Gerbes

Laffi

Lenz

Petrillo

Salerno

English

Gerbes, Alexander L.

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

Vol. 10, No. 5, 1989 HEPATOLOGY Elsewhere 897 the present study, high enkephalin levels were restricted to patients with ascites. Finally, most other peptides and amines found in increased circulating levels in patients with advanced cirrhosis (e.g. insulin, renin, catechol- amines) have an enhanced release rate-and not an impaired hepatic inactivation-as the main cause of the increased plasma levels (5, 6). However, in my opinion, an enhanced release of methionine enkephalin would be equally interesting. As admitted by the authors, there is experimental evidence of the co-release of methionine enkephalin and epinephrine from the adrenal glands during sympathetic activation, which is in accord with the positive correla- tion between plasma methionine enkephalin and epi- nephrine demonstrated in their study. Thus, the in- creased methionine enkephalin might simply follow the sympathoadrenal overactivity in the same way as neu- ropeptide Y follows the release of norepinephrine. Like most previous reports on endogenous vasodi- lators, Thornton and coworkers did not find any rela- tionship between the circulating level of the potential vasodilator and the decreased arterial blood pressure. This may be due to the fact that a t  least three powerful vasoconstrictor systems (renin-angiotensin-aldosterone, sympathoadrenal and vasopressin) may compensate for the fall in arterial blood pressure (1). The authors propose that increased plasma opioid peptide activity increases histamine release, which in turn leads to increased lymphatic permeability in the liver, lymph leakage and ascites formation. However, available evidence suggests that microvascular permea- bility is decreased in the cirrhotic liver, with defenestra- tion and appearance of a basement membrane (6). More likely, in my opinion, would be an effect of histamine on sinusoidal pressure (7). Moreover, these patients do not show signs of general edema due to lymphatic leakage, as one would expect if a blood-borne substance had increased the lymphatic permeability. Although some aspects of Thornton and coworkers’ interpretation may be questioned, the essential finding of a highly increased endogenous, vasodilator peptide is very important, and future longitudinal studies during development of hepatic ascites are anticipated with in- terest. JENS H. HENRIKSEN, M.D. Department of Clinical Physiology Hvidovre University Hospital DK-2650 Copenhagen, Denmark REFERENCES Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988 81151- 1157. Imura H, Kato Y ,  Nakai Y, et al. Endogenous opioids and related peptides: from molecular biology to clinical medicine. J Endocrinol 1985; 107:147-157. Szabo B, Hedler L, Ensinger H, et al. Opioid peptides decrease noradrenaline release and blood pressure in the rabbit at peripheral receptors. Naunyn-Schmiedeberg’s Arch Exp Pathol Pharmakol 1986; 33250-56. 4. Guillemin R. Endorphins, enkephalins, and other opioid peptides: their significance in physiology and medicine. In: Wyngaarden JB, Smith LH Jr, eds. Cecil textbook of medicine. Philadelphia: W. B. Saunders Co., 1985: 1234-1237. 5. Arroyo V, Bosch J ,  Mauri M, et al. Renin, aldosterone, and renal haemodynamics in cirrhosis with ascites. Eur J Clin Invest 1979; 9:69-73. 6. Keller U, Gerber PPG, Buhler FR, et al. Role of the splanchnic bed in extracting circulatory adrenaline and noradrenaline in nor- mal subjects and in patients with cirrhosis of the liver. Clin Sci 7. Henriksen JH, Thorn T, Christoffersen P. The blood-lymph barrier in the liver. A review based on morphological and functional concepts of normal and cirrhotic liver. Liver 1984; 4:221-232. 