrine appears to
be predominantly vasoconstrictor in its action,
for total peripheral resistance is increased (3).
These differences may be manifestations of the
specific functions which these substances perform
in the body; von Euler (4) believes that nor-epi-
nephrine is the sympathetic mediator for general
purposes, while epinephrine acts as an adjuvant
for more special functions, especially in regard to
metabolic actions.

In view of the importance of epinephrine and
nor-epinephrine in physiological processes, their
occurrence in pheochromocytomas, their use as
therapeutic agents, and the possible relation of
nor-epinephrine to essential hypertension (3),
information regarding their effect on cerebral blood
flow and cerebral metabolism is desirable. A pre-
liminary report by Sensenbach, Madison, and
Ochs (5) indicates that nor-epinephrine is a
The animal
studies upon epinephrine have yielded conflicting
results (6-8). Qualitative measurements of cere-
bral blood flow in man by means of a thermoelectric

powerful cerebral vasoconstrictor.

t This project was supported (in part) by grants from
the National Heart Institute, United States Public Health
Service,

flow recorder led Gibbs, Gibbs, and Lenox (9) to
report an increase in cerebral blood flow following
the intravenous injection of adrenalin, probably
secondary to the increase in blood pressure.

The present study was undertaken to provide
quantitative measurements of cerebral blood flow,
vascular resistance and oxygen consumption in
man during the intravenous infusion of synthetic
J-epinephrine or /-nor-epinephrine.

METHODS

Subjects varied in age from 19 to 50 years. They were
either volunteers or hospital patients with apparently
normal cardiovascular systems. Two subjects (T. I.
and T. C.) who received epinephrine served also as sub-
jects for the nor-epinephrine study at a later date.
Cerebral blood flow (CBF) was determined by the ni-
trous oxide method (10). Blood pressure and pulse rate
were obtained by means of a Lilly capacitance electro-
manometer (11, 12) attached to the needle in the femoral
artery, and recorded continuously by means of a Brush
direct-inking oscillograph except when arterial blood sam-
ples were being drawn. Mean arterial blood pressure
(MABP) was obtained by either a damped mercury
manometer or by electrical integration of the pressure
pulse curves from the Lilly manometer. Cerebral meta-
bolic rate in terms of cerebral oxygen consumption
(CMRo:) and cerebrovascular resistance (CVR) were
calculated as previously described (10). Blood gas
analyses were made by the manometric technique of Van
Slyke and Neill (13). Measurements of blood pH were
made anaerobically at room temperature by means of a
glass clectrode and a Cambridge potentiometer and cor-
rected to 37° C. by the factors of Rosenthal (14). Val-
ues for blood carbon dioxide tension were calculated by
means of the nomograms of Pcters and Van Slyke (13).
Total hemoglobin concentration of arterial blood was de-
termined by a modification of the method of Evelyn and
Malloy (15).

Before the control measurements, an intravenous in-
fusion of physiological saline was begun. Subsequently
the infusion was changed to one containing either synthetic

273
274

BENTON PD.

l-epinephrine or [-nor-epinephrine,? 4 or 8 micrograms of
drug per ce. of saline. The rate of drug infusion was ad-
justed until the desired pressor response was acquired
and maintained or until undesired side effects occurred.
When a steady state had been attained, a second set of
blood flow determinations was made. The total quantity
of drug and the rate at which it was administercd are indi-
cated for each subject in Table I.

RESULTS

The data are presented in Tables 1, IT, and TI.
Values for systolic and diastolic blood pressure and
pulse rate were obtained for each blood flow de-
termination by averaging measurements secured
at five intervals on the continuous record. A
maximum and minimum of blood pressure were se-
lected at each of these intervals to take into ac-

21-Epinephrine as “Suprarenin” and /-nor-epinephrine
as “Levophen” or “Levophed” were provided through the
g
courtesy of Winthrop-Stearns.

KING, LOUIS SOROLOFF, AND RICHARD L. WECTISLER

count the effects of the respiratory cycle on blood
pressure.

