Blood concentration of catecholamines and their hemodynamic effects in man

Blood Concentration

of Catecholamines

Their Hemodynamic

Effects in Man*

ROBERT H. EICH, M.D., RICHARD P. CUDDY, M.D., JOSEPH A. BARRY, and HAROLD SMULYAN, M.D. Syracuse,

plays

M.D.

New York

A role in the regulation of the cardiovascular system, few studies other than of blood pressure LTHOUGH norepinephrine

and

ing a breakfast of toast and coffee, patients were studied in the supine position. Under local anesthesia, an indwelling Cournand needle was introduced into the right brachial artery and a polyethylene catheter (length 30 cm., internal diameter 1.5 mm.) into the left antecubital vein. The catheter was used both for obtaining venous samples and injecting indicator for determination of cardiac output. A No. 18 gauge needle introduced into a vein on the volar surface of the right I’orearm was used for infusion of norepinephrine. The patient then rested for 20 minutes or until the blood pressure, determined by auscultation, and the pulse were stable. Following this, the control cardiac output determination was made, and arterial and venous blood samples were obtained for the determination of catecholamine concentration. Then norepinephrine infusion was started and a motor-driven infusion pump used.t The initial infusion rate was 7.5 micrograms per minute of norepinephrine as the bitartrate (Levophed@, bitartrate monohydrate). Previous work with 20 control sub.jects had established this as the minimal rate at which all would respond by either a rise in blood pressure of at least 10 mm. Hg or a fall in pulse rate of 6 beats per minute. Blood pressure and pulse were taken every two minutes after infusion began; after eight minutes the measurement of cardiac output was repeated followed by sampling of arterial and venous blood for catecholamine determination. The next infusion rate was then begun, and after an additional eight minutes the measurements were repeated. Cardiac output determinations were made by using the dye dilution technic with radioactive iodinated human serum albumin as the indicator, and interrupted samples were taken at two second intervals. The samples were analyzed and the results calculated as described in previous publications.* The blood levels of catecholamines were determined by a modification (similar to that of Coheng) of the

a major

have been made on the relationship between circulating blood levels of the catecholamine in and its hemodynamic effects.’ 2’ Except pheochromocytoma, no relationship has been shown between blood pressure and catecholamines. While both the hemodynamic effects of norepinephrine infusion and the effect of infusion on the blood level have been investino studies have been made gated separately,3-7 that measured the two variables simultaneously. The present study was undertaken to investigate further the relationship between blood catecholamine concentration and the resultant hemodynamic effects both in normal subjects and patients with labile hypertension. METHODS Thirty-nine patients with labile hypertension and 27 control subjects were used in the study; most of them were from the general medical and surgical wards of a Veterans Administration Hospital. Subjects with labile hypertension were used because prior studies had shown that a wide range of cardiac output and total peripheral resistance could be found in this The criteria for selection required blood group. pressure taken at admittance be above 150/90 mm. Hg, and that during the next three days in the hospital, at least one blood pressure reading below this be recorded. Patients with obvious heart or kidney disease were excluded from the study. No patients were receiving medication other than nighttime barbiturate sedation. The control subjects were also hospitalized patients, but without evidence of cardiovascular disease. All studies were done in a similar manner. The test was explained in advance to the patient, and every effort was made to minimize anxiety. Follow-

t Process and Instruments

Company,

New York, N. Y.

* From the State University of New York, Upstate Medical Center and the Veterans Administration Syracuse, New York. Supported in part by grant H-4707 from the U. S. Public Health Service, National of Health. DECEMBER

1962

819

Hospital, Institutes

820 Norepinephnne

Eptnephnne

ResIstawe 20~

Dynes

cm-5

Resistance

set

Dynes

cm-5

set

I 1800

18001

.

.

I 1600 ’

.

.

!

.

l

!

.

“i

.

600

1

2

FIG. 1. Relationship labile hypertcnGon.

4

8

1.0

Noreplnephrine

.6

v-/L.

between

control

2.5

,repinephrine

1.4

peripheral

.2

4

6

.8

wsistance

and

arterial

1.0

catecholamine

rlwepine@ine mcg./L.