1984; 67~45-49. AUGMENTATION OF THE NATRIURETIC RESPONSE TO ATRIAL NATRIURETIC FACTOR IN CIRRHOSIS Ganger DR, Gottstein J,  Blei AT. Hemodynamic and renal effects of atrial natriuretic factor in portal hyper- tensive rats. Potentiation by Phe-Ile-Om-vasopressin. J Pharmacol Exp Ther 1988; 246941-945. ABSTRACT The effects of atrial natriuretic factor (ANF) on splanchnic hemodynamics and renal function in portal hypertensive models are described incom- pletely. Furthermore, ANF-induced vasodilata- tion and hypotension may limit the assessment of its own renal physiological effects. We infused ANF (human ANF 102-126) to anesthetized portal vein-ligated rats, a model with prehepatic portal hypertension. Arterial pressure was reduced by 1796, but portal pressure was unaffected. Diuresis and natriuresis were explained in part by an in- crease in glomerular filtration rate; in addition, renal vascular resistance was significantly de- creased. The natriuretic response to ANF was slightly, but significantly, decreased in portal hy- pertensive rats as compared to controls (fractional excretion of sodium, 1.8 f 0.4 us. 2.9 f 0.3; P < .05). The addition of Phe-Ile-Orn-vasopressin, a V 1 receptor agonist, normalized arterial pressure but induced a significant decrease in the portal pressure (15 f 0.9 mm Hg base line us. 12.8 f 0.7 combination group; P < .01). Furthermore, the combination of both drugs markedly potentiated the natriuretic effects (0.4 2 0.1 pEq/min of con- trol us. 10.0 f 2.3 ANF us. 32.2 f 3.3 combination group; P < .001). The natriuretic potentiation re- sulted from increments in glomerular filtration rate and renal blood flow. Normalization of arte- rial pressure may enhance the renal physiological effects of ANF, in this portal hypertensive model. COMMENTS Identification, characterization and synthesis of atrial natriuretic factor (ANF) has raised considerable interest regarding volume regulation in cirrhosis (1). The natri- HEPATOLOGY Elsewhere HEPATOLOGY 898 uresis observed subsequent to administration of ANF is due to several factors, e.g. increase in glomerular filtra- tion rate (GFR), inhibition of tubuloglomerular feedback, induction of medullary “washout” and direct inhibition of tubular sodium reabsorption, the relative effects of which are difficult to determine. In addition, ANF sup- presses plasma concentrations of renin and aldosterone by inhibiting the synthesis of aldosterone and by block- ing the release of renin and aldosterone (1). ANF is of considerable therapeutic interest in cirrhosis with its proximal and distal tubular sodium retention and acti- vation of the renin-aldosterone system due to decreased, centrally effective, intravascular volume. In patients with cirrhosis, particularly those with as- cites, response to stimulation of endogenous release of ANF (2) as well as to low-dose infusion of synthetic ANF seems to be blunted (3). The reduced response might be due to alterations in the status of renal ANF receptors and/or to systemic and renal hemodynamic abnormali- ties. Several investigations support the contention that the decrease in mean arterial pressure following ANF administration in cirrhosis mediates the blunted natri- uresis (4-6). Following a bolus administration of 1 pg per kg ANF, mean arterial pressure decreased by 18 f 3 mmHg in cirrhotic patients compared to 9 k 2 mmHg in control subjects (4). Thus, cirrhotic subjects with an activated renin-angiotensin-aldosterone system seem particularly sensitive to the vasodilatory effects of ANF. Natriuretic response of ANF (50 pg bolus followed by 50 ng per kg.min infusion) in cirrhosis with ascites was more pronounced in those patients with lower basal plasma renin activity and plasma aldosterone concentra- tions (5). In contrast, patients with an activated renin- aldosterone system show further increase of plasma renin activity after ANF, concomitant with a decrease of renal plasma flow and of GFR, and no increase of natriuresis. In another study, the increase of natriuresis was