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Plasma norepinephrine concentrations: No differences among normal volunteers and low, high or normal renin hypertensive patients
Pergamon Press
Life Sciences Vol . 22, pp . 1499-1510 Printed in the U .S .A .
PLASMA NOREPINEPHRINE CONCENTRATIONS : NO DIFFERENCES AMONG NORMAL VOLUNTEERS AND LOW, HIGH OR NORMAL RENIN HYPERTENSIVE PATIENTS Addison A. Taylor, James L . Pool, C . Raymond Lake, Michael G. 2legler, Robert A. Rosen, Douglas E. Rollins and Jerry R. Mitchell Hypertension-Endocrine Branch and the Section on Clinical Pharmacology and Metabolism, National Heart, Lung, and Blood Institute, and the Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20014 (Received in final form March 7, 1978) Summary Plasma norepinephrine concentrations were measured by a sensitive radioenzymatic method in 51 patients with essential hypertension and 26 age-matched normal volunteers under conditions of ad libitum sodium intake, after volume expansion by infusion of saline intravenously, and after volt+ma contraction by administration of furosemide orally . The hypertenaive patienta were classified into low, normal and high renia groupa both by renia-sodium indexing and by their renia response to furosemide and saline administration . Plasma norepinephrine concentrations were similar among normal volunteers and patients with low, normal or high renia hypertension while the people were either recumbent or after they stood for 5 min . These and other results do not support the hypothesis that abnormal activity of the sympathetic nervous system accounts for the low or high renia values seen in many hypertenaive patients . The sympathetic nervous system is critical for the maintenance of blood pressure in man. In addition to direct effects oa cardiac hemodynamics and oa blood vessel tone (1), the sympathetic system can secondarily affect blood pressure through regulation of fluid volume by altering secretion of renin by the kidneys (2) . It was recently postulated that sympathetic activity is as important determinant of the low (3) or high (4,5), plasma renia activity observed in some hypertensioe patients . To examine this possibility more carefully we measured plasma norepinephrine, as an indicator of sympathetic neural activity, by a sensitive radioeazymatic method (6) in hypertensioe patients who were classified into ream subgroups by ream-sodium indexing and by furoaemide administration or saline infusion . Methods Fifty-one hyperteasive patienta
(22 females, 29 males) and 26 normo-
Address reprint requests to : Dr . Addieoa A . Taylor, Department of Internal Medicine, Baylor College of Medicine, Houston, Texas 77030.
0300-9653/78/0501-1499502 .00/0 Copyright © 1978 Pergamon Press
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tensive volunteers (11 females, 15 males) were studied on a metabolic ward at the National Institutes of Health . The investigation was approved by the National Heart, Lung and Blood Institute Human Research Review Committee . Each subject gave written informed consent prior to participating is the study. All hypertensioe patients had multiple blood pressure values greater than 140/90 mmHg when determined at home (blood pressure recorded by the patient 3-4 times per day) and by one of us in the Hypertension Clinic . All antihypertensive medications were discontinued at leant 3 weeks prior to the study. Secondary forms of hypertension were excluded by history and physical examination, measurements of urinary and plasma aldosterone, determination of routine serum chemistries including potassium, and performance of rapidsequence intravenous urography . Renal arteriography and renal vein resin sampling were performed in selected patients . Plasma resin activity was measured at Hazleton Laboratories (Government contract $NIH 273-76-C-0641CC) by radioimmunoaoeay of generated angioteaein I (7) . Blood was obtained in both hypertensioe and normotensive people after 3 hours of upright posture while sodium intake was unrestricted . The resin values were plotted against daily urinary sodium excretion as as approximation of the patient's state of sodium balance (resin-sodium indexing) (8) . Subjects were then given 40 mg furoaemide orally at 0800 hours, 1200 hours and 1800 The hours and their sodium intake was restricted to 10 mEq during that day . next morning subjects walked quietly for 2 hours before blood was obtained . Low resin hypertensioe patients were defined as those whose values were less than 4 ng/ml/hr, the lowest of the resin values in a group of 32 age-matched normal volunteers evaluated by the same teat (8) . Volume expansion was induced in patients at bedrent by infusion of 2L of 0.9% saline intravenously over a 4-hr interval and then blood was obtained for determination of plasma resin activity . Patients whose plasma resin activity did not suppress below the upper limits of normal values (1 ng/ml/hr) were considered to have high resin hypertension (8) . Plasma norepinephrine was measured in all subjects under 3 different conditions : 1) during unrestricted dietâry sodium intake, 2) after the intravenous infusion of 2L of 0.9Z saline over 4 hours and 3) after administration of 120 mg furoaemide in 3 divided doses and ingestion of a 10 mEq sodium diet over 24 hours . An indwelling plastic catheter was inserted into a forearm vein ; after 30 minutes in the supine position and again after standing for 5 minutes, the subject's blood pressure and pulse ware recorded and blood for determination of plasma norepinephrine was collected in tubes containing acid-citratedextroae anticoagulant and stored on ice until plasma was separated and frozen . Plasma norepinephrine was measured by a radioenzymatic method (6) . Data were analyzed statistically by Student's "t" test (grouped data) and by linear regression analysis according to tha method of least squares (individual values) (9) . Results Two different methods were used to categorize the hypertensioe patiente by renia subgroup ; the renia-sodium index and the resin response to administration of furonemide and saline . Hypertenaive patients were not consistently divided into the same renia subgroups by these two methods since their criteria for identifying normal versus low versus high resin categories differ (8) . Connequently, the plasma norepinephrine and hemodynamic responses of the hyperteasive patients to standing and to volume contraction and expansion have been analysed first according to resin classification by renia-sodium index and again by renia response to furoaemide and saline administration .
