Gerbes, Alexander L.

Jüngst, Dieter

Pilz, A.

Wernze, Heinrich

English

Universität München: Elektronischen Publikationen

Clin Investig (1993) 71 : 894-897 
0riginaJ Article 
Glinical 
Investigator 
© Springer-Verlag 1993 
Renal sodium handling and neurohumoral systems in patients 
with cirrhosis in sitting posture: effects of spironolactone 
and water immersion* 
A.L. Gerbes 1, A. Pilz 1, H. Wernze 2, D. Jiingst 1 
1 Medizinische Klinik II, Klinikum Grol3hadern, Ludwig-Maxirnilians-Universit/it Miinchen 
2 Universit/itsklinik Wiirzburg 
Summary. Renal sodium handling, neurohumoral 
systems, and systemic hemodynamics were investi- 
gated under baseline conditions in sitting posture 
in 10 healthy subjects, 11 patients with cirrhosis 
without, and 10 patients with cirrhosis with ascites. 
Furthermore, the effects of head-out water immer- 
sion, 1-week spironolactone administration, or 
their combination was assessed in the two groups 
of patients. Patients without ascites exhibited a sig- 
nificant increase in plasma norepinephrine concen- 
tration and a tendency toward an increase in plas- 
ma aldosterone concentration. Patients with ascites 
had a significantly lower mean arterial blood pres- 
sure despite significant reduction of urinary sodi- 
um excretion and fractional sodium excretion as 
well as an increase of plasma renin activity, plasma 
aldosterone, and norepinephrine concentration. In 
patients with ascites, the increase in renal sodium 
excretion and fractional sodium excretion follow- 
ing water immersion or spironolactone was clearly 
augmented by the combination of the two maneu- 
vers. The same pattern was observed in patients 
without ascites. Our findings (a) underscore the 
importance of studying hemodynamics, renal func- 
tion, and neurohumoral systems also in upright 
posture, (b) suggest a role of sympatico-adrenergic 
activation and proximal sodium retention in preas- 
citic patients, and (c) are compatible with the vaso- 
dilation hypothesis of ascites formation. 
Key words: Ascites formation - Peripheral vasodi- 
lation - Proximal tubular sodium retention - Liver 
cirrhosis 
New concepts have recently been introduced in the 
understanding of the pathophysiology of ascites 
* Dedicated to Prof. Dr. G. Paumgartner  on the occasion of 
his 60th birthday 
formation and renal sodium retention in cirrhosis 
of the liver (for review see [8]). The seeming contra- 
diction of a reduced centrally effective blood vol- 
ume in the presence of an augmented total blood 
volume in cirrhosis has lately been explained by 
peripheral arterial vasodilation [14]. Compensa- 
tion of peripheral vasodilation in patients with cir- 
rhosis without ascites may be achieved by total 
hypervolemia [1]. The latter may result from renal 
sodium retention due to activation of sodium-re- 
taining neurohumoral systems. This activation is 
generally believed to contribute to ascites forma- 
tion in patients with decompensated cirrhosis [2, 
3, 8]. In patients without ascites, however, incon- 
sistent findings have been reported regarding renal 
sodium handling and activation of the renin-aldos- 
terone system. This may be due in part to the fact 
that patients have usually been investigated in the 
supine position where there may be no central un- 
derfilling whereas subjects normally spend two- 
thirds of a regular day in the upright position [1]. 
Therefore it seemed useful to investigate sub- 
jects in the upright position and also to apply a 
maneuver inducing central volume expansion by 
intravascular fluid shifting, namely head-out water 
immersion [5, 7]. Other groups as well as our own 
have previously demonstrated the usefulness of 
water immersion for investigating neurohumoral 
systems and renal sodium handling [5, 7, 9]. Water 
immersion, by increasing distal tubular sodium de- 
livery [5], may also elucidate the role of proximal 