Effects of nor-epinephrine

Subjective sensations, except for a feeling that
the heart was beating more forcefully, were notably
absent during the infusions of nor-epinephrine.
The skin and mucous membranes became pale.
The pressor effect was more marked than with
epinephrine and was produced with a much lower
dose. Slowing of the pulse rate accompanied the
rise in blood pressure in every case.

The hemoglobin concentration of arterial blood
was increased significantly ; this might he a result
of fluid dislocation from the vascular bed or of
emptying of red cell reservoirs. Arterial carbon
dioxide tension was decreased, probably as a re-
sult of hyperventilation although this was not evi-

dent by inspection. These alterations im carbon

TABLE I

Effects of l-nor-epinephrine and l-epincphrine on blood pressure and pulse rate

 

 

 

Dose Syst. & Diast.
Subject Age Sex Total Rate Blood Pressure Pulse Rate
ug. gg./min. C+ Et Cc E
1-nor-epinephrine
(1) HA. 39 M 770 22 128/82 160/81 90 99
(2) E.H. 50 F 312 10 141/77 185/84 112 79
(3) A.H. 48 F 454 16 138/89 185/85 88 66
(4) L.W. 38 F 576 16 142/81 184/86 80 53
(5) M.S. 36 M 760 25 126/73 165/77 65 52
(6) T.C. 24 M 500 17 106/68 134/81 84 63
(7) T.1. 24 M 840 28 110/72 150/89 65 51
(8) L. HLT. 19 M 200 6 116/61 173/89 65 52
(9) N.Y. 22 M 300 9 125/78 172/97 74 61
Mean 33.3 524.7 16.6 126/75 168/85 80.3 52.6
Stand.error 13.8 5.2 13.0
p* <0. 001
L-epinephrine
(10) A.M. 34 F 1732 73 135/81 145/79 100 116
(11) T.1. 24M 800 47 112/73 159/91 81 91
(12) T.C. 24 M 664 33 112/65 175/84 75 72
(18) J. ¥. 25 M 976 34 109/79 134/76 71 83
(14) L.H. 25 M §00 30 103/65 126/74 04 78
(15) A. Mc. 22 M 4890 19 117/67 132/63 70 72
(16) D. F. i9 M 480 a2 131/72 173/75 97 115
Mean 24.7 847.4 36.9 117/72 149/77 78.3 89.6
Stand.error 11.7 46.4 t7.1
p* <0. 02

* Determined from the t value obtained by dividing the mean of the

ston

individual changes by i's

 

dard error.
+ Control pericd ~ Saline infusion.

+ Experimental period - Drug infusion.
l-Nor-Epinephrine

1-Epinephrine

TABLE Ii

Effect of l-nor-epinephrine and I-cpinephrine on blood constituents

 

 

 

UNIda

INTYH dé

Ks

HNUMLLGSINTGa-YON ONV

 

Subject Hemoglobin O2 Content CO2 Content CO2 Tension
Concentration vol. & vol. & Blood pH mm. Hg
Gms. % Arterial Int. Jugular Arterial Int. Jugular Arterial Int. Jugular Arterial Int, Jugular
C+ Et c E c E c E c E c E c E c E c E

(1) HLA. 15.17 15.51 19.75 i925 12.08 10.79 49.79 44.22 56.75 52.66 7.41 7.42 7.37 7.37 42 38 52 48
EH. 10.48 10.39 13.89 13.80 8.47 8.91 53.08 51.04 56.97 56.02 7.43 7.42 7.38 7.37 40 40 48 48
(3) AH. 10.07 10,07 13.47 13.72 7,00 97.37 51.17 48.60 56.91 55.17 1.42 7.43 7.36 7.36 40 37 49 48
(4) LW. 10.72 10.56 14.37 14.61 7.89 7.48 56.23 51.92 61.75 59.05 TAY 7.43 7.37 7.37 44 40 53 50
(5) M.S. 14.23. 15.07 20.20 19.18 13.08 12.99 49.19 53.28 56.83 59.73 7.38 7.38 7.32 7.36 44 48 57 56
(6) f.C. 13.56 13.94 16.23 16.66 12.53 12.39 48.87 45.34 52.68 49.83 7.38 7.38 7.37 7.36 43 40 48 46
(3) TL. 13.64 14.64 17.27 18.88 11.91 11.62 48.23 42.75 52.95 49.64 1.36 7.84 7.34 7.32 44 42 50 50
(8) L.B.L. 16.16 16.73 19.88 20.96 13.37 13.44 48.37 45.35 54.29 52.07 7.35 7.38 7.30 7.30 46 42 57 55
(9) WY. 17.16 17.64 21.86 22.5) 15.75 16.53 47.53 42.93 53-31 49.19 . 7.397. 41 7.35 7.37 43 38 5 46
Mean 13.47 13.84 (47.44 7.73 10.34 11.28 90.27 47.27 95.83 63.71 7.39 7.40 7.35 7.35 42.9 40.5 51.8 48.
Stand.error +0.85 *0.95 71.04 ‘11.06 70.87 ‘11.00 70.93 141.34 ‘10.96 71.33 to. to.o1 70.01 ‘to o1 to? fia T1200 fh