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Benin Clase ificat ion ~Renin-Sodium Index Hypertensioe patients were divided into low, normal and high renia groupe depending on whether their plasma renia activity after 3 hours of upright posture vs . 24 hour excretion of sodium on an ad libitum sodium diet was above, within or below the range of values obtained is 89 normal volunteers under similar conditions (8) . Plasma norepinphrine concentrations were measured in 26 of these 89 normal subjects . Selected characteristics of these 26 normal subjects and of the 51 patienta classified as normal, low and high renia by renia-sodium index are compared in Table 1 . Patienta with low and normal renia hypertension were somewhat older than volunteers or those with high renia hypertension . Outpatient mean arterial pressure of high renia hypertensives was slightly lower than that of normal renia patients (P G .05) but not significantly different from that of low renia patiente (P 7 .1) . Mean plasma aorepinephriae concentrations obtained while patients were supine were not significantly different in the normal volunteer group from the low, normal or high renia groups (P ~ .05 for each intergroup comparison) classified by renin-sodium indexing (Fig . 1) . Although mean plasma norepinephriae concentrations increased in each of the 4 groups after 5 min . of TABLE 1 CLASSIFICATION BY BENIN-SODIUM INDER
Age (yrs)
Normal Subjects(26) 40 + 3*
Mean arterial pressure (mmHg)
89 + 2
Renia Class of Hypertensioe Patiente Low (11) Normal (34) High (6) 49 + 3 47 + 2 38 + 6 116 + 3
120 + 1
0 .4
0 .5 + 0 .3
3 .8 + 2 .3
13 .6 + 6 .0
Standing PRA after furosemide (ng/ml/hr) 9 .8 + 0 .2
3 .4 + 1 .3
9 .0 + 5 .8
8 .8 + 3 .0
Supine PRA before saline (ag/ml/hr) 1 .4 + 0 .2
0 .3 + 0 .2
2 .0 + 1 .4
5 .8 + 3 .3
Supine PRA after saline (ng/ml/hr) 0 .4 + 0 .05
0 .2 + 0 .2
0 .7 + 0 .6
1 .4 + 1 .1
Standing PRA** after ad lib diet (ag/ml/hr) 3 .2
115 + 3
Supine pulse+ (beats/min)
76 + 8
71 + 2
75 + 2
66 + 3
Standing pulae~ (beats/min)
72 + 3
77 + 3
87 + 3
79 + 3
( ) ~ number of subjects ; * ~ Mean + SEM ; ** ~ Plasma renia ac ivity . Pulse obtained after patienta were supine+ for 30 min . or standing ~ for 5 mis .
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CLASSIFICATION BY RENIN - SODIUM INDEX 1250
z m x
1000
d W o ,., z_ E < b d W
750
S00
"
""
A
"
z
d H
e
Y50
-__
Z
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N L Lib Ne Ad
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L
Saline
N
H~
_1_
_L_ T
t t
0
Z
_s_
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T
t V
L N Furosemide
H
FIG . 1 Supine values for plasma norepinephrine during ad libitum sodium intake (left), after infusion of 2L of saline intravenously (middle) and after oral administration of 120 mg furosemide (right) in normal volunteers (V) and in patiente with eeeantial hypertenaioa classified as low (L), normal (N) and high (H) renia by renia-urinary sodium indexing (8) . Dots represent individual values . Horizontal solid lines indicate mean values for the groupe sad dashed lines reflect + SFM . standing (supine vs . standing values for each group, P ~ .05) (Fig . 2), the increase upong standing was similar in all groupe (P ~ .05 for each intergroup comparison) . Saline infusion did not alter supine or standing values or the increases in standing compared to supine values in any of the groupa when compared with the values obtained on an ad libitum sodium diet (P ~ .05 for. each intergroup comparison) (Fig . 1,2) . Following furoaemide administration, supine values for plasma norepinephrine in patients with high renia hyperteaaion were leas than the norepinephrine values is normal renia patients (1 .005) but not significantly lower than corresponding values is normal volunteers (P 7 .1) or in patients with low renia hypertension (P ~ .1) due to the variability in the values in these last 2 groups (Fig . 1) . Values in the high renia group after 5 mis . of standing were slightly but not significantly (P~ .1) lower than mesa plasma norepinephrine concentrations in each of the other 3 groupe (Fig . 2) .
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CLASSIFICATION BY RENIN-SODIUM INDEX .~
1500
1250
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1000
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1656
750
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FIG . 2 Values for plasma norepinephriae after 5 min. of standing in the same groups, following the same treatments and classified by the same renia-urinary sodium indexing method as in Fig. 1. Hospitalization resulted in the well documented lowering of mean arterial pressure in most hypertensive patients (Table 2) compared to values obtained in the outpatient clinic (Table 1) . Ia the hospital mean arterial pressures both in the supine and standing positions tended to be slightly lower in high ream and slightly higher in normal resin patients than in low ream hypertensive patients during unrestricted sodium intake or after saline administration (fable 2) . An increase was seen is the standing versus supine mean arterial pressure in the high resin group following furoaemide administration whereas either no change or a decrease occurred in the standing versus supine presaurea is the other 3 groups . In spite of these blood pressure differences, the absolute or incremental values for plasma norepinephriae were not significantly correlated with corresponding mean arterial pressure values in any of the hypertenaive groups after furoaemide-induced volume depletion. In contrast, there were significant correlations between plaam norepinephriae concentrations
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TABLE 2 CLASSIFICATION BY BENIN-SODIUM INDEXING
Normal Subjects (26) mean + SEM
Re~in Class of Hypertensive Patients Low (11) Normal (34) High (6)
89 + 1+ 87 + 3 -2 _+ 3
111 + 4 113 + 3 +2 _+ 2
116 + 3 117 + 3 +1 + 1
103 + 4~ 104 + 3 +1 + 5
Saline MAP-supine MAP-standing MAP - net change (standing-supine)
92 + 2+ 94 + 2 +2 _+ 2
114 + 5 117 + 5 +1 _+ 3
118 + 2 123 + 2 +4 _+ 2
111 + 4 112 + 3~ +1 + 5
Furoaemide MAP-supine MAP-standing MAP - net change (standing-supine)
86 + 2+ 81 + 4+ -5 _+ 4
102 + 4 98 + 4 -3 _+ 3
104 + 2 104 + 4 0 _+ 3
98 + 1$ 107 + 5 +9 _+5**
Ad lib Na MAP*-supine MAP-standing MAP - net change (standing-supine)
( ) ~ number of subjects ; * ~ mean arterial pressure (pulse pressure/3 + diastolic blood pressure) in mmHg . Values obtained from patients who were supine or standing for 5 min. or the difference of these 2 values (net change) under the three test conditions are tabulated; + - significantly different from all ream subgroups of hypertensive patients (P -significantly leas than normal renia hypertensive group (P ** ~ significantly different from normal volunteers (P < .05) .