tubular sodium retention, thought to be important 
particularly in patients with ascites [13]. We also 
studied the effects of the aldosterone antagonist 
spironolactone, acting at the distal tubule. There- 
fore the aim of this study was to compare - in 
cirrhosis with and without ascites in upright pos- 
ture - systemic hemodynamics, renal sodium han- 
dling, the renin-aldosterone system, and plasma 
norepinephrine as an indicator of sympathetic ner- 
vous activity contributing to proximal tubular so- 
895 
dium retention. The effect of head-out water im- 
mersion or spironolactone administration or their 
combination was investigated. 
Patients and methods 
Ten healthy subjects aged 40-65 years (mean 48 ± 
3) and 21 patients with cirrhosis, 11 without ascites 
(61_+2 years) and 10 with ascites (56+3 years), 
were investigated after informed consent had been 
obtained. The protocol was approved by the Ethics 
Committee of the Faculty of Medicine, University 
of Munich. The subjects showed no evidence of 
cardiovascular, renal, pulmonary, or endocrine 
diseases. All subjects were prohibited alcohol, to- 
bacco, tee, and coffee on the day before and during 
the experiment and were on a hospital diet contain- 
ing approximately 150 mEq sodium per day. The 
diagnosis of cirrhosis was established by biopsy 
and clinical and laboratory data. In 11 patients 
no ascites was detected by abdominal ultrasound. 
The etiology of cirrhosis was alcoholic in six, post- 
hepatitic in four, and cryptogenic in one; the 
Child-Pugh classification [~2, 15] was A/B in nine/ 
two of these patients. Ten patients suffered from 
ascites as confirmed by abdominal ultrasound. The 
Child-Pugh classification was B/C in six/four of 
them; the etiology of cirrhosis was alcoholic in 
six, posthepatitic in two, and cryptogenic in two 
patients. Both groups of patients were studied 
without diuretic treatment for 1 week, as reported 
earlier [9], and again following 1 week of spirono- 
lactone (200 mg orally per day). Controls were in- 
vestigated only in baseline conditions. 
In the morning after complete emptying of the 
bladder an intravenous catheter was placed in a 
peripheral vein, patients drank 400 ml water and 
assumed a sitting position. After 1 h the patients 
were immersed to the neck into thermoneutral 
water (34.5_+0.2 ° C) for 1 h, maintaining the same 
sitting position. Patients were told to empty the 
bladder following the preimmersion and the im- 
mersion periods. Blood pressure and heart rate 
were monitored, and blood samples were collected 
before and after J h of immersion. 
Urine was analyzed for sodium by flame photo- 
metry and for creatinine (Jaffe's reaction). Plasma 
renin activity was measured as described previous- 
ly [16]. Plasma aldosterone concentration was de- 
termined with a commercial kit (Diagnostic Prod- 
ucts, Los Angeles, USA). Plasma norepinephrine 
was determined radioenzymatically by a modified 
Peuler-Johnson method [11, 17]. Fractional sodi- 
um excretion was calculated by standard formulas. 
Mean arterial pressure was calculated as the sum 
of diastolic pressure and one-third of the difference 
between systolic and diastolic pressure. Data are 
presented as mean and standard error. The ran- 
dom distribution of data was tested by the Kolmo- 
gorov-Smirnoff test. Statistical evaluation of ran- 
domly distributed data was performed by the un- 
paired t test between groups and by paired t test 
within groups. Nonrandomly distributed data were 
analyzed by Mann-Whitney test between groups 
and by Wilcoxon test within groups. A P value 
of 0.05 or less was considered statistically signifi- 
cant. 
Results 
Comparison of baseline values without diuretics 
of both groups of patients with a group of healthy 
controls of similar age is shown in Table 1. Patients 
with decompensated cirrhosis exhibited a de- 
creased mean arterial blood pressure despite an 