3.0

blood level

0

2.c

A

t&ad level

I

lnfusi011 Rote vs Level g ;$$;,

,

with

Blood

o

0

o

0

lobiles 0 0 0 0 0

l

0 00

I.4

levels in subjects

2.5

2.0

1.2

v-/L

Rate

mcg./L

I. 5

. I

Epinephrine

total

Infusion 3.0

I.2

4oo

. .

.

800.

.

.

.

100

4oo

.

l

12ccl f

.

.

.

1400’

.

WO

.

l600i .

a

I.5

%

0

0

j

1.0

a' .5

06

08 Infusion

FIG. 2.

IO Rate

.I2 .I4 v/kilogram

Relationship

.I6

between

Infush

infusion

rate of norepincphrine

trihydroxyindole method of Lund.‘O Thirty cubic centimeters of blood was draw-n into a syringe containing 25 mg. of heparin and transferred immediately to a glass-stoppered centrifuge tube and immersed in ice water. At the end of the study these were centrifuged at 12,000 r.p.m. for 15 minutes. The catecholamines were adsorbed onto alumina, after the pH had been adjusted to 8.4 with NaLD.1. The alumina was transferred to a chromatographic column 5 mm. in diameter, and the catecholamines The were eluted using 20% normal acetic acid. eluate was oxidized using potassium ferricyanide with ascorbic acid as the stabilizer. Fluorescence was read against standard solutions and a biank by an Aminco Bowman spectrophotofluorimeter. An activating wave length of 405 rnp and fluorescent wave length of 490 mp were used to measure adrenolutin and noradrenolutin, while 435 mp and 580 mp were used for adrenolutin. Calculations were made as de-

Rate

and changes

dkilogmm

in the arterial

level

scribed by Cohen.” ‘The method for measuring catecholamines was repeatedly evaluated with recoveries of added norepinephrine and epinephrine from plasma by using a concentration of 10 to 20 micrograms per liter. Mean recoveries for norepinephrine were 93 per cent i 14 per cent and for epinephrinc 92 per cent + 11 per cent. RESULTS The

results

are

shown

Figures

1 through

arterial

catecholamines

and

figures,

as we

circulating trol

in

total

are believe and

peripheral

jects

with

labile

with

measurable

used they

resistance and was

II and

the

study,

the

tables

in

epinephrine

there

I and

best

In

hypertension, levels

Tables

Throughout

catecholamines.

norepinephrine

against

8.

reflect

Figure are for even

the

1, conplotted the

sub-

in those

no correlation

‘THE AMERICAN JOURNAL OF CARDIOLOGY

Hemodynamic

Effects TABLE

Changes in Hemodynamics

821

of Catecholamines I

and Catecholamines

in Labile Hypertensive Patients

I

B.P.

Subject

B.P II

I

co

I

co II

(L. /min. j

: Arterial Catecholamines TPR I TPR 1, 1 I (dynes sec. cm. -5)i NE NE E

(pg./L.)

I, E

Over 10 Minute Period 1

2 3 4 5 6a 6b 7a 7h 8 9a 9h 10a IOb 11 12a 12b 13 Mean S.D.

112/72 128/88 130/80 154/92 126/80 200/l 05 200/100 155/90 140/90 160/100 155/105 160/100 152/100 160/105 134/90 130190 126/84 118/80

118/72 128/88 125/75 154190 128184 205/l 10 205/l 10 155/90 140/90 160/100 150/105 160/100 146/102 155/105 130/80 135/90 132/82 124/84

5.84 5.49 6.24 6.81 6.18 3.75 4.95 7.56 9.00 6.87 7.53 9.31 5.03 6.60 8.70 7.42 7.23 7.06

7.45 6.48 5.00 7.04 6.56 3.96 5.36 7.02 8.95 6.74 7.06 9.28 5.45 5.10 8.48 6.49 7.22 6.80

1168 1476 1240 1339 1227 2920 2150 1185 952 1396 1295 1031 1855 1490 1041 1108 1081 1054

937 1250 1465 1261 1195 2870 2060 1276 956 1424 1358 1035 1715 1930 915 1420 1050 1140

148/92

148/92

6.75 1.47

6.69 1.39

1389 487

1403 489 - _.~

From Day to 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Mean SD.