p* <0. 05 > 0.6 70.7 < 0.02 < 0.02 > 0.2 ~6.7 < 0.05 «6.02
(10) A.M. 12.72 12.35 16.91 16.61 10.07 9.82 47.85 39.01 57.42 45.76 7.35 7.34 7.33 7.32 44 36 54 44
(14) TAL 13,10 13.86 18.92 20.51 13.32 14.25 48.12 44.75 53.27 50.88 7.44 7.45 7.33 7.34 38 34 2 49
(12) T.c, 12.18 13.01 17.12 18.08 11.15 13.48 46.55 44.86 51,58 49.92 7.45 7.41 7.39 1,37 35 37 44 45
(13) J.F. 13.48 13.86 19.38 20.12 11.93 11.90 51.23 44.55 58.02 52.40 7.39 7.47 7.37 7.33 44 33 53 51
(14) LH. 15.15 15.37 20.53 21.74 11.24 11.93 45.09 40.67 53.15 49.72 7.37 7.36 7.30 7.31 41 38 55 50
(I5}A.Mc. 16.90 16.90 21.16 22.45 15.80 16.37 43.42 41.57 48.92 47.27 7.33 7,383 7.28 7.24 43 42 57 57
(18) D. F. 15.08 16.38 19.56 20.23 11.67 12,07 43.90 41.61 51.19 49.70 7.34 7.32. 7.28 7.30 42 42 55 52
Mean 14.09 14.39 19.08 19.97 12.17 12.83 46.59 42.43 §3.36 49. 38 7.38 7.38 7.33 7.32 41.07 37.4 53.043.
Stand. error +*0.63 +¢o.59 +*0.60 10.77 *0.71 ‘*o.79 41.04 70.87 71.25 70.84 t0.02 +%0.02 70.02 0,02 71.300 51,30 Tn6 0 31.

pt >o.1 < 0.01 > 0,05 <0. 01 < 0, 05 70.9 70.3 >0, 05 20, 65

* Determined from the t value obtained by dividing the mean of the individual
changes by its standard error.

+ Control period - Saline infusion,

$ Experimental - Drug infusion.

TAILVUVdI NOD

i

LTH

SI

SLE
276 BENTON D. KING,

LOUIS SOKOLOFF,

AND RICHARD L, WECHSLER

TABLE III

Effects of l-nor-epinephrine and l-epinephrine on cerebral circulation and oxyyen consuntption

 

 

Subject MABP CBF CVR (A-W)O% CMR O2 RQ
mm. Hg. ec/100gm/ tes. Hy vol % ee/ WO gui/ (cerebral)
nin. ee/I 00g mm,’ tain
Mir,