increase in heart rate, plasma renin activity, plasma 
aldosterone concentration, and plasma norepi- 
nephrine concentration, resulting in a reduction in 
urinary sodium excretion and fractional sodium 
excretion. Patients without ascites, not differing 
from controls in blood pressure or heart rate, 
showed a significant elevation in plasma norepi- 
nephrine concentration and a nonsignificant ten- 
dency towards increased plasma renin activity and 
plasma aldosterone concentration and a trend to- 
ward decreased renal sodium excretion and frac- 
tional sodium excretion. 
Patients with as compared to patients without 
ascites exhibited a decrease in mean arterial pres- 
sure despite a further activation of sodium-retain- 
ing hormones and an increased heart rate (Table 
2). Spironolactone administration clearly aug- 
mented urinary sodium excretion and fractional 
sodium excretion in decompensated patients with- 
out affecting the hemodynamics or the neurohu- 
moral systems investigated. The renal effect of spir- 
onolactone was less marked in patients without 
ascites, who exhibited a trend toward activation 
of the renin-aldosterone and sympaticoadrenergic 
systems, almost reaching the level of patients with 
ascites. Water immersion reduced the activation of 
neurohumoral systems in both groups of patients, 
without the concomitant increase in sodium excre- 
tion reaching the level of statistical significance. 
Interestingly, the combination of spironolactone 
and water immersion significantly increased uri- 
nary sodium excretion and fractional sodium ex- 
cretion not only in patients with ascites but also 
in those without ascites. 
896 
Table 1. Baseline hemodynamics, hormonal, and renal parameters in controls and in patients without and in patients without 
ascites, in sitting posture 
Controls Patients without Patients with 
(n = 10) ascites ascites 
(n = I l) (n = I o) 
Mean arterial pressure 86 +- 2 85 -+ 3 78 -+ 3 * 
(ram Hg) 
Heart rate (min/1) 71 ± 2 74-+ 2 83 -+ 3 *' ** 
Plasma renin activity 6-+ 2 9-+ 3 29 -+ 9 * 
(ng AI/ml per hour) 
Plasma aldosterone 13 -+ 3 38 -+ 11 64-+20* 
concentration (ng/100 ml) 
Plasma norepinephrine 227 -+ 23 430 -+ 70" 705 ± 106" 
concentration (pg/ml) 
Urinary sodium excretion 105 -+ 24 74-+ 15 28 -+ 11 *' ** 
(gmol/min) 
Fractional sodium 0.8 _+ 0.2 0.6 -+ 0.1 0.2 ± 0.1 *' ** 
excretion (%) 
* P < 0.05 versus controls, ** P <0.05 versus patients without ascites 
Table 2. Effects of i-week spironolactone administration (200 mg orally per day) or I-h head-out water immersion or combination 
of both maneuvers in patients without and in patients with ascites 
Patients without ascites (n = 11) Patients with ascites (n = 10) 
Without With Without With 
spironolactone spironolactone spironolactone spironolactone 
Mean arterial pressure 
(ram Hg) 
Heart rate (rain/l) 
Plasma renin activity 
(ng AI/ml per hour) 
Plasma aldosterone con- 
centration (ng/100 ml) 
Plasma norepinephrine 
concentration (pg/ml) 
Urinary sodium excretion 
(pmol/min) 
Fractional sodium 
excretion (%) 
Baseline 
Immersion 
Baseline 
Immersion 
Baseline 
Immersion 
Baseline 
Immersion 
Baseline 
Immersion 
Baseline 
Immersion 
Baseline 
Immersion 
85_+ 3 85_+ 3 78_+ 3* 78± 3 
81+_ 3 78± 3"*'**** 72± 3"**  72+ 3**'**** 
74_+ 2 80-+ 3 83-+ 3* 80-+ 2 
77-+ 3** 76-+ 3 84_+ 3 79-+ 3 
9-+ 3 28-+13 29+ 9* 26___ 6 
5-+ 2** 12-+ 5 17-+ 7** 14-+ 3** 
38-+11 • 74±13 64-+20 43-+ 9 
27-+ 9** 39-+ 6** 49-+19 33-+ 8"*'**** 
430-+70 530-+65 705-+ 106 657-+90 
320-+69** 360-+49** 512-+80'* 521 -+78** 
74-+15 130-+54 28-+11" 149_+54"** 
149 -+ 50 170 -+ 28 **** 71 -+ 28 239 -+ 74"**' **** 
0.6-+0.1 0.8-+0.2 0.2-+0.1" 1.8+-0.7"** 
0.9-+0.3 1.5+0.2'*' **** 0.4-+0.1 2.6-+0.9***' **** 
* P <0.05 versus patients without ascites, ** P <0.05 versus before water immersion, *** P < 0.05 versus without spironolactone, 
**** P <0.05 versus before water immersion without spironolactone 
Discussion 