L .05) ;
4 .O1) ;
and mean arterial pressure in normal volunteers while they were supine during unrestricted sodium intake (r - .495, P < .05), while standing after saline administration (r .~ .431, P ~ .05), and in both supine (r = .535, P x .05) and standing (r . .414, P x .05) positions following administration of furoaemide . There were, however, no significant correlations in this group between the increases in plasma norepinephriae concentrations upon standing and the corresponding changes in mean arterial pressure either when sodium intake was unrestricted or after acute volume expansion or contraction. Benin Classification by Benin Response to Furosemide and Saline Characteristics of these same 51 hypertensive patiente reclassified into normal or low renia categories by the furoaemide teat (8) or into a high renia group by the saline teat (8) are presented in Table 3. The mean age of the 25 normal renia patients and 16 low renia patienta was higher than the mean age of either the 10 high renia hypertensive patients or 26 normal subjects . Mean arterial pressures in the outpatient clinic were not significantly different among the 3 groupe of hypertensive patients . Since patienta with low renia were selected by their abnormally low response to a potent stimulus of renia secretion, the mean poet-furosemide renia activity in these patienta was lower when employing the furosemide and saline criteria than the renia-sodium index criteria for classification (Tables 1, 3) . Conversely, supine values for plasma renia activity after saline infusion were higher in high renia patiente
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Normal Norapinephrine is Hypertension
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TABLE 3 CLASSIFICATION BY FUROSEMIDE AND SALINE
Age (yrs)
Normal Subjecta(26) 40 + 3*
Mean arterial pressure (mmHg)
89 + 2
Renia Class of Aypertensive Patients Low (16) Normal (25) High (10) 51 + 2 40 +.4 47 + 2 119 + 2
118 + 1
121 + 1
Standing PRA** after ad lib diet (ng/ml/hr) 3.2 + 0.4
1 .7 + 0 .4
3.6 + 0 .6
9 .9 + 1 .9
Standing PRA after furoaemide (ag/ml/hr) 9.8 + 2 .0
1 .7 + 0.2
10 .1 + 1 .1
10 .3 + 1 .2
Supine PRA before saline (ng/ml/hr) 1 .4 + 0 .2
0 .7 + 0.2
1.7 + 0 .2
4 .9 + 0.8
Supine PRA after saline (ng/ml/hr)
0.3 + 0.06
0 .4 + 0 .04
1.9 + 0 .2
(
0 .4 + 0 .05
) = number of subjects ; * ~ mean + SEM; ** = Plasma renin activity
than the values observed in nox~al or low renia hypertensivea or normal volunteers. No significant differences in plasma norepinephrine concentrations were found among the normal volunteers and the ream subgroups of hypertensivea patients when they were classified by the furoaemide and saline teats (Fig . 3, 4) . Plasma norepinephrine values when patieata were standing were approximately 65% greater than the values obtained whoa the groups were supine (Fig . 3, 4) . Saline infusion did not significantly affect either supine (Fig . 3) or standing (Fig . 4) values for plasma norepinephrine in any of the 4 groups . Supine and standing values for plasma norepinephrine in all groups were increased following administration of 120 mg furoaemide as compared to the corresponding values obtained after saline infusion or an ad libitum sodium diet . These increases in plasma norepinephrine were not accounted for by changes in mean arterial pressure, since neither the absolute values for this parameter nor the changes produced by standing versus recumbency (Table 4) were significantly correlected with plasma norepinephrine concentrations in any of the hypertensive subgroups. Mean arterial pressure increased in the high ream group upon standing after furoaemide whereas it fell in normal and low ream hypertensive and normal volunteer groups (Table 4) . The percent decrease from initial body weight and the 24-hr urinary excretion of sodium and volume during furoaemide administration were measured to examine the possibility that less reduction in body fluid volume in the high ream compared to other hypertensive groups or volunteers after diuretic administration might account for the observed differences There were no significant in the arterial pressure responses to standing . differences in the percent change in body weight after furoaemide adminiatra-
Normal Norepinaphriae in Hypertension
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Vol . 22, No . 17, 1978
CLASSIFICATION BY FUROSEMIDE AND SALINE 1250
W z oc x d W z
d W 0 z .~ < E N G < -. d W z d N
1000
750 "
" 500
"
"
"
r
A
"
N
H
e
250 "s
_
Z
_
#. _~ .
_~_ - _*_ ~ "
0
V
L
N
H
V
L
N
Saline
Ad Lib Na
H
~
I
s V
L
Furosemide
FIG . 3 Supine values for plasma aorepinephrine during ad libitum sodium intake (left), after infusion of 2 L of of saline intravenously (middle) and after oral administration of 120 mg furosemide (right) in normal volunteers (V) and in patients with essential hypertension classified as low (L) or normal (N) renia by response to furosemide and as high renia (H) by response to saline infusion . Dots represent individual values . Horizontal solid lines indicate mean values for the groups and dashed lines represent + SEM . tioa compared to pretreatment values in high renia (-2 .13 + 0 .32 kg/kg initial body weight R 100, mean _+ SEM) compared to normal (-2 .67 _+0 .19) or low (-2 .02 _+ 0 .21) renia hypertensives or to normal volunteers (-2 .45 _+ 0 .27) (P .1) . Values for 24-hr urine sodium and volume (per kg body weight X 100) were 357 + 50 mEq and 4454 + 437 ml in high renia, 396 + 31 mEq and 5340 + 298 ml in low renia patients and 408 _+ normal renia, 373 + 29 mEq and 5069 + 494 ml 20 mEq and 5224 + 281 ml in normal volunteers . There were no significant differences in these values among of the groupe (P> .1 for all comparisons) . In addition,~no significant differences were observed between males and females for each of these three parameters in any of the four groupe (P> .1 for all comparisons) .
in
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Normal Norepinephrine in Hypertension
Vol . 22, No . 17, 1978
CLASSIFICATION 0Y FUROSEMIDE AND SALINE 1500
1P50 W
z
1000
d W = ti
_ I50
e
d z
c z <
-ai
r 500
_ ._
250
0
~. .
___
s ; i V
L N Ad Lib Nt
_s_ ..
T
i t
H
V
t
___
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-s-
t
"
t
i
N L Sellne
H
I
V
L N Furosemide
H
FIG . 4 Values for plasma norepinephrine after 5 min . of standing in the same groups, following the same treatments and classified by renia response to furosemide and saline as indicated in Fig . 3 . Discussion The sympathetic nervous system is known to be a mediator of the secretion of ream by the kidney (2) . It has recently been suggested that sympathetic neural activity may even be the dominant factor in the regulation of ream secretion in patients with hypertension . In support of this proposal plasma norepinephrine concentrations in the resting state have been reported to be high in high ream hypertensioe patients (4,5) whereas they were low in those patients with low ream and they did not increase appropriately after sympathetic nervous system stimulation of low ream patients by head-up tilt (3) . In two of these three studies (3,4) hypertensioe patients were grouped into high, normal and low categories according to their ream response to 1 hr . of upright posture during unrestricted sodium intake compared to plasma ream activity in 41 age-matched normotensive volunteers studied by the same procedure .