C+ Et Cc E c E Cc E c E c gE
Q) HLA. 92 115045 40 2.0 2.9 7.67 8.46 3.5 3.4 O91 1.00
(2) E.H. 1090 123 «61 49 16 25 5.42 4.89 3.32 2.4 O72 1.02
» (3) AH. 86 11256 52 15 2.2 647 635 3.6 3.3 06.89 1.03
& (4) Lew. 100 130 60 56 17 #23 648 7.138 3.9 46 O85 1.0L
s (5) M.S. 95 118 = 70 72 14 1.6 7.15 619 5&9 45 1.067 1.04
ge (6) T.C. 84 102-80 80 ltl 61.300 3.70 4.27 3.0 24 1.03 1.05
a (1) TAL 86 10671 59 1.2 1.6 5.38 7.28 3.8 4.3 9.88 0.95
a (8) LL 83 12469 52 1.2 24 651 7.52 45 3.9 6.92 690
& (9) N.Y. 93 123. 41 40 2.3 3.1 G11 6.91 25 24 095 i.04
z Mean 91.0 217.0 61.4 55.6 1.56 2.23 6.10 6.46 2.68 3.51 6.51 1.00
-  Stand.error 42.2 143.0 44.2 44.5 10.13 *o.20 to.39 to.44 fo.25 to.25 to.G3 *o. c2

p* <0. 001 <0. 05 <0. 001 >0.2 >03 <0. 08
(10) A.M. 103 109 47 49 2.2 2.2 6.84 6.79 3.2 3.3 1.00 6.99
g (4) TL 90 133-60 85 1.5 1.6 560 626 3.4 5.3 0.80 0.98
2 (12) T.c, 88 128 049 68 1.8 1.9 5.97 4.60 2.9 3.1 0.84 1.10
& (13)5.F 107 120-56 65 1.9 1.8 7.45 8.22 42 5.3 0.91 6.96
g (14) L.8 78 90 35 44 2.2 2.0 9.29 981 3.2 40 0.97 0.92
B (15) A. Mc 65 86 6-50 59 1.7 1.5 5.36 6.08 2.7 3.6 1.03 0.94
™, (18) D. F 85 95-54 55 1.6 1.7 7.89 8.16 43 45 0.92 0.98
Mean 90.9 108.7 50.1 60.7 1.84 1.81 6.91 7.13 3.41 4.16 0.94 0.98
Stand.error 13.9 +7,.1 73.0 45.2 40.10 to.09 140.53 to.65 to.14 *%o.34 to.02 to. 02

p* <0. 05 <0, 02 >0.6 70.4 <0. 05 >0.3

* Determined from the t value obtained by dividing the mean
of the individual changes by its standard error.

+ Control period - Saline infusion.

+ Experimental period - Drug infusion.

dioxide tension were not of sufficient magnitude to
have a significant effect on cerebrovascular dy-
namics (16).

Despite the marked rise in mean arterial blood
pressure from 91 to 117 mm. Hg, cerebral blood
flow decreased from 61 to 56 cc./100 gm./min,
(p < 0.05), apparently because of an increase in
cerebrovascular resistance from 1.6 to 2.2 resistance
units (p < 0.001). An increase in resistance oc-
curred in each of the individuals studied. There
was no significant alteration in cerebral metabolism.

Effects of epinephrine

The administration of epinephrine was often ac-
companied by palpitation, tremor of the hands, or
a sense of excitement or apprehension. Cutaneous
and mucosal pallor was usually marked. The
pulse rate, although significantly increased during
the blood flow determinations, accelerated more at
the beginning and immediately after the termina-
tion of the infusions when the blood pressure ele-
vation was less prominent.

Mean arterial blood pressure increased from 91
to 109 mm. Hg, and cerebral blood flow rose from

a mean of 50 to 61 cc./100 gm./min. (p < 0.02).
This increase in cerebral blood flow is accounted
for by the lack of significant change in cerebro-
vascular resistance during the period of hyperten-
sion. Of particular interest was the augmentation
of cerebral oxygen consumption from 3.4 to 4.2

cc. O,/100 gim./min. (p < 0.05).