In  the  presen t  inves t iga t ion  we s tudied  sys temic  
h e m o d y n a m i c s ,  n e u r o h u m o r a l  systems,  a nd  renal  
s o d i u m  h a n d l i n g  in pa t ien ts  wi th  c i r rhos is  wi th  and  
w i t h o u t  ascites, ex tend ing  a p rev ious  s tudy  [9]. 
Based  on  recent  f indings  by  Bernard± et al. [1] as 
well as o n  the o b v i o u s  o b s e r v a t i o n  t h a t  h u m a n s  
spend  a b o u t  two- th i rds  o f  the  d a y  in up r i gh t  posi-  
t ion  we used  the  si t t ing pos t u r e  as basa l  cond i t ion .  
Pa t ien ts  w i t h o u t  ascites c o m p a r e d  to  con t ro l s  o f  
s imilar  age s h o w e d  a s ignif icant  e leva t ion  in plas-  
m a  n o r e p i n e p h r i n e  c o n c e n t r a t i o n  as an  ind ica to r  
o f  sympa the t i c  ne rvous  sys tem act ivi ty  and  a ten-  
dency  t o w a r d  an  increased  p l a s m a  a ldos t e ro n e  
concen t r a t i on .  These  n e u r o h u m o r a l  changes  m a y  
resul t  in  the obse rved  t rends  t o w a r d  renal  s o d i u m  
re tent ion.  T h u s  ou r  f indings  are  c o m p a t i b l e  wi th  
the  recent  sugges t ion  by  Bernard± et al. [1] t ha t  
pa t ien ts  w i t h o u t  ascites cou ld  c o m p e n s a t e  for  dila- 
t a t i on  o f  the  sp lanchn ic  vascu la r  bed  t h r o u g h  to ta l  
hype rvo lemia .  F u r t h e r m o r e ,  the increased  s y m p a -  
t i coadrenerg ic  act ivi ty  m a y  cause p r o x i m a l  t u b u l a r  
s o d i u m  re t en t ion  in these pat ients ,  w h o  are  still 
in the state of compensation. This contention is 
supported by the results of the combination of 
water immersion and spironolactone. Patients with 
ascites showed an increase in sodium excretion and 
in fractional sodium excretion upon spironolac- 
tone or water immersion, and the effect of the com- 
bination of these maneuvers was clearly enhanced. 
Interestingly, patients without ascites showed the 
same pattern, especially regarding fractional sodi- 
um excretion. These findings suggest that sympath- 
icoadrenergic activation and proximal sodium re- 
tention, known to be of major importance in pa- 
tients with ascites [2, 4, 6, 10, 13] may play a role 
even in preascitic patients. 
In patients without ascites spironolactone ad- 
ministration tended to increase plasma renin activi- 
ty and norepinephrine concentration, compatible 
with volume depletion following the spironolac- 
tone therapy. These patients reached renin, aldos- 
terone, and norepinephrine concentrations similar 
to baseline values of untreated patients with as- 
cites. In contrast to decompensated patients, how- 
ever, they maintained their mean arterial pressure. 
Thus, the decrease in mean arterial pressure despite 
further activation of sodium-retaining hormones  
and increased heart rate in patients with ascites 
suggests further vasodilation in these decompen- 
sated patients. 
Our findings underscore the importance of 
studying hemodynamics, renal function, and neu- 
rohumoral systems in cirrhosis in the upright pos- 
ture. Our observations are compatible with the va- 
sodilation hypothesis and suggest a continuous de- 
velopment from healthy subjects via the state of 
compensation toward patients with ascites: activa- 
tion of sodium-retaining neurohumoral systems, 
decrease in mean arterial pressure despite an in- 
crease of heart rate and renal sodium retention. 
Acknowledgements. This research was supported by the 
Deutsche Forschungsgemeinschaft (Ge 576). T. Koberling is 
thanked for the preparation of the manuscript. 
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Received: June 21, 1993 
Returned for revision: July 12, 1993 
Accepted: July 15, 1993 
Priv.-Doz. Dr. A.L. Gerbes 
Medizinische Klinik II 
Klinikum Grol3hadern 
Marchioninistrasse 15 
D-81366 Mtinchen 
Germany 