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Normal Norepinephrine in Hypertension
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TABLE 4 CLASSIFICATION BY FUROSEMIDE AND SALINE Normal Subjects (26) Ad lib Na MAP* - supine MAP - standing MAP - net change (standing-supine)
Renia Class of Hypertenaive Patient Low (16) Normal (25) High (10)
mean + SEM 89 + 1+ 87 + 3+ -2 _+ 3
117 + 3 117 + 4 0 _+ 1
109 + 3 112 + 2 +3 _+ 1
118 + 6 116 + 4 -2 _+ 4
92 + 2+ 94 + 2+ +2 _+ 2
116 + 4 120 + 4 +4 _+ 7
116 + 2 120 + 2 +4 _+ 5
118 + 4 121 + 5 +3 _+ 4
86 + 2+ 81 + 4 -5 + 4
101 + 3 98 + 4 -3 + 2
103 + 2 101 + 4 -2 + 4
111 + 5 118 + 5$ +8 + 4**
Saline MAP - supine MAP - standing MAP -net change (standing - supine) Furosemide MAP - supine MAP - standing MAP - net change
( ) - number of subjects ; * - mean arterial pressure in mmHg ; + ~ significantly different from all renia subgroups of hypertensive patienta (P< .O1) ; + aignificaatly different from normal and low renie subgroups (P< .05) ; ** _ significantly different from low renia hypertensive and normal volunteer groups (Pc .05) . Aypertenaive patients in the third study (5) were classified in the low ream group when plasma ream activity after oral administration of 80 mg furosemide and 1 hr . of standing was less than 2 S .D . below the mean values in 20 normal volunteers . Conversely, plasma resin activity in their high resin hypertensive group was greater than 2 S .D . above the mean value for 54 normotenaive volunteers when all subjects were studied after being recumbent for 1 hr . on a diet containing 100 - 180 mEq sodium/day . The two methods employed in the present study to classify hypertensive patients by resin sbugroup were different from those utilized by other investigators (3-5) . Our finding that the resin category of any one patient may vary according to the type of test used underscores one of the difficulties in comparing our results with those of other studies (3-5) . However, the results of the present study do not support the concluaioa that abnormal sympathetic neural activity, as measured by plasma norepinephrine, is primarily responsible for the low and high resin values observed in our patienta with essential hyperRegardless of the method used to divide patients into the various tension . resin categories, neither those with low nor high resin had recumbent values for plasma norepinephrine different from normal volunteers or normal resin The increase in hypertensive patients during unrestricted sodium intake . plasma norepinephrine concentrations in response to standing was neither impaired in low resin patients nor exaggerated in those with high resin
hol . 22, No . 17, 1979
Normal Norepinaphriae in Hypertension
1509
hypertension . After furoaemide-induced volume contraction, which is a more potent stimulus to renia secretion than standing, plasma renia activity remained low in low resin patients in spite of increases in both recumbent and standing values for plasma norepinephriae comparable to the increases measured in normal renia hypeitensives and in volunteers . Low ream patients increase their cyclic adenosine 3'S'-monophosphate concentrations in plasma to the same extent as normal ream patients during stimulation of the sympathetic nervous system by insulin-induced hypoglycemia but fail to increase their plasma ream activity (10) . Moreover, infusion of direct agoniste, such as norepinephriae (3,11,12) or theophylline (10), fails to elevate plasma renia activity normally in low ream patients in comparison with normal ream hyperteasives or normal volunteers although the heart rate response to catecholaminea is not impaired (3) . Thus, these data are consistent with the view that the low plasma ream activity in most patients with essential hypertension is due to a primary renal defect in ream secretion and is not a consequence of diminished activity of the sympathetic nervous system . In contrast to previous reports (4,5), neither supine nor standing values for plasma norepinephriae in the 6 hypertensioe patients in this study with high ream by ream-sodium indexing or the 10 patients in this study with elevated ream after the saline infusion test were greater than those of volunteers . In fact, supine values for plasma norepinephriae in the high renia patients classified by renia-sodium indexing were slightly lower after furosemide administration than those of normal subjects or of normal or low ream patients . Since plasma norepinephriae concentrations increase with age (13), the younger mean age of the high ream patients may account in part for their slightly lower plasma norepinephriae concentrations after furosemide . The alight reduction in standing values for plasma norepinephriae in the high ream group after furosemide might also reflect a decreased need for sympathetic nervous system-mediated vasconstriction since blood pressure increased with standing only is this group . There was no evidence, however, that the increase in standing blood pressure and the lower plasma norepinephriae values in the high ream group could be accounted for by lean volume reduction after furosemide since the diuretic produced similar effects on body weight and on sodium and volume excretion in the high ream compared to other hypertenaive groups or volunteers when conditions were carefully controlled on a metabolic ward . The severity of hypertension in our ream groups were approximately equal both at home (data not shown) and during hospitalization (Tables 1-4) . Thin is important because plasma catecholaminea have been shown to increase as diastolic blood pressure increases (14,15), and high plasma ream activity is associated with accelerated forms of hypertension (16) . Thus, elevated values for both catecholaminea and ream will occur in some hypertensioe patients . Although the measurement of norepinephriae is plasma provides a more dynamic assessment of sympathetic nervous system function than does the determination of urinary catecholamines, better biochemical and pharmacological methods are needed for evaluating sympathetic neuronal activity . Studies that evaluate the production and metabolism of catechols and other vasoactive amines by various organs including the central nervous system will be critical in establishing the precise role of the sympathetic nervous system in the initiation and maintenance of hypertension in man. Acknowled~ements We wish to thank Dr . Robert Goldberg of Rutgers University and the National Institutes of Health, Division of Computer Research and Technology for their development and support of the Biomedical Research Information
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Normal Norepinephrine in Hyperteasion
Vol . 22, No . 17, 1978
Gathering and Handling Tool (Bright) program used to store and analyze the patient data generated during this study. References 1. 2. 3. 4. 5. 6. 7. 8. 9.
10 . 11 . 12 . 13 . 14 . 15 . 16 .
A. J . EDIS, J. T. SHEPHERD, Arch . Intern . Med . 125 716-724 (1970) . J . 0. DAVIS, R. H. FREEMAN, Phyeiol . Rev . _56 1-56 (1976) . M. ESLER, 0 . RANDALL, J. BENNETT, A. ZWEIFLER, S . JULIUS, P . RYDELER, E. COHEN, V . DeQUATTRO, The Lancet _2 115-118 (1976) . M. ESLER, S . JULIUS, A. ZWEIFLER, 0 . RANDALL, E. HARBURG, H. GARDINER, V . DeQUATTRO, New Engl J . Med . _296, 405-411 (1977) . V . DeQUATTRO, V. CAMPESE, Y . MIURA, D . MEIJER, Am . J . Cardiol _38 801-804 (1976) . C . R. LAKE, M. G. ZIEGLER, I. J. KOPIN, Life Sci . _18 1315-1325 (1976) . J . MENARD, K. J . CATT, Endocrinology _90 422-430 (1972) . J . R. MITCHELL, A . A. TAYLOR, J . L. POOL, C . R. LABE, D . E . ROLLILAS, F . C . BARTTER, Ann. Intern . Med . _87 596-612 (1977) . R . D . Remington and M. A . Schark, S tatistics with Applications to the Biological and Health Sciences , pp . 213 and 274, Prentice-Hall, Englewood Cliffs, NJ (1970) . S . C . LOWDER, P. HAMET, G . W. LIDDLE, Circ . Res . _38 105-108 (1976) . A . JOSE, J . R. CROUT, N. M. KAPLAN, Ann . Intern . Med . _72 9-16 (1970) . N . D . VLACHAKIS, L. R . RRAKOFF, M. MENDLOWITZ, Clin . Res . _25 550A (1977) . M . E . ZIEGLER, C . R. LABE, I. J. KOPIN, Nature _261 333-335 (1976) . W . J . LOUIS, A. E . DOYLE, S. ANAVEYAR, New Engl . J. Med . _288 559-601 (1973) . J . deCHAMPLAIN, L . FARLEY, D. COUSINEAU, M. vanAMIItINGEN, Circ . Rea . _38 109-114 (1976) . R . G . McALLISTER, C . W. VANWAY, R. DAYANI, W. J . ANDERSON, F. TEMPLE, A . M . MICHELAKIS, W. S . COPPAGE, J. A. OATES, Circ . Res . (Suppl . 2) _28 II-160 - II-173 (1971) .