0 1.28 0.14 0.55 0.23 0.81 0.55 0 0 0.32 0.73 0 0 0.19 0.32 0 0.19 0.28

0.82 0.10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0.26 0.32 ~

0.02 0.07

0.31 0.35

0.06 0.19

Day

112/76 152/60 128/80 1651105 136186 148/83 118/80 127177 126/81 186/97 114/88 168/114 120/83 121/90

6.15 6.80 7.33 8.18 8.86 5.35 8.10 6.14 8.40 6.41 5.97 7.41 6.65 4.75

5.01 5.46 9.62 9.33 9.52 6.78 6.48 8.09 9.53 6.50 5.58 6.09 5.50 4.72

1286 1282 1179 1242 1000 1630 910 1224 886 1635 1260 1350 1286 1700

1405 1312 798 1071 856 1239 1143 930 806 1553 1390 1734 1386 1697

0.37 0.37 0.50 0 0 0.05 0 1 0.71 0 0.96 0 0 0 0.30

0 0.73 0 0.14 0 0.38 0 0.33 1.47 0.23 0 0 0.38 0

0.41 0.32 0.37 0.50 0.61 0.34 0.55 0.76 1 00 0.74 0.37 0.92 0 0.05

0.27 0.64 0 0 0.73 1.14 0.82 0.71 0.14 0.32 0 0.68 0.81 0.38

142/90

137/86

6.89 1.23

7.01 1.85

1276 250

1237 466

0.23 0.31

0.26 0.41

0.50 0.20

0.49 0.37

CO

= cardiac output;

T.P.R.

between the catecholamines and the resistance. Likewise, in the same patient studied over a 10 minute interval or from day to day (Table I), there was no directional relationship between changes in catecholamines and the hemodynamic parameters measured. The response to infusion of norepinephrine bitartrate at 7.5 and 14.9 gg./min. is sum1962

0.27 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.14

0

127/85 178174 146/90 170/105 144194 153/87 119/78 126178 114/82 185/105 116183 155/110 134/93 124/90

B.P. = blood pressure; and E = epinephrine.

DECEMBER

0.41 0 0.18 0.36 1.01 0.55 0 0 0.32 0.36 0.96 0 0 0.32 0 0 0.27

’ 0

= total peripheral resistance;

N.E. = norepinephrine

marized in Table II and in Figures 224. There was no difference between the catecholamines in the control subjects and the labile hypertensive subjects, in spite of the latter having a somewhat elevated total peripheral resistance. There was no relationship between the infusion rate and the blood level attained (Fig. 2), but the infusion rates are somewhat lower than

822

Eich et al. TABLE

Effect of Norepinephrine

II

Infusion on

Control -____~

~~_~~-.-.Subjects (No.)

Normal 14 Labile hypertensive 11 Labile hypertensive 5 Normal 5 Labile hypertensive 5

~~CO (I../min.) 6.55 f0.58 6.65 fl.69 7.13 fl.61 6.85 fl.41 8.03 +2 31

~~~~~~.~~~ ~~~~~_ ~_~ _~ TPR (dynes sec. cm. 5, 1035 f91 1361 f235 1154 f208 1057 xt-173 957 zt435

those used by others who did find a relationship. With infusion there was no change in blood levels of epinephrine in either group. Xormal Suhjds: The hemodynamic responses to infusion of norepinephrine were consistent in the normal subjects (Table II, Fig. 3), since total peripheral resistance increased in every subject, and cardiac output fell in all but three.

FIG. 3. Hemodynamic tensives.

~~~~_.____~~

Arterial Ckecholamines NE E 0.68 zkO.61 0.42 ho.36 0.33 +0.15

Infusion Speed 1 (pg./min.)

0.40 f0.58 0.24 f0.78 0.21 zkO.63

60 (L. /min.