Renal sodium handling and neurohumoral systems in patients with cirrhosis in sitting posture

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Clin Investig (1993) 71 : 894-897 0riginaJ Article Glinical Investigator © Springer-Verlag 1993 Renal sodium handling and neurohumoral systems in patients with cirrhosis in sitting posture: effects of spironolactone and water immersion* A.L. Gerbes 1, A. Pilz 1, H. Wernze 2, D. Jiingst 1 1 Medizinische Klinik II, Klinikum Grol3hadern, Ludwig-Maxirnilians-Universit/it Mi nchen 2 Universit/itsklinik Wiirzburg Summary. Renal sodium handling, neurohumoral systems, and systemic hemodynamics were investi- gated under baseline conditions in sitting posture in 10 healthy subjects, 11 patients with cirrhosis without, and 10 patients with cirrhosis with ascites. Furthermore, the effects of head-out water immer- sion, 1-week spironolactone administration, or their combination was assessed in the two groups of patients. Patients without ascites exhibited a sig- nificant increase in plasma norepinephrine concen- tration and a tendency toward an increase in plas- ma aldosterone concentration. Patients with ascites had a significantly lower mean arterial blood pres- sure despite significant reduction of urinary sodi- um excretion and fractional sodium excretion as well as an increase of plasma renin activity, plasma aldosterone, and norepinephrine concentration. In patients with ascites, the increase in renal sodium excretion and fractional sodium excretion follow- ing water immersion or spironolactone was clearly augmented by the combination of the two maneu- vers. The same pattern was observed in patients without ascites. Our findings (a) underscore the importance of studying hemodynamics, renal func- tion, and neurohumoral systems also in upright posture, (b) suggest a role of sympatico-adrenergic activation and proximal sodium retention in preas- citic patients, and (c) are compatible with the vaso- dilation hypothesis of ascites formation. Key words: Ascites formation - Peripheral vasodi- lation - Proximal tubular sodium retention - Liver cirrhosis New concepts have recently been introduced in the understanding of the pathophysiology of ascites * Dedicated to Prof. Dr. G. Paumgartner on the occasion of his 60th birthday formation and renal sodium retention in cirrhosis of the liver (for review see [8]). The seeming contra- diction of a reduced centrally effective blood vol- ume in the presence of an augmented total blood volume in cirrhosis has lately been explained by peripheral arterial vasodilation [14]. Compensa- tion of peripheral vasodilation i patients with cir- rhosis without ascites may be achieved by total hypervolemia [1]. The latter may result from renal sodium retention due to activation of sodium-re- taining neurohumoral systems. This activation is generally believed to contribute to ascites forma- tion in patients with decompensated cirrhosis [2, 3, 8]. In patients without ascites, however, incon- sistent findings have been reported regarding renal sodium handling and activation of the renin-aldos- terone system. This may be due in part to the fact that patients have usually been investigated in the supine position where there may be no central un- derfilling whereas subjects normally spend two- thirds of a regular day in the upright position [1]. Therefore it seemed useful to investigate sub- jects in the upright position and also to apply a maneuver inducing central volume expansion by intravascular fluid shifting, namely head-out water immersion [5, 7]. Other groups as well as our own have previously demonstrated the usefulness of water immersion for investigating neurohumoral systems and renal sodium handling [5, 7, 9]. Water immersion, by increasing distal tubular sodium de- livery [5], may also elucidate the role of proximal tubular sodium retention, thought o be important particularly in patients with ascites [13]. We also studied the effects of the aldosterone antagonist spironolactone, acting at the distal tubule. There- fore the aim of this study was to compare - in cirrhosis with and without ascites in upright pos- ture - systemic hemodynamics, renal sodium han- dling, the renin-aldosterone system, and plasma norepinephrine as an indicator of sympathetic ner- vous activity contributing to proximal tubular so- 895 dium retention. The effect of head-out water im- mersion or spironolactone administration or their combination was investigated. Patients and methods Ten healthy subjects aged 40-65 years (mean 48 ± 3) and 21 patients with cirrhosis, 11 without ascites (61_+2 years) and 10 with ascites (56+3 years), were investigated after informed consent had been obtained. The protocol was approved by the Ethics Committee of the Faculty of Medicine, University of Munich. The