Life Sciences Vol . 22, pp . 1499-1510 Printed in the U .S .A .
PLASMA NOREPINEPHRINE CONCENTRATIONS : NO DIFFERENCES AMONG NORMAL VOLUNTEERS AND LOW, HIGH OR NORMAL RENIN HYPERTENSIVE PATIENTS Addison A. Taylor, James L . Pool, C . Raymond Lake, Michael G. 2legler, Robert A. Rosen, Douglas E. Rollins and Jerry R. Mitchell Hypertension-Endocrine Branch and the Section on Clinical Pharmacology and Metabolism, National Heart, Lung, and Blood Institute, and the Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20014 (Received in final form March 7, 1978) Summary Plasma norepinephrine concentrations were measured by a sensitive radioenzymatic method in 51 patients with essential hypertension and 26 age-matched normal volunteers under conditions of ad libitum sodium intake, after volume expansion by infusion of saline intravenously, and after volt+ma contraction by administration of furosemide orally . The hypertenaive patienta were classified into low, normal and high renia groupa both by renia-sodium indexing and by their renia response to furosemide and saline administration . Plasma norepinephrine concentrations were similar among normal volunteers and patients with low, normal or high renia hypertension while the people were either recumbent or after they stood for 5 min . These and other results do not support the hypothesis that abnormal activity of the sympathetic nervous system accounts for the low or high renia values seen in many hypertenaive patients . The sympathetic nervous system is critical for the maintenance of blood pressure in man. In addition to direct effects oa cardiac hemodynamics and oa blood vessel tone (1), the sympathetic system can secondarily affect blood pressure through regulation of fluid volume by altering secretion of renin by the kidneys (2) . It was recently postulated that sympathetic activity is as important determinant of the low (3) or high (4,5), plasma renia activity observed in some hypertensioe patients . To examine this possibility more carefully we measured plasma norepinephrine, as an indicator of sympathetic neural activity, by a sensitive radioeazymatic method (6) in hypertensioe patients who were classified into ream subgroups by ream-sodium indexing and by furoaemide administration or saline infusion . Methods Fifty-one hyperteasive patienta
(22 females, 29 males) and 26 normo-
Address reprint requests to : Dr . Addieoa A . Taylor, Department of Internal Medicine, Baylor College of Medicine, Houston, Texas 77030.
0300-9653/78/0501-1499502 .00/0 Copyright © 1978 Pergamon Press
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tensive volunteers (11 females, 15 males) were studied on a metabolic ward at the National Institutes of Health . The investigation was approved by the National Heart, Lung and Blood Institute Human Research Review Committee . Each subject gave written informed consent prior to participating is the study. All hypertensioe patients had multiple blood pressure values greater than 140/90 mmHg when determined at home (blood pressure recorded by the patient 3-4 times per day) and by one of us in the Hypertension Clinic . All antihypertensive medications were discontinued at leant 3 weeks prior to the study. Secondary forms of hypertension were excluded by history and physical examination, measurements of urinary and plasma aldosterone, determination of routine serum chemistries including potassium, and performance of rapidsequence intravenous urography . Renal arteriography and renal vein resin sampling were performed in selected patients . Plasma resin activity was measured at Hazleton Laboratories (Government contract $NIH 273-76-C-0641CC) by radioimmunoaoeay of generated angioteaein I (7) . Blood was obtained in both hypertensioe and normotensive people after 3 hours of upright posture while sodium intake was unrestricted . The resin values were plotted against daily urinary sodium excretion as as approximation of the patient's state of sodium balance (resin-sodium indexing) (8) . Subjects were then given 40 mg furoaemide orally at 0800 hours, 1200 hours and 1800 The hours and their sodium intake was restricted to 10 mEq during that day . next morning subjects walked quietly for 2 hours before blood was obtained . Low resin hypertensioe patients were defined as those whose values were less than 4 ng/ml/hr, the lowest of the resin values in a group of 32 age-matched normal volunteers evaluated by the same teat (8) . Volume expansion was induced in patients at bedrent by infusion of 2L of 0.9% saline intravenously over a 4-hr interval and then blood was obtained for determination of plasma resin activity . Patients whose plasma resin activity did not suppress below the upper limits of normal values (1 ng/ml/hr) were considered to have high resin hypertension (8) . Plasma norepinephrine was measured in all subjects under 3 different conditions : 1) during unrestricted dietâry sodium intake, 2) after the intravenous infusion of 2L of 0.9Z saline over 4 hours and 3) after administration of 120 mg furoaemide in 3 divided doses and ingestion of a 10 mEq sodium diet over 24 hours . An indwelling plastic catheter was inserted into a forearm vein ; after 30 minutes in the supine position and again after standing for 5 minutes, the subject's blood pressure and pulse ware recorded and blood for determination of plasma norepinephrine was collected in tubes containing acid-citratedextroae anticoagulant and stored on ice until plasma was separated and frozen . Plasma norepinephrine was measured by a radioenzymatic method (6) . Data were analyzed statistically by Student's "t" test (grouped data) and by linear regression analysis according to tha method of least squares (individual values) (9) . Results Two different methods were used to categorize the hypertensioe patiente by renia subgroup ; the renia-sodium index and the resin response to administration of furonemide and saline . Hypertenaive patients were not consistently divided into the same renia subgroups by these two methods since their criteria for identifying normal versus low versus high resin categories differ (8) . Connequently, the plasma norepinephrine and hemodynamic responses of the hyperteasive patients to standing and to volume contraction and expansion have been analysed first according to resin classification by renia-sodium index and again by renia response to furoaemide and saline administration .