in- versely related to changes in plasma renin activity, blood pressure and heart rate induced by ANF (6). Therefore, in cirrhotic patients with ascites, low-dose infusions of ANF (50 or 60 ngper kg-min) of ANF may induce greater natriuresis than high-dose infusions (75 or 300 ng per kg- min) (6). Thus, renal response to ANF administration may be optimized by a dosage large enough to induce natriuresis but small enough to avoid systemic hemody- namic alterations that activate compensatory responses. Alternatively, ANF-induced hypotension might be pre- vented by coadministration of vasconstrictor substances. Vasopressin (VP) would seem a suitable candidate with considerable natriuretic potential in patients with ascites and impaired renal function (7). In the study of Ganger et al. under comment, the effects of ANF were investigated in rats with portal hypertension induced by portal vein constriction. Infu- sion of ANF in high dose (500 ng per kg - min) induced a similar decrease of mean arterial pressure to that seen in control rats and only a small decrease in natriuresis. Interpretation of these data is somewhat difficult since no baseline renal perfusion and function values for the control group were provided. The second part of this pared the effects of an infusion of ANF (500 ng per kg. min) and of VP (5 ng per kg-min) individually and together. Indeed, the ANF-induced decrease in mean arterial pressure was prevented by the co-infusion of VP. Renal blood flow and GFR, which were only slightly affected by either agent alone, were increased signifi- cantly by the combination. The most remarkable find- ings were the potentiation of natriuresis and of diuresis by the combined infusion. Thus, in this model of portal hypertension, coadministration of VP with ANF over- came hypotension, the limiting factor for ANF adminis- tration, and potentiated the natriuresis and diuresis. If further studies in animal models confirm these findings, clinical trials of ANF together with vasopressin should be 1. 2. 3. 4. 5. 6. 7. undertaken. ALEXANDER L. GERBES, M.D. Medizinische Klinik II Klinikum Grosshadern University of Munich Marchionistr. 15 0-8000 Miinchen 70 Federal Republic of Germany REFERENCES Gerbes AL, Arendt RM, Paumgartner G. Editorial review. Atrial natriuretic factor-possible implications in liver disease. J Hepatol Gerbes AL, Wernze H, Arendt RM, et al. Atrial natriuretic factor and renin-aldosterone in volume regulation of patients with cirrho- sis. Hepatology 1989; 9:417-422. Gerbes AL, Arendt RM, Stangl E, et al. Characterization of the ANF system in patients with cirrhosis of the liver. In: Forssman WG, Scheuermann DW, Alt J, eds. Functional morphology of the endocrine heart. Darmstadt: Steinkopff, 1988 229-234. Salerno F, Badalamenti S, Incerti P, et al. Renal response to atrial natriuretic peptide in patients with advanced liver cirrhosis. He- patology 1988; 8:21-26. Laffi G, Pinzani M, Meacci E, et al. Renal hemodynamic and natriuretic effects of human atrial natriuretic factor infusion in cirrhosis with ascites. Gastroenterology 1989; 96167-177. Petrillo A, Scherrer U, Gonvers J, et al. Atrial natriuretic peptide administered as intravenous infusion or bolus injection to patients with liver cirrhosis and ascites. J Cardiovasc Pharmacol 1988 1987; 5~123-132. 12:279-285. Lenz K. Hortnagl H. Drum1 W. et al. Beneficial effect of 8-ornithine - .  vasopressin on renal dysfunction in decompensated cirrhosis. Gut 1989 30:90-96. HEPATOLOGY EZsewhere CORRESPONDENCE ANIMAL MODELS FOR ALCOHOLIC LIVER DISEASE To the Editor: We agree with most of the comments made in Dr. Mezey’s review of the paper of Ainley et al. in HEPA- TOLOGY Elsewhere (Hepatology 1989; 9:904). However, we disagree when Dr. Mezev writes that the intragastric Y u paper provides fascinating data. The investigators com- tube feeding rat model of experimental liver disease does 