subjects showed no evidence of cardiovascular, enal, pulmonary, or endocrine diseases. All subjects were prohibited alcohol, to- bacco, tee, and coffee on the day before and during the experiment and were on a hospital diet contain- ing approximately 150 mEq sodium per day. The diagnosis of cirrhosis was established by biopsy and clinical and laboratory data. In 11 patients no ascites was detected by abdominal ultrasound. The etiology of cirrhosis was alcoholic in six, post- hepatitic in four, and cryptogenic in one; the Child-Pugh classification [~2, 15] was A/B in nine/ two of these patients. Ten patients uffered from ascites as confirmed by abdominal ultrasound. The Child-Pugh classification was B/C in six/four of them; the etiology of cirrhosis was alcoholic in six, posthepatitic n two, and cryptogenic in two patients. Both groups of patients were studied without diuretic treatment for 1 week, as reported earlier [9], and again following 1 week of spirono- lactone (200 mg orally per day). Controls were in- vestigated only in baseline conditions. In the morning after complete mptying of the bladder an intravenous catheter was placed in a peripheral vein, patients drank 400 ml water and assumed a sitting position. After 1 h the patients were immersed to the neck into thermoneutral water (34.5_+0.2 ° C) for 1 h, maintaining the same sitting position. Patients were told to empty the bladder following the preimmersion and the im- mersion periods. Blood pressure and heart rate were monitored, and blood samples were collected before and after J h of immersion. Urine was analyzed for sodium by flame photo- metry and for creatinine (Jaffe's reaction). Plasma renin activity was measured as described previous- ly [16]. Plasma aldosterone concentration was de- termined with a commercial kit (Diagnostic Prod- ucts, Los Angeles, USA). Plasma norepinephrine was determined radioenzymatically b  a modified Peuler-Johnson method [11, 17]. Fractional sodi- um excretion was calculated by standard formulas. Mean arterial pressure was calculated as the sum of diastolic pressure and one-third of the difference between systolic and diastolic pressure. Data are presented as mean and standard error. The ran- dom distribution of data was tested by the Kolmo- gorov-Smirnoff test. Statistical evaluation of ran- domly distributed ata was performed by the un- paired t test between groups and by paired t test within groups. Nonrandomly distributed data were analyzed by Mann-Whitney test between groups and by Wilcoxon test within groups. A P value of 0.05 or less was considered statistically signifi- cant. Results Comparison of baseline values without diuretics of both groups of patients with a group of healthy controls of similar age is shown in Table 1. Patients with decompensated cirrhosis exhibited a de- creased mean arterial blood pressure despite an increase in heart rate, plasma renin activity, plasma aldosterone concentration, and plasma norepi- nephrine concentration, resulting in a reduction in urinary sodium excretion and fractional sodium excretion. Patients without ascites, not differing from controls in blood pressure or heart rate, showed a significant elevation in plasma norepi- nephrine concentration and a nonsignificant ten- dency towards increased plasma renin activity and plasma aldosterone concentration and a trend to- ward decreased renal sodium excretion and frac- tional sodium excretion. Patients with as compared to patients without ascites exhibited a decrease in mean arterial pres- sure despite a further activation of sodium-retain- ing hormones and an increased heart rate (Table 2). Spironolactone administration clearly aug- mented urinary sodium excretion and fractional sodium excretion in decompensated patients with- out affecting the hemodynamics or the neurohu- moral systems investigated. The renal effect of spir- onolactone was less marked in patients without ascites, who exhibited a trend toward activation of the renin-aldosterone and sympaticoadrenergic systems, almost reaching the level of patients with ascites. Water immersion reduced the activation of neurohumoral systems in both groups of patients, without he concomitant increase in sodium excre- tion reaching the level of statistical significance. Interestingly, the combination of spironolactone and water immersion significantly increased uri- nary sodium excretion and fractional sodium ex- cretion not only in patients with ascites but also in those without ascites. 