Vol . 22, No . 17, 1978
Normal Norepinephrine in Hypertension
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Benin Clase ificat ion ~Renin-Sodium Index Hypertensioe patients were divided into low, normal and high renia groupe depending on whether their plasma renia activity after 3 hours of upright posture vs . 24 hour excretion of sodium on an ad libitum sodium diet was above, within or below the range of values obtained is 89 normal volunteers under similar conditions (8) . Plasma norepinphrine concentrations were measured in 26 of these 89 normal subjects . Selected characteristics of these 26 normal subjects and of the 51 patienta classified as normal, low and high renia by renia-sodium index are compared in Table 1 . Patienta with low and normal renia hypertension were somewhat older than volunteers or those with high renia hypertension . Outpatient mean arterial pressure of high renia hypertensives was slightly lower than that of normal renia patients (P G .05) but not significantly different from that of low renia patiente (P 7 .1) . Mean plasma aorepinephriae concentrations obtained while patients were supine were not significantly different in the normal volunteer group from the low, normal or high renia groups (P ~ .05 for each intergroup comparison) classified by renin-sodium indexing (Fig . 1) . Although mean plasma norepinephriae concentrations increased in each of the 4 groups after 5 min . of TABLE 1 CLASSIFICATION BY BENIN-SODIUM INDER
Age (yrs)
Normal Subjects(26) 40 + 3*
Mean arterial pressure (mmHg)
89 + 2
Renia Class of Hypertensioe Patiente Low (11) Normal (34) High (6) 49 + 3 47 + 2 38 + 6 116 + 3
120 + 1
0 .4
0 .5 + 0 .3
3 .8 + 2 .3
13 .6 + 6 .0
Standing PRA after furosemide (ng/ml/hr) 9 .8 + 0 .2
3 .4 + 1 .3
9 .0 + 5 .8
8 .8 + 3 .0
Supine PRA before saline (ag/ml/hr) 1 .4 + 0 .2
0 .3 + 0 .2
2 .0 + 1 .4
5 .8 + 3 .3
Supine PRA after saline (ng/ml/hr) 0 .4 + 0 .05
0 .2 + 0 .2
0 .7 + 0 .6
1 .4 + 1 .1
Standing PRA** after ad lib diet (ag/ml/hr) 3 .2
115 + 3
Supine pulse+ (beats/min)
76 + 8
71 + 2
75 + 2
66 + 3
Standing pulae~ (beats/min)
72 + 3
77 + 3
87 + 3
79 + 3
( ) ~ number of subjects ; * ~ Mean + SEM ; ** ~ Plasma renia ac ivity . Pulse obtained after patienta were supine+ for 30 min . or standing ~ for 5 mis .
Vol . 22, No . 17, 1978
Normal Norepiaephrine in Hypertension
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CLASSIFICATION BY RENIN - SODIUM INDEX 1250
z m x
1000
d W o ,., z_ E < b d W
750
S00
"
""
A
"
z
d H
e
Y50
-__
Z
V
N L Lib Ne Ad
" V
L
Saline
N
H~
_1_
_L_ T
t t
0
Z
_s_
I
T
t V
L N Furosemide
H
FIG . 1 Supine values for plasma norepinephrine during ad libitum sodium intake (left), after infusion of 2L of saline intravenously (middle) and after oral administration of 120 mg furosemide (right) in normal volunteers (V) and in patiente with eeeantial hypertenaioa classified as low (L), normal (N) and high (H) renia by renia-urinary sodium indexing (8) . Dots represent individual values . Horizontal solid lines indicate mean values for the groupe sad dashed lines reflect + SFM . standing (supine vs . standing values for each group, P ~ .05) (Fig . 2), the increase upong standing was similar in all groupe (P ~ .05 for each intergroup comparison) . Saline infusion did not alter supine or standing values or the increases in standing compared to supine values in any of the groupa when compared with the values obtained on an ad libitum sodium diet (P ~ .05 for. each intergroup comparison) (Fig . 1,2) . Following furoaemide administration, supine values for plasma norepinephrine in patients with high renia hyperteaaion were leas than the norepinephrine values is normal renia patients (1 .005) but not significantly lower than corresponding values is normal volunteers (P 7 .1) or in patients with low renia hypertension (P ~ .1) due to the variability in the values in these last 2 groups (Fig . 1) . Values in the high renia group after 5 mis . of standing were slightly but not significantly (P~ .1) lower than mesa plasma norepinephrine concentrations in each of the other 3 groupe (Fig . 2) .
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CLASSIFICATION BY RENIN-SODIUM INDEX .~
1500
1250
W
Z s d W
1000
Z d W K Z
N" d C7 z
1656
750
"
_ _
"
e 500 - i
_s_
i_ 250
0
1
r~ i
V
v
.. a
;
N L Ad Lib Ne
"
i
i
I
H
V
r »
=__
_7_ "
e
"
~
e
e
i t "
N L Seline
H
I
,
V
L N Furosemide
H
FIG . 2 Values for plasma norepinephriae after 5 min. of standing in the same groups, following the same treatments and classified by the same renia-urinary sodium indexing method as in Fig. 1. Hospitalization resulted in the well documented lowering of mean arterial pressure in most hypertensive patients (Table 2) compared to values obtained in the outpatient clinic (Table 1) . Ia the hospital mean arterial pressures both in the supine and standing positions tended to be slightly lower in high ream and slightly higher in normal resin patients than in low ream hypertensive patients during unrestricted sodium intake or after saline administration (fable 2) . An increase was seen is the standing versus supine mean arterial pressure in the high resin group following furoaemide administration whereas either no change or a decrease occurred in the standing versus supine presaurea is the other 3 groups . In spite of these blood pressure differences, the absolute or incremental values for plasma norepinephriae were not significantly correlated with corresponding mean arterial pressure values in any of the hypertenaive groups after furoaemide-induced volume depletion. In contrast, there were significant correlations between plaam norepinephriae concentrations
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Vol. 22, No . 17, 1978
TABLE 2 CLASSIFICATION BY BENIN-SODIUM INDEXING
Normal Subjects (26) mean + SEM
Re~in Class of Hypertensive Patients Low (11) Normal (34) High (6)
89 + 1+ 87 + 3 -2 _+ 3
111 + 4 113 + 3 +2 _+ 2
116 + 3 117 + 3 +1 + 1
103 + 4~ 104 + 3 +1 + 5
Saline MAP-supine MAP-standing MAP - net change (standing-supine)
92 + 2+ 94 + 2 +2 _+ 2
114 + 5 117 + 5 +1 _+ 3
118 + 2 123 + 2 +4 _+ 2
111 + 4 112 + 3~ +1 + 5
Furoaemide MAP-supine MAP-standing MAP - net change (standing-supine)
86 + 2+ 81 + 4+ -5 _+ 4
102 + 4 98 + 4 -3 _+ 3
104 + 2 104 + 4 0 _+ 3
98 + 1$ 107 + 5 +9 _+5**
Ad lib Na MAP*-supine MAP-standing MAP - net change (standing-supine)
( ) ~ number of subjects ; * ~ mean arterial pressure (pulse pressure/3 + diastolic blood pressure) in mmHg . Values obtained from patients who were supine or standing for 5 min. or the difference of these 2 values (net change) under the three test conditions are tabulated; + - significantly different from all ream subgroups of hypertensive patients (P -significantly leas than normal renia hypertensive group (P ** ~ significantly different from normal volunteers (P < .05) .