7.5

-0.34 f0.44 -0.42 fO.64 -0.53 f0.87 -0.45 f0.69 -0.60 z&o 86

7.5 7.5 14.9

0 42 f0.33

0 48 f0.39

)

14.9

The mean blood pressure increased from 86 to 96 mm. Hg, while the pulse fell from 71 to 65. There was no relationship between the changes in total peripheral resistance and those in arThus a rise in terial catecholamine levels. total peripheral resistance of 160 dynes sec. cm.? was accompanied by a rise in arterial norepinephrine of 1.62 p,g.,‘L. in one subject

effects of norepinephrine infusion at 7.5 and 14.9 rg./min.

THE

in normal subjects and labile hyper-

AMERICAN

JOURNAL

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CARDIOLOGY

Hemodynamic

Hemodynamics

Effects

of Catecholamines

and Blood Catecholamines Infusion Speed II

Infusion Speed I Arterial Catecholamines NE E

TPR

+I80 f58 +236 f191 +I87 fl78 +249 f184 +263 f177

Infusion Speed (Mg./min.)

+2.11

+0.05

14.9

+1.33 f0.44 +I.16 f0.27

-l-o.11 f0.37 f0.13 f0.37

14.9

co (L./min.)

TPR

-0.01 10.47 f0.81 &I.36 +0.31 f0.98 -0.26 10.52

+142 fl56 -87 f332 +32 f170 +175 +103

11 22

+2.11 f0.91

Norepimphino v/Llfor Plasma

3.0

x

X

’

2.0

’

1.5 l

.

500400

4.

1.0

.59 0

xx)m n

Total

R**i*fwa

Relationship between changes in catecholamines

DECEMBER1

962

hyprhnsiwr

7.5 wmin.

n

from

7.5

14.9 v/min.

I.WI

,'O

O Oxx 0

oo

0

0

0

0

.

l~-Otl~ Pwiphsml

O-labile

7.5 VAnin.

0

oeoo

0

0

rubjuts

0

l 0

X-nwmpl

b

0

FIG.

+0.14 f0.28 +o .22 zkO.58

l - labifa hypwfensivw

2.5

min.

+1.05 f0.73 +0.83 f0.47

in all except 1. The mean increase in total peripheral resistance was not significantly There greater than that in the normal group. was no correlation between the changes in hemodynamics and in the catecholamines (Fig. 4). Doubling the infusion rate to 14.9 pg./min., while producing a further rise of 5.5 mm. Hg in blood pressure and fall of 2.8 in pulse: did not produce the expected consistent rise in total peripheral resistance. Instead, the resistance increased in only one half of the observations, and the mean actually decreased. This fall was accounted for b>- a rise in cardiac output which occurred in 11 of the 17 studies. Again, there was no consistent change in catecholamines associated with the rise in cardiac output. E$ect of Dose and Duration: Two of the pos-

AArfwid

600

Arterial Catecholamines 1: NE

+0.15 f0.46

and 3.18 pg./L. in another. In the control subjects, increasing the infusion rate to 14.9 resulted in a further elevation of blood pressure to 105 mm. Hg. and fall in the pulse rate to 60. The cardiac output fell in 6 subjects, remained constant in 7 and rose in 3. The total peripheral resistance increased in all except the 3 with the rise in cardiac output. Labile Hypertensive Subjects: A total of 17 observations were made in 11 labile hypertensive subjects at the same infusion rates (Table II, Fig. 3). The blood pressure response to infusion of norepinephrine at 7.5 pg./min. was similar to that of the control subjects, increasing 10 mm. Hg in spite of the control level being higher (110 mm. Hg). Pulse fell from The cardiac output fell in all except 78 to 72. 3, and the total peripheral resistance increased

-700

823

2003004~ Dynes

~600700+

cm.-5 YC.

and hemodynamics

with norepinephrine

infusion at 7.5 pg./

824

Eich

ct al.

4

FIG.

5.