896 Table 1. Baseline hemodynamics, hormonal, and renal parameters in controls and in patients without and in patients without ascites, in sitting posture Controls Patients without Patients with (n = 10) ascites ascites (n = I l) (n = I o) Mean arterial pressure 86 +- 2 85 -+ 3 78 -+ 3 * (ram Hg) Heart rate (min/1) 71 ± 2 74-+ 2 83 -+ 3 *' ** Plasma renin activity 6-+ 2 9-+ 3 29 -+ 9 * (ng AI/ml per hour) Plasma aldosterone 13 -+ 3 38 -+ 11 64-+20* concentration ( g/100 ml) Plasma norepinephrine 227 -+ 23 430 -+ 70" 705 ± 106" concentration (pg/ml) Urinary sodium excretion 105 -+ 24 74-+ 15 28 -+ 11 *' ** (gmol/min) Fractional sodium 0.8 _+ 0.2 0.6 -+ 0.1 0.2 ± 0.1 *' ** excretion (%) * P < 0.05 versus controls, ** P <0.05 versus patients without ascites Table 2. Effects of i-week spironolactone administration (200 mg orally per day) or I-h head-out water immersion r combination of both maneuvers in patients without and in patients with ascites Patients without ascites (n = 11) Patients with ascites (n = 10) Without With Without With spironolactone spironolactone spironolactone spironolactone Mean arterial pressure (ram Hg) Heart rate (rain/l) Plasma renin activity (ng AI/ml per hour) Plasma aldosterone con- centration (ng/100 ml) Plasma norepinephrine concentration (pg/ml) Urinary sodium excretion (pmol/min) Fractional sodium excretion (%) Baseline Immersion Baseline Immersion Baseline Immersion Baseline Immersion Baseline Immersion Baseline Immersion Baseline Immersion 85_+ 3 85_+ 3 78_+ 3* 78± 3 81+_ 3 78± 3"*'**** 72± 3"** 72+ 3**'**** 74_+ 2 80-+ 3 83-+ 3* 80-+ 2 77-+ 3** 76-+ 3 84_+ 3 79-+ 3 9-+ 3 28-+13 29+ 9* 26___ 6 5-+ 2** 12-+ 5 17-+ 7** 14-+ 3** 38-+11 • 74±13 64-+20 43-+ 9 27-+ 9** 39-+ 6** 49-+19 33-+ 8"*'**** 430-+70 530-+65 705-+ 106 657-+90 320-+69** 360-+49** 512-+80'* 521 -+78** 74-+15 130-+54 28-+11" 149_+54"** 149 -+ 50 170 -+ 28 **** 71 -+ 28 239 -+ 74"**' **** 0.6-+0.1 0.8-+0.2 0.2-+0.1" 1.8+-0.7"** 0.9-+0.3 1.5+0.2'*' *** 0.4-+0.1 2.6-+0.9***' *** * P <0.05 versus patients without ascites, ** P <0.05 versus before water immersion, *** P < 0.05 versus without spironolactone, **** P <0.05 versus before water immersion without spironolactone Discussion In the present invest igation we studied systemic hemodynamics ,  neurohumora l  systems, and renal sod ium handl ing in patients with cirrhosis with and wi thout  ascites, extending a previous study [9]. Based on recent f indings by Bernard± et al. [1] as well as on the obvious observat ion that  humans  spend about  two-thirds o f  the day  in upr ight  posi- t ion we used the sitting posture as basal condit ion.  Patients w i thout  ascites compared  to controls  o f  similar age showed a signif icant elevation in plas- ma norepinephr ine concentrat ion  as an indicator  o f  sympathet ic  nervous system activity and a ten- dency toward  an increased p lasma aldosterone concentrat ion.  These neurohumora l  changes may result in the observed trends toward  renal sod ium retention. Thus our  f indings are compat ib le  with the recent suggest ion by Bernard± et al. [1] that  patients w i thout  ascites could compensate  for dila- tat ion of  the splanchnic vascular bed through total  hypervolemia.  Fur thermore,  the increased sympa-  t icoadrenergic activity may cause prox imal  tubular  sodium retent ion in these patients, who are still in the state of compensation. This contention is supported by the results of the combination of water immersion and spironolactone. Patients with ascites howed an increase in sodium excretion and in fractional sodium excretion upon spironolac- tone or water immersion, and the effect of the com- bination of these maneuvers was clearly enhanced. Interestingly, patients without ascites showed the same pattern, especially regarding fractional sodi- um excretion. These findings uggest that sympath- icoadrenergic activation and proximal sodium re- tention, known to be of major importance in pa- tients with ascites [2, 4, 6, 10, 13] may play a role even in preascitic patients. In patients without ascites spironolactone ad- ministration tended to increase plasma renin activi- ty and norepinephrine concentration, compatible with volume depletion following the spironolac- tone therapy. These patients reached renin, aldos- terone, and norepinephrine concentrations similar to baseline values of untreated patients with as- cites. In contrast o decompensated patients, how- ever, they maintained their mean arterial pressure. Thus, the decrease in mean arterial pressure despite further activation of sodium-retaining hormones and increased heart rate in patients with ascites suggests further vasodilation in these decompen- sated patients. Our findings underscore the importance of studying hemodynamics, renal function, and neu- rohumoral systems in cirrhosis in the upright pos- ture. Our observations are compatible with the va- sodilation hypothesis and suggest a continuous de- velopment from healthy subjects via the state of compensation toward patients with ascites: activa- tion of sodium-retaining eurohumoral systems, decrease in mean arterial