L .05) ;
4 .O1) ;
and mean arterial pressure in normal volunteers while they were supine during unrestricted sodium intake (r - .495, P < .05), while standing after saline administration (r .~ .431, P ~ .05), and in both supine (r = .535, P x .05) and standing (r . .414, P x .05) positions following administration of furoaemide . There were, however, no significant correlations in this group between the increases in plasma norepinephriae concentrations upon standing and the corresponding changes in mean arterial pressure either when sodium intake was unrestricted or after acute volume expansion or contraction. Benin Classification by Benin Response to Furosemide and Saline Characteristics of these same 51 hypertensive patiente reclassified into normal or low renia categories by the furoaemide teat (8) or into a high renia group by the saline teat (8) are presented in Table 3. The mean age of the 25 normal renia patients and 16 low renia patienta was higher than the mean age of either the 10 high renia hypertensive patients or 26 normal subjects . Mean arterial pressures in the outpatient clinic were not significantly different among the 3 groupe of hypertensive patients . Since patienta with low renia were selected by their abnormally low response to a potent stimulus of renia secretion, the mean poet-furosemide renia activity in these patienta was lower when employing the furosemide and saline criteria than the renia-sodium index criteria for classification (Tables 1, 3) . Conversely, supine values for plasma renia activity after saline infusion were higher in high renia patiente
Vol . 22, No . 17, 1978
Normal Norapinephrine is Hypertension
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TABLE 3 CLASSIFICATION BY FUROSEMIDE AND SALINE
Age (yrs)
Normal Subjecta(26) 40 + 3*
Mean arterial pressure (mmHg)
89 + 2
Renia Class of Aypertensive Patients Low (16) Normal (25) High (10) 51 + 2 40 +.4 47 + 2 119 + 2
118 + 1
121 + 1
Standing PRA** after ad lib diet (ng/ml/hr) 3.2 + 0.4
1 .7 + 0 .4
3.6 + 0 .6
9 .9 + 1 .9
Standing PRA after furoaemide (ag/ml/hr) 9.8 + 2 .0
1 .7 + 0.2
10 .1 + 1 .1
10 .3 + 1 .2
Supine PRA before saline (ng/ml/hr) 1 .4 + 0 .2
0 .7 + 0.2
1.7 + 0 .2
4 .9 + 0.8
Supine PRA after saline (ng/ml/hr)
0.3 + 0.06
0 .4 + 0 .04
1.9 + 0 .2
(
0 .4 + 0 .05
) = number of subjects ; * ~ mean + SEM; ** = Plasma renin activity
than the values observed in nox~al or low renia hypertensivea or normal volunteers. No significant differences in plasma norepinephrine concentrations were found among the normal volunteers and the ream subgroups of hypertensivea patients when they were classified by the furoaemide and saline teats (Fig . 3, 4) . Plasma norepinephrine values when patieata were standing were approximately 65% greater than the values obtained whoa the groups were supine (Fig . 3, 4) . Saline infusion did not significantly affect either supine (Fig . 3) or standing (Fig . 4) values for plasma norepinephrine in any of the 4 groups . Supine and standing values for plasma norepinephrine in all groups were increased following administration of 120 mg furoaemide as compared to the corresponding values obtained after saline infusion or an ad libitum sodium diet . These increases in plasma norepinephrine were not accounted for by changes in mean arterial pressure, since neither the absolute values for this parameter nor the changes produced by standing versus recumbency (Table 4) were significantly correlected with plasma norepinephrine concentrations in any of the hypertensive subgroups. Mean arterial pressure increased in the high ream group upon standing after furoaemide whereas it fell in normal and low ream hypertensive and normal volunteer groups (Table 4) . The percent decrease from initial body weight and the 24-hr urinary excretion of sodium and volume during furoaemide administration were measured to examine the possibility that less reduction in body fluid volume in the high ream compared to other hypertensive groups or volunteers after diuretic administration might account for the observed differences There were no significant in the arterial pressure responses to standing . differences in the percent change in body weight after furoaemide adminiatra-
Normal Norepinaphriae in Hypertension
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Vol . 22, No . 17, 1978
CLASSIFICATION BY FUROSEMIDE AND SALINE 1250
W z oc x d W z
d W 0 z .~ < E N G < -. d W z d N
1000
750 "
" 500
"
"
"
r
A
"
N
H
e
250 "s
_
Z
_
#. _~ .
_~_ - _*_ ~ "
0
V
L
N
H
V
L
N
Saline
Ad Lib Na
H
~
I
s V
L
Furosemide
FIG . 3 Supine values for plasma aorepinephrine during ad libitum sodium intake (left), after infusion of 2 L of of saline intravenously (middle) and after oral administration of 120 mg furosemide (right) in normal volunteers (V) and in patients with essential hypertension classified as low (L) or normal (N) renia by response to furosemide and as high renia (H) by response to saline infusion . Dots represent individual values . Horizontal solid lines indicate mean values for the groups and dashed lines represent + SEM . tioa compared to pretreatment values in high renia (-2 .13 + 0 .32 kg/kg initial body weight R 100, mean _+ SEM) compared to normal (-2 .67 _+0 .19) or low (-2 .02 _+ 0 .21) renia hypertensives or to normal volunteers (-2 .45 _+ 0 .27) (P .1) . Values for 24-hr urine sodium and volume (per kg body weight X 100) were 357 + 50 mEq and 4454 + 437 ml in high renia, 396 + 31 mEq and 5340 + 298 ml in low renia patients and 408 _+ normal renia, 373 + 29 mEq and 5069 + 494 ml 20 mEq and 5224 + 281 ml in normal volunteers . There were no significant differences in these values among of the groupe (P> .1 for all comparisons) . In addition,~no significant differences were observed between males and females for each of these three parameters in any of the four groupe (P> .1 for all comparisons) .
in
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Normal Norepinephrine in Hypertension
Vol . 22, No . 17, 1978
CLASSIFICATION 0Y FUROSEMIDE AND SALINE 1500
1P50 W
z
1000
d W = ti
_ I50
e
d z
c z <
-ai
r 500
_ ._
250
0
~. .
___
s ; i V
L N Ad Lib Nt
_s_ ..