Hemodynamic

effects of norepinephrine

sible variables involved in this limitation of vasoconstriction, i.e., dose and infusion duration, were then investigated further. First, 5 labile hy-pertensive subjects were given an infusion of a lower dose of norepinephrine for the second infusion speed, 11 pg./min. instead of 14.9. .4s shown in Table II, the mean increase in total peripheral resistance with the second infusion speed was only- 32 dynes sec. cm.?, and in 3 of the 8 observations the resistance actually fell. Again, this was a reflection of a rise in cardiac output, and again there was no relationship between the hemodynamic changes Giving and the changes in catecholamines. the higher infusion rate first (Table II, Fig. 5) still produced a definite vasoconstrictor effect, total peripheral resistance increasing in all except one subject: and cardiac output decreasing in all except two. LYhen the infusion rate was decreased to 7.5 pg./min. after the 14.9 (Fig. 6, bottom), cardiac output rose while total peripheral resistance fell. This suggests that 7.5 pg. is not the more active dose in terms of vasoconstrictive effect. ?%e efecl of duration of infusion was evaluated in 5 labile hypertensive subjects. Three of

infusion at 14.9 and 22 pg./min.

these were given 7.5 pg.jmin. for 20 minutes (Fig. 6, top), and 2 subjects (not shown) were For those given 14.9 pg./min. for 20 minutes. given 7.5, the total peripheral resistance deIn the subjects creased in 3 of 4 observations. given 14.9 pg./min., there was no significant change in the total peripheral resistance between the 10 and 20 minute observations. a group of control subjects were Finally, studied by using higher infusion rates following atropinization, and for 20 to 30 minutes using a If the limited vasoconstant infusion rate. constriction was related to an actual inability of the vessels to constrict further beyond a certain peripheral resistance level, then normal subjects given a high enough dose of norepinephFive rine might show the same limitation. control subjects, 4 of whom were studied twice, were given 14.9 followed by 22 pg./min.; the results are shown in Figure 5. With the initial infusion rate, the mean blood pressure increased 14 mm. Hg and the pulse fell 10. Cardiac output decreased in all except one subject, and the total peripheral resistance increased in those whose cardiac output fell. Increasing the infusion rate to 22 pg.;‘min. resulted in a further THE

AMERICAN

JOURNAL

OF

CARDlOLOGY

Hemodynamic

6.0 COHTSOL

(4.97 IO min. INFUSION

Effects

7.5, IO ml”. RATE

of Catecholamines

,000

-

CONTROL

825

14.9, 10 In,“. ,NFUSlON

723, 10 mtn. RATE

(upper chart), changes in hemodynamics with norepinephrine infusion at 7.5 pg./min. over 20 minutes in labile hypertensives. B (lower chart), changes in hemodynamics with norepinephrine infusion at 14.9 and 7.5 pg./min. in labile hypertensives. FIG.

6.

A

in resistance in all subjects. It is entirely possible, however, that an even higher infusion rate would have produced a different effect. Eight normal subjects were studied following atropinization with 1.2 mg. of atropine given intravenously (Fig. 7). In spite of what was felt to be full atropinization, the pulse fell with infusion of norepinephrine although the cardiac output did not. Removal of the vagally mediated compensatory reflexes did not result in any limitation of the vasoconstrictor effect. Finally, the effect of the duration of infusion was studied in 8 control subjects given 7.5 hg. for 10 and 20 minutes and in 3 subjects for 30 minutes. (Fig. 8). After 30 minutes the total peripheral resistance did fall and cardiac output rose. This emphasizes the importance of duration of infusion and suggests that the control subjects may differ from the subjects with labile hypertension only in that the decrease in total peripheral resistance did not occur so soon. rise

DISCUSSION Although norepinephrine plays a major role in the regulation of the cardiovascular system, DECEMBER

1962

there have been few studies of the relationship between circulating levels of it and hemodynamics other than blood pressure. One of the reasons for this deficiency has been technical difficulty with the method of measuring circulating catecholamines in blood. Both the present chemical methods, the trihydroxyindole of LundlO and the ethylenediamine method of Weil-Melherbe and Bone” have limitations, the former being somewhat more specific, but less sensitive. With either of the two methods final proof is lacking l4 that the substances measured are indeed biologically active norepinephrine and epinephrine. With infusion of norepinephrine it has been shown that by the trihyclroxyindole method no change in epinephrine is produced.7 Likewise, a constant level is produced after 8 to 10 minutes, which suggests that breakdown products are not measured.? Dopamine, with the trihydroxyindole method modified by Cohen, would only alter the results by 7 per and isopropyl norepinephrine, which cent, would interfere, has never been isolated by other methods such as chromatography.g Because of the greater degree of specificity

826

Eich et al.