pressure despite an in- crease of heart rate and renal sodium retention. Acknowledgements. This research was supported by the Deutsche Forschungsgemeinschaft (Ge 576). T. Koberling is thanked for the preparation of the manuscript. References 1. Bernardi M, Di Marco C, Trevisani F, De CoIlibus C, For- nal6 L, Baraldini M, Andreone P, Cursaro C, Zacfi F, Li- gabue A, Gasbarrini G (1992) Hemodynamic status of pre- ascitic irrhosis : an evaluation under steady state conditions and after postural change. Hepatology 16:341-346 2. Bichet DG, van Punen VJ, Schrier RW (1982) Potential role of increased sympathetic activity in impaired sodium 897 and water excretion in cirrhotic patients. N Engl J Med 307:1552-1557 3. Bosch J, Arroyo V, Betriv A, Mas A, Rivera F, Navarro- Lopez F, Rodes J (1980) Hepatic hemodynamics and the renin-angiotensin-aldosterone system in cirrhosis. Gas- troenterology 78: 92-99 4. DiBona GF (1982) The function of renal nerves. Rev Phys- iol Biochem Pharmacol 94: 75-i 81 5. Epstein M, Saruta T (1971) Effect of water immersion on renin-aldosterone and renal sodium handling in normal man. J Appl Physiol 31:368-374 6. Epstein M, Pins DS, Schneider N, Levinson R (1976) Deter- minants of deranged sodium and water homeostasis in de- compensated cirrhosis. J Lab Clin Med 87:822-839 7. Gauer OH, Henry JP, Behn C (1970) The regulation of extrace!lular fluid volume. Annu Rev Physiol 1970:547-595 8. Gerbes AL (1991) Pathophysiology of ascites formation in cirrhosis of the liver. Hepatogastroenterology 38:360-364 9. Gerbes AL, Wernze H, Arendt RM, Riedel A, Sauerbruch T, Paumgartner G (1989) Atrial natriuretic factor and renin- aldosterone in volume regulation of patients with cirrhosis. Hepatology 9: 417-422 I0. Henriksen JH, Ring-Larsen H, Christensen NJ (1985) Cir- culating noradrenaline and central haemodynamics in pa- tients with cirrhosis. Scand J Gastroenterol 20:1185-1190 11. Peuler JD, Johnson GA (1977) Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, pineph- rine and dopamine. Life Sci 21:625-636 12. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni ML, Williams R (1973) Transsection of oesophagus for bleeding oesophageal varices. Br J Surg 60 : 646-649 13. Sch6tmerich J (1991) Aszites. Springer, Berlin Heidelberg New York 14. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J (1988) Peripheral rterial vasodilation hypothe- sis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 8 : 1151-1157 15. Terblanche J, Northover JMA, Bornman P, Kahn D, Silber W, Barbezat GO, Sellars S, Campbell JAH, Saunders SJ (1979) A prospective controlled trial of sclerotherapy in the long term management of patients after oesophageal vari- ceal bleeding. Surg Gynecol Obstet 148:323-333 16. Wernze H, Spech HI, Mfiller G (1978) Studies on the activi- ty of the renin-angiotensin-aldosterone syst m (RAAS) in patients with cirrhosis of the liver. Klin Wochenschr 36:389-397 17. Wernze H (1983) Endokrinologische Diagnostik des Hoch- drucks. In: Kfihn HA, Lasch HG (eds) Untersuchungsme- thoden und Funktionsprfifungen in der Inneren Medizin. Thieme, Stuttgart, pp 110-123 Received: June 21, 1993 Returned for revision: July 12, 1993 Accepted: July 15, 1993 Priv.-Doz. Dr. A.L. Gerbes Medizinische Klinik II Klinikum Grol3hadern Marchioninistrasse 15 D-81366 Mtinchen Germany 

A prospective controlled trial of sclerotherapy in the long term management of patients after oesophageal variceal bleeding.

Atrial natriuretic factor and reninaldosterone in volume regulation of patients with cirrhosis.

Determinants of deranged sodium and water homeostasis in decompensated cirrhosis.

Effect of water immersion on renin-aldosterone and renal sodium handling in normal man.

Endokrinologische Diagnostik des Hochdrucks. In: Kfihn HA, Lasch HG (eds) Untersuchungsmethoden und Funktionsprfifungen in der Inneren Medizin.

Hemodynamic status of preascitic cirrhosis : an evaluation under steady state conditions and after postural change.

Hepatic hemodynamics and the renin-angiotensin-aldosterone system in cirrhosis.

Pathophysiology of ascites formation in cirrhosis of the liver.

Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.

Potential role of increased sympathetic activity in impaired sodium and water excretion in cirrhotic patients.

Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine.

Studies on the activity of the renin-angiotensin-aldosterone system (RAAS) in patients with cirrhosis of the liver.

The function of renal nerves.

The regulation of extrace!lular fluid volume.

Transsection of oesophagus for bleeding oesophageal varices.

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Renal sodium handling and neurohumoral systems in patients with cirrhosis in sitting posture

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