DISCUSSION

These studies show that /epinephrine and
l-nor-epinephrine act differently with respect to
both cerebral circulation and cerebral metabolism.
The significant increase in cerebral oxygen con-
sumption accompanying epinephrine infusions is
of particular interest. Such observations indicate
that the brain shares in the metabolic augmenta-
tion which is produced in the body as a whole by
One subject (No. 11), in whom
marked sensations of apprehension followed ad-

epinephrine.

ministration of the drug, had an increase in cere-
bral oxygen consumption from 3.4 to 5.3 ce. O,/100
gn../min. The fact that a state of anxiety or ap-
prehension may be associated with a greatly aug-
mented cerebral oxygen consumption has been
EPINEPHRINE AND NOR-EPINEPHRINE—COM PARATIVE EFFECTS

pointed out by Kety (17), who reported a value of
5.0 ce. O,/100 gm./min. under such circumstances
when previous resting values were 3.4, 3.9, 3.2,
and 4.2 cc. O./100 gm./min, These observations
lead to speculation as to whether the increased
cerebral oxygen consumption during apprehension
is due to the liberation of endogenous epinephrine.
Nor-epinephrine, which does not appear to pro-
duce such psychic effects, is not associated with
such increases in ecrebral oxygen consumption.
These findings controvert the suggestion made by
Scheinberg (18) that cerebral metabolism nor-
mally functions at nearly its maximal rate and that
“no effective means of increasing cerebral metabo-
lism in man have been found.”

It should be pointed out that a rise in mean ar-
terial blood pressure does not necessarily result
Despite a
marked rise in blood pressure caused by nor-epi-

in an increase in cerebral blood flow.

nephrine, there was a decrease in blood flow be-
cause of the simultaneous
vascular resistance. Since an important aspect
of cerebral homeostasis consists in an adjustment
of circulation to local metabolic needs (17), it is
providential that epinephrine, which increases
cerebral metabolism, does not simultaneously in-

increase in cerebro-

crease cerebrovascular resistance. It is possible
that epinephrine might exert a vasoconstricting ac-
tion on the cerebral vessels which is balanced by
a vasodilator effect resulting from an accumulation
of substances produced by the increased cerebral
metabolism. However, the higher oxygen con-
tent and lower carbon dioxide tension existing in
the internal jugular blood during the drug infu-
sion indicate that cerebral blood flow is more than
adequate, which prevents metabolic products from
accumulating.
resistance following the administration of epimeph-
rine seems to indicate that if there were vasocon-
striction from this drug, it was not sufficient to do
more than overcome any passive dilatation re-
sulting from increased systemic blood pressure.
Experiments upon anesthetized animals have
indicated that epinephrine can cause cerebral vaso-
constriction (6, 7). Our results may differ be-
cause of species difference, the state of conscious-

The unchanged cerebrovascular

ness, composition of the drug, or mode of adminis-
tration. Both of the drugs used in this study were
synthetic preparations, believed to be free from
contamination by each other. On the other hand,

277

chemical analysis of U.S.P. grade epinephrine has
revealed that the nur-epinephrine content of epi-
nephrine from animal sources may be as high as
18.5% (19); such contaminated epinephrine may
have been used in earlier studies. Although the
quantities of nor-epinephrine contained in natural
epinephrine do not appear to alter significantly
the hemodynamic actions of the latter drug (20),
one cannot be assured such is the case in relation
to cerebrovascular actions.

In this study the drug was given by continuous
intravenous infusion. The concentration reaching
the cerebral vessels under such circumstances Is
undoubtedly much lower than was attained in
those animal experiments in which the drug was
applied topically (7) or injected into the carotid
artery (6) and in which cerebral vasconstriction
was reported,

The question may be raised whether epinephrine
could cause cerebral vasoconstriction if given in
sufficient quantity to produce a pressor effect
equivalent to that elicited by nor-epinephrine.
Side effects such as arrhythmias, palpitation, or
apprehension placed limitations on the amount
of epinephrine which could be used in this study.
However, in two individuals (Nos. 11 and 12)
to whom sufficient epinephrine was given to pro-
duce pressor effects equal to or greater than those
obtained in any of the subjects receiving nor-epi-
nephrine, there was no significant rise in cerebro-
vascular resistance. We conclude that epinephrine,
given systemically and within the limits of physio-
logical tolerance, does not produce cerebral vaso-
constriction in man.

Our data for nor-epinephrine are essentially in
agreement with those of Sensenbach, Madison, and
Ochs (5). The primary difference is a lack of a
statistically significant decrease in cerebral blood
This might be attributed to
the variability of absorption of the drug from an
intramuscular depot. In our series, a continuous
intravenous infusion associated with continuous
blood pressure recording allowed us to achieve a
constant pressor effect.