FIG. 7. Hemodynamic control subjects.

effects of norepinephrine

the trihydroxyindole method was suggested, chosen for this study. By using a modification similar to Cohen’s, recoveries of added norepinephrine and epinephrine were comparable to those in the literature.7,‘3J4 Infusion of 0.10 pg./kg./min. of norepinephrine as the bitartrate resulted in a consistent and significant rise in norepinephrine levels without affecting those of epinephrine. Similarly, the greatest rise occurred at the arterial level, as found by others.‘* The normal range was similar to that reported bv both Price12J4 and Cohen’3 with the A-V difference of norepinephrine negative and of epinephrine positive. The arterial level was used throughout this study, both because with norepinephrine infusion it was the higher of the two, and because it was felt to be a more accurate reflection of the circulating norepinephrine than that from a forearm vein. Previous studies of the hemodynamic effects of norepinephrine infusion, while showing a consistent increase in calculated peripheral resistance, had shown an inconsistent effect on cardiac output. In an effort to produce a consistent hemodynamic effect, the studies of

infusion at 7.5 and 14 rg./min.

in atropinized

norepinephrine infusion were made with the lowest dose which prior studies had shown would produce a consistent, although often transient, effect on either blood pressure or pulse. This dose was somewhat lower than that used by others. The results can be summarized as follows : 1. There was no relationship between the control catecholamines and the hemodynamics, neither in normal subjects nor in those with labile hypertension. 2. No relationship could be demonstrated between changes in catecholamines and hemodynamics over a 10 minute period or from day to day. 3. With the infusion of norepinephrine the hemodynamic response was consistent for both the control subjects and the labile hypertensive subjects. In the control subjects there was a consistent fall in cardiac output and a rise in total peripheral resistance for both infusion rates of 7.5 and 14.9 pg. min. This consistent hemodynamic response is somewhat at variance with the results of other workers and would appear to be best explained by the use of a lower THE

AMERICAN

,JOURNAL

OF CARDIOLOGY

Hemodynamic 90

CARDIAC -L/min

83

-

70

65

OUTPUT

MEAN -

-

70

-

-

65

-

CM,,Ol

-

I 10

827

of Catecholamines 95

60

II00

Effects

60 cmlml

BLOOD

I IO

PRESSURE

I PO minutes

30

PULSE

RESISTANCE

110 100 -

800

-

700

-

600 Confml

70 I 10

I 20 mlcYt.l

30

60 control

, 10

I 7.0 mlnufal

I 30

FIG. 8. Hemodynamic effects of norepinephrine infusion at 7.5 pg./min. over 30 minutes in control subjects. infusion rate of norepinephrine. For subjects with labile blood pressure the response to infusion of norepinephrine at 7.5 pg./min. was similar to that of the control subjects in that the cardiac output fell, and the total peripheral resistance rose in the majority. There was no relationship between the control resistance and the height of the resistance response. Likewise, while initial blood pressure and total peripheral resistance values were somewhat higher in the labile hypertensive subjects, the response to norepinephrine was parallel to the control; sensitivity could not be thus, an increased demonstrated. This again could be a function of the infusion rate or the fact that the subjects were not fixed hypertensives as studied by In one half of the labile hyperGoldenberg. tensive subjects given either 11 or 14.9 pg./min., increasing the infusion rate did not result in a further rise in total peripheral resistance. In this group at least, a limitation of the vasoconstrictor effect of norepinephrine as measured by total peripheral resistance could be demonstrated, without limitation of the pressor effect. 4. With the infusion of norepinephrine there was no correlation between the blood levels of catecholamines and the hemodynamic effects, DECEMBER