T
i t
H
V
t
___
T
-s-
t
"
t
i
N L Sellne
H
I
V
L N Furosemide
H
FIG . 4 Values for plasma norepinephrine after 5 min . of standing in the same groups, following the same treatments and classified by renia response to furosemide and saline as indicated in Fig . 3 . Discussion The sympathetic nervous system is known to be a mediator of the secretion of ream by the kidney (2) . It has recently been suggested that sympathetic neural activity may even be the dominant factor in the regulation of ream secretion in patients with hypertension . In support of this proposal plasma norepinephrine concentrations in the resting state have been reported to be high in high ream hypertensioe patients (4,5) whereas they were low in those patients with low ream and they did not increase appropriately after sympathetic nervous system stimulation of low ream patients by head-up tilt (3) . In two of these three studies (3,4) hypertensioe patients were grouped into high, normal and low categories according to their ream response to 1 hr . of upright posture during unrestricted sodium intake compared to plasma ream activity in 41 age-matched normotensive volunteers studied by the same procedure .
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Normal Norepinephrine in Hypertension
Vol . 22, No . 17, 1978
TABLE 4 CLASSIFICATION BY FUROSEMIDE AND SALINE Normal Subjects (26) Ad lib Na MAP* - supine MAP - standing MAP - net change (standing-supine)
Renia Class of Hypertenaive Patient Low (16) Normal (25) High (10)
mean + SEM 89 + 1+ 87 + 3+ -2 _+ 3
117 + 3 117 + 4 0 _+ 1
109 + 3 112 + 2 +3 _+ 1
118 + 6 116 + 4 -2 _+ 4
92 + 2+ 94 + 2+ +2 _+ 2
116 + 4 120 + 4 +4 _+ 7
116 + 2 120 + 2 +4 _+ 5
118 + 4 121 + 5 +3 _+ 4
86 + 2+ 81 + 4 -5 + 4
101 + 3 98 + 4 -3 + 2
103 + 2 101 + 4 -2 + 4
111 + 5 118 + 5$ +8 + 4**
Saline MAP - supine MAP - standing MAP -net change (standing - supine) Furosemide MAP - supine MAP - standing MAP - net change
( ) - number of subjects ; * - mean arterial pressure in mmHg ; + ~ significantly different from all renia subgroups of hypertensive patienta (P< .O1) ; + aignificaatly different from normal and low renie subgroups (P< .05) ; ** _ significantly different from low renia hypertensive and normal volunteer groups (Pc .05) . Aypertenaive patients in the third study (5) were classified in the low ream group when plasma ream activity after oral administration of 80 mg furosemide and 1 hr . of standing was less than 2 S .D . below the mean values in 20 normal volunteers . Conversely, plasma resin activity in their high resin hypertensive group was greater than 2 S .D . above the mean value for 54 normotenaive volunteers when all subjects were studied after being recumbent for 1 hr . on a diet containing 100 - 180 mEq sodium/day . The two methods employed in the present study to classify hypertensive patients by resin sbugroup were different from those utilized by other investigators (3-5) . Our finding that the resin category of any one patient may vary according to the type of test used underscores one of the difficulties in comparing our results with those of other studies (3-5) . However, the results of the present study do not support the concluaioa that abnormal sympathetic neural activity, as measured by plasma norepinephrine, is primarily responsible for the low and high resin values observed in our patienta with essential hyperRegardless of the method used to divide patients into the various tension . resin categories, neither those with low nor high resin had recumbent values for plasma norepinephrine different from normal volunteers or normal resin The increase in hypertensive patients during unrestricted sodium intake . plasma norepinephrine concentrations in response to standing was neither impaired in low resin patients nor exaggerated in those with high resin
hol . 22, No . 17, 1979
Normal Norepinaphriae in Hypertension
1509
hypertension . After furoaemide-induced volume contraction, which is a more potent stimulus to renia secretion than standing, plasma renia activity remained low in low resin patients in spite of increases in both recumbent and standing values for plasma norepinephriae comparable to the increases measured in normal renia hypeitensives and in volunteers . Low ream patients increase their cyclic adenosine 3'S'-monophosphate concentrations in plasma to the same extent as normal ream patients during stimulation of the sympathetic nervous system by insulin-induced hypoglycemia but fail to increase their plasma ream activity (10) . Moreover, infusion of direct agoniste, such as norepinephriae (3,11,12) or theophylline (10), fails to elevate plasma renia activity normally in low ream patients in comparison with normal ream hyperteasives or normal volunteers although the heart rate response to catecholaminea is not impaired (3) . Thus, these data are consistent with the view that the low plasma ream activity in most patients with essential hypertension is due to a primary renal defect in ream secretion and is not a consequence of diminished activity of the sympathetic nervous system . In contrast to previous reports (4,5), neither supine nor standing values for plasma norepinephriae in the 6 hypertensioe patients in this study with high ream by ream-sodium indexing or the 10 patients in this study with elevated ream after the saline infusion test were greater than those of volunteers . In fact, supine values for plasma norepinephriae in the high renia patients classified by renia-sodium indexing were slightly lower after furosemide administration than those of normal subjects or of normal or low ream patients . Since plasma norepinephriae concentrations increase with age (13), the younger mean age of the high ream patients may account in part for their slightly lower plasma norepinephriae concentrations after furosemide . The alight reduction in standing values for plasma norepinephriae in the high ream group after furosemide might also reflect a decreased need for sympathetic nervous system-mediated vasconstriction since blood pressure increased with standing only is this group . There was no evidence, however, that the increase in standing blood pressure and the lower plasma norepinephriae values in the high ream group could be accounted for by lean volume reduction after furosemide since the diuretic produced similar effects on body weight and on sodium and volume excretion in the high ream compared to other hypertenaive groups or volunteers when conditions were carefully controlled on a metabolic ward . The severity of hypertension in our ream groups were approximately equal both at home (data not shown) and during hospitalization (Tables 1-4) . Thin is important because plasma catecholaminea have been shown to increase as diastolic blood pressure increases (14,15), and high plasma ream activity is associated with accelerated forms of hypertension (16) . Thus, elevated values for both catecholaminea and ream will occur in some hypertensioe patients . Although the measurement of norepinephriae is plasma provides a more dynamic assessment of sympathetic nervous system function than does the determination of urinary catecholamines, better biochemical and pharmacological methods are needed for evaluating sympathetic neuronal activity . Studies that evaluate the production and metabolism of catechols and other vasoactive amines by various organs including the central nervous system will be critical in establishing the precise role of the sympathetic nervous system in the initiation and maintenance of hypertension in man. Acknowled~ements We wish to thank Dr . Robert Goldberg of Rutgers University and the National Institutes of Health, Division of Computer Research and Technology for their development and support of the Biomedical Research Information
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Normal Norepinephrine in Hyperteasion
Vol . 22, No . 17, 1978
Gathering and Handling Tool (Bright) program used to store and analyze the patient data generated during this study. References 1. 2. 3. 4. 5. 6. 7. 8. 9.
10 . 11 . 12 . 13 . 14 . 15 . 16 .
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