Goldenberg and his co-workers (3) have sug-
gested that a disturbed balance between nor-epi-
nephrine and epinephrine might be an etiologic
factor in essential hypertension.

flow in their series.

Evidence sup-
porting this view is the fact that essential hyper-
tension and infusions of nor-epinephrine are both
278 BENTON D,. KING, LOUIS SOKOLOFF, AND RICHARD L. WECHSLER

associated with increases in total peripheral re-
sistance and blood pressure without any increase
in cardiac output. Evidence against this view
consists of the finding that nor-epinephrine de-
creases forearm blood flow and produces facial
pallor and bradycardia, manifestations which are
not characteristic of essential hypertension (21).
Our data show another similarity between essential
hypertension (22) and the state produced by in-
fusions of nor-epinephrine, namely that both are
associated with an increase in cerebrovascular
resistance. Although cerebral blood flow was sig-
nificantly decreased by nor-epinephrine, it still
remained within normal limits, as is the case with
essential hypertension (22).

Nor-epinephrine has been proposed as a useful
and potent pressor drug (23), and is now available
for clinical use. If the vascular beds of other vital
organs such as the heart, liver, and kidneys re-
spond with vasoconstriction as do the vessels of
the brain, situations could occur where therapy
with this and similarly acting drugs might be un-
satisfactory or actually harmful. For example, if
sympathetically induced vasoconstriction through
most of the body was already maximal during an
episode of hypotension, nor-epinephrine, which
is unquestionably a cerebral vasoconstrictor, might
increase cerebrovascular resistance out of propor-
tion to the increase in perfusion pressure so that
cerebral blood flow might actually decrease. For
this reason, nor-epinephrine and related drugs
should be evaluated not only by measurement of
their pressor effects but also by measurement of
blood flow through vital organs in normotensive
and hypotensive states.

SUMMARY

1. The effects of continuous intravenous in-
fusions of synthetic /-epinephrine and /-nor-epi-
nephrine upon arterial blood pressure and pulse
rate, arterial and internal jugular blood gases, and
cerebral blood flow, oxygen consumption, and vas-
cular resistance have been studied in man.

2. Epinephrine produced an increase in mean
arterial blood pressure and cerebral blood flow
without a significant change in cerebrovascular
resistance. In addition there was a significant in-
crease in cerebral oxygen consumption.

3. Nor-epinephrine, a more potent pressor drug,
produced a marked increase in cerebrovascular

resistance, and a decrease in cerebral blood flow
despite a substantial increase in mean arterial
blood pressure. Cerebral oxygen consumption was
not significantly altered. The significance of these
findings in relation to the clinical use of nor-epi-
nephrine is discussed.

ACKNOWLEDGMENTS

The authors wish to express their appreciation to
Dr. Seymour S. Kety for his advice and guidance and
to Miss Hilda Klotz, Miss Carolyn Dvernbach, Miss
Grace Mellwig, and Mrs. de Camp Elder for their tech-
nical assistance.

REFERENCES

1. Starr, I, Gamble, C. J., Margolies, A., Donal, J. 3.,
Jr., Joseph, N., and Eagle, E., A clinical study of
the action of 10 commonly used drugs on cardiac
output, work and size; on 1espiration, on metabolic
rate and on the electrocardiogram. J. Clin. In-
vest., 1937, 16, 799.

2. Reale, A., Kappert, A., Skoglund, C. H., and Sutton,
G. C., The effect of /-nor-adrenaline on the oxygen
consumption of human beings. Acta physiol.
Scandinav., 1950, 20, 153.

3. Goldenberg, M., Pines, K. L., Baldwin, E. del,
Greene, D. G., and Roh, C. E., The hemodynamic
response of man to nor-epinephrine and epineph-
rine and its relation to the problem of hypertension.
Am. J. Med., 1948, 5, 792.

4. von Euler, U. S., Hormones of the sympathetic nervous
system and the adrenal medulla. Brit. M. J., 1951,
1, 105.