1962

either in the control subjects or those with labile hypertension. This lack of correlation is best explained by the fact that the blood level attained with infusion is a complex variable dependent not only on infusion rate and duration, but also on such factors as diffusion, excretion, metabolic transformation and binding, as well as the limitations of the method.’ 5. ‘The final part of the study was concerned with an investigation of the factors involved in the limitation of the vasoconstrictor effect of norepinephrine. Because of the design of the experiment (making determinations at 8 minute intervals), after 16 minutes of infusion it was possible to demonstrate a decrease in total peripheral resistance in the subjects with labile hypertension. This decrease appears to be a function of the duration of infusion rather than the rate of infusion. Similarly, in control subjects this limitation of vasoconstriction could be demonstrated, but only by continuing the infusion for 30 minutes. Although it occurred in both groups, the fall in total peripheral resistance with continuing infusion appeared sooner in the subjects with labile hypertension. Whether this fall in total peripheral resistance was the result of an actual decrease in vasocon-

Eich striction or \zras secondary to a rise in cardiac output was not determined in this stud).

1. By using the trihydroxyindole method to measure catecholamines in both control subjects and subjects with labile hypertension, no relationship could be demonstrated between changes in blood pressure, cardiac output, total peripheral resistance and catecholamines over a 10 minute period, from da)- to da)-, or following norepinephrine infusion. 2. The explanation for this lack of correlation would appear to be largely- a function of ~hc multiple factors, in addition to the infusion rate, which determine the blood level of catecholamines, and possibl) the lack of sensitivity of the method. 3. A consistent hemodynamic eft‘ect coulcl be demonstrated in response to norepinephrine infusion in both the control subjects and those Although the rrwith labile hypertension. sponse was similar at the initial infusion rate, increasing the rate resulted in a fall in total peripheral resistance in the labile hypertensive subjects. The explanation for this appears to be the duration of infusion rather than the dose.

1. VON EULER, adrenaline

u. S. Some aspects of the role of norand adrenaline in circulation. Am. Heart J., 56: 469, 1958. 2. MANGER, W. M., KHALII., G. LV. and BOLLMAN, J. I,. Chemical Quantitation of Epinephrine and Norepinephrine in the Plasma. Springfield, Ill., 1959. Charles C Thomas. 3. GOLDENRERG, M., PINES, K. L., BALDWIN, E. F., GREEN, D. G. and ROH, C. E. The hemodynamic response of man to norrpincphrinr and epineph-

et al. rinr and its relation to thr problem of hypcrtension. :lm. J. Med., 5: 792, 1948. 4. ‘TUCKMAN. .J. and FINNERTV, I;. A., JR. Cardiac index during intravenous levartcrenol infusion in Czrc7rlntion I3.r.. 7: 988, 1059. man. 5. FOWLER, N. O., \V’ESTC~ITT. R. N., SCOTT, K. C. and MCGLJIRF. .J. ‘The rffrct of norepinephrinr upon pulmonary artrriolar r&stance in man. J. C/in. INWJ~., 30: 517. 1951. 6. PAW.L, U. .J.. IANOE, K. L. and HEWT, H. H. Some rvid?ncc for active constriction in the human pulmonary vascular bed. Ci~culnfion. 18: 19, 1958. 7. COHEN. G., HOLLANI). B.. SH.A, .I. and GOLDENRICRC.M. Plasma concrntrations of rpinephrinc and norepinrphrinr dnrin,q intrac-enous infusion in man. .J. C/:/in. Inwrt.. 38 : 1935, 1959. 8. J. Icstimation of epinrphrine and norrpinrphrinc concentrations in human plasma by In : Symposium thv trihydrosyindole method. on Catecholamines, 1058. Philadelphia, 1959. \Villiams and \Vilkins Co. 13. COHEN, G. and GOLDKNBERG, M. The simultaneous fluorimrtric drtrrmination of adrenaline and norII. Peripheral venous adrenalin? in plasma. plasma concentrations in normal subjects and in patirnts with phrochromocytoma. .J. Nmrochern., 2: 71,1957. 14. PRICE, H. 1,. and PRICE, M. L. Thr chemical Pstimation of rpinephrinr and norepinephrine in human and canine plasma. II. A critique of the trihydroxyindole method. J. Lab. & C/in. Med., 50: 769, 1957.

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