5. Sensenbach, W., Madison, L., and Ochs, I.., Iffect of
I-nor-epinephrine on the cerebral circulation in
normotensive males. Am. J. Med., 1951, 11, 250.

6. Dumke, P. R., and Schmidt, C. F., Quantitative meas-
urements of cerebral blood flow in the macacque
monkey. Am. J. Phystol., 1943, 138, 421.

. Forbes, H. S., Finley, &. H., and Nason, G. I., Cere-
bral circulation. XXIV. A. Action of epinephrine
on pial vessels; 8B. Action of pituitary and Pitres-
sin on pial vessels; C. Vasomotor response in the
pia and the skin. Arch. Neurol. & Psychiat., 1933,
30, 957.

8. Fog, M., Cerebral circulation. I. Reaction of pial ar-
teries to epinephrine by direct application and by
intravenous injection. Arch. Neurol. & Psychiat.
1939, 41, 109.

9. Gibbs, F. A., Gibbs, E. L., and Lennox, W. G., The
cerebral blood flow in man as influenced by adren-
alin, caffein, amyl nitrite and histamine. Am.
Heart J., 1935, 10, 916.

10. Kety, S. S., and Schmidt, C. F., The nitrous oxide
method for the quantitative determination of cere-
bral blood flow in man; theory, procedure and
normal values. J. Clin. Invest., 1948, 27, 476.

“I
Mi.

13.

15.

EPINEPHRINE AND NOR-EPINEPHRINE—COMPARATIVE EFFECTS 279

Lilly, J. C., Legallais, V., and Cherry, R., A variable
capacitor for measurements of pressure and me-
chanical displacements; a theoretical anatysis and
its experimental evaluation . J. Appl. Physics, 1947,
18, 613.

. Peterson, L. H., Dripps, R. D., and Risman, G. C.,,

A method for recording the arterial pressure, pulse
and blood pressure in man. Am. Heart J., 1949,
37, 771.

Peters, J. P., and Van Slyke, D. D., Quantitative
Clinical Chemistry. Vol. I], Methods. Williams
& Wilkins, Baltimore, 1932.

. Rosenthal, T. B., Effect of temperature on pH. of

blood and plasma in vitro. J. Biol. Chem., 1948,
173, 25.

Ievelyn, K. A., and Malloy, H. T., Microdetermination
of oxyhemoglobin, methemoglobin, and sulfhemo-

globin ina single sample of blood. J. Biol. Chem.,

1938, 126, 655.

. Kety, S. S., and Schmidt, C. I-., The effects of active

and passive hyperventilation on cerebral blood
flow, cerebral oxygen consumption, cardiac output
and blood pressure of normal young men. J. Clin.
Invest., 1946, 25, 107.

17.

18.

19.

20.

al.

i)
bd

23.

Kety, S. S., Circulation and metabolism of the hu-
man brain in health and disease. Am. J. Med.,
1950, 8, 205.

Scheinberg, P., Cerebral circulation and metabolism
in hyperthyroidism. J. Clin. Invest., 1950, 29, 1010.

Tullar, B. F., The separation of L-arterenol from nat-
ural U.S.P. epinephrine. Science, 1949, 109, 536.

Goldenherg, M., Faber, M., Alston, E. J., and Char-
gaff, E. C., Evidence for the occurrence of nor-epi-
nephrine in the adrenal medulla. Science, 1949, 109,
534.

Barnett, A. J., Blacket, R. B., Depoorter, A. E., San-
derson, P. H., and Wilson, G. M., The action of
noradrenaline in man and its relation to phaeo-
chromocytoma and hypertension. Clin. Sci., 1950,
9, 151.

. Kety, S. S., Hafkenschiel, J. H., Jeffers, W. A., Leo-

pold, I. IL, and Shenkin, H. A., The blood flow,
vascular resistance, and oxygen consumption of the
brain in essential hypertension. J. Clin. Invest.,
1948, 27, 511.

Goldenberg, M., Apgar, V., Deterling, R. A., Jr., and
Pines, K. L., Nor-epinephrine (arterenol, sympa-
thin N) as a pressor drug. J.A.M.A., 1949, 140,
776.