Atrial natriuretic peptide administered as intravenous infusion or bolus injection to patients with liver cirrhosis and ascites.

Characterization of the ANF system in patients with cirrhosis of the liver.

Editorial review. Atrial natriuretic factor-possible implications in liver disease.

Renal hemodynamic and natriuretic effects of human atrial natriuretic factor infusion in cirrhosis with ascites. Gastroenterology

Renal response to atrial natriuretic peptide in patients with advanced liver cirrhosis. Hepatology

vasopressin on renal dysfunction in decompensated cirrhosis. Gut

Augmentation of the natriuretic response to atrial natriuretic factor in cirrhosis

Universität München: Elektronischen Publikationen

Vol. 10, No. 5, 1989 HEPATOLOGY Elsewhere 897 
the present study, high enkephalin levels were restricted 
to patients with ascites. Finally, most other peptides and 
amines found in increased circulating levels in patients 
with advanced cirrhosis (e.g. insulin, renin, catechol- 
amines) have an enhanced release rate-and not an 
impaired hepatic inactivation-as the main cause of the 
increased plasma levels (5, 6). However, in my opinion, 
an enhanced release of methionine enkephalin would be 
equally interesting. 
As admitted by the authors, there is experimental 
evidence of the co-release of methionine enkephalin and 
epinephrine from the adrenal glands during sympathetic 
activation, which is in accord with the positive correla- 
tion between plasma methionine enkephalin and epi- 
nephrine demonstrated in their study. Thus, the in- 
creased methionine enkephalin might simply follow the 
sympathoadrenal overactivity in the same way as neu- 
ropeptide Y follows the release of norepinephrine. 
Like most previous reports on endogenous vasodi- 
lators, Thornton and coworkers did not find any rela- 
tionship between the circulating level of the potential 
vasodilator and the decreased arterial blood pressure. 
This may be due to the fact that a t  least three powerful 
vasoconstrictor systems (renin-angiotensin-aldosterone, 
sympathoadrenal and vasopressin) may compensate for 
the fall in arterial blood pressure (1). 
The authors propose that increased plasma opioid 
peptide activity increases histamine release, which in 
turn leads to increased lymphatic permeability in the 
liver, lymph leakage and ascites formation. However, 
available evidence suggests that microvascular permea- 
bility is decreased in the cirrhotic liver, with defenestra- 
tion and appearance of a basement membrane (6). More 
likely, in my opinion, would be an effect of histamine on 
sinusoidal pressure (7). Moreover, these patients do not 
show signs of general edema due to lymphatic leakage, 
as one would expect if a blood-borne substance had 
increased the lymphatic permeability. 
Although some aspects of Thornton and coworkers’ 
interpretation may be questioned, the essential finding 
of a highly increased endogenous, vasodilator peptide is 
very important, and future longitudinal studies during 
development of hepatic ascites are anticipated with in- 
terest. 
JENS H. HENRIKSEN, M.D. 
Department of Clinical Physiology 
Hvidovre University Hospital 
DK-2650 Copenhagen, Denmark 
REFERENCES 
Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial 
vasodilation hypothesis: a proposal for the initiation of renal 
sodium and water retention in cirrhosis. Hepatology 1988 81151- 
1157. 
Imura H, Kato Y ,  Nakai Y, et al. Endogenous opioids and related 
peptides: from molecular biology to clinical medicine. J Endocrinol 
1985; 107:147-157. 
Szabo B, Hedler L, Ensinger H, et al. Opioid peptides decrease 
noradrenaline release and blood pressure in the rabbit at peripheral 
receptors. Naunyn-Schmiedeberg’s Arch Exp Pathol Pharmakol 
1986; 33250-56. 
4. Guillemin R. Endorphins, enkephalins, and other opioid peptides: 
their significance in physiology and medicine. In: Wyngaarden JB, 
Smith LH Jr, eds. Cecil textbook of medicine. Philadelphia: W. B. 
Saunders Co., 1985: 1234-1237. 
5. Arroyo V, Bosch J ,  Mauri M, et al. Renin, aldosterone, and renal 
haemodynamics in cirrhosis with ascites. Eur J Clin Invest 1979; 
9:69-73. 
6. Keller U, Gerber PPG, Buhler FR, et al. Role of the splanchnic 
bed in extracting circulatory adrenaline and noradrenaline in nor- 
mal subjects and in patients with cirrhosis of the liver. Clin Sci 
7. Henriksen JH, Thorn T, Christoffersen P. The blood-lymph barrier 
in the liver. A review based on morphological and functional 
concepts of normal and cirrhotic liver. Liver 1984; 4:221-232. 
1984; 67~45-49. 
AUGMENTATION OF THE NATRIURETIC 
RESPONSE TO ATRIAL NATRIURETIC 
FACTOR IN CIRRHOSIS 
Ganger DR, Gottstein J,  Blei AT. Hemodynamic and 
renal effects of atrial natriuretic factor in portal hyper- 
tensive rats. Potentiation by Phe-Ile-Om-vasopressin. J 
Pharmacol Exp Ther 1988; 246941-945. 
ABSTRACT 
The effects of atrial natriuretic factor (ANF) on 
splanchnic hemodynamics and renal function in 
portal hypertensive models are described incom- 
pletely. Furthermore, ANF-induced vasodilata- 
tion and hypotension may limit the assessment of 
its own renal physiological effects. We infused 
ANF (human ANF 102-126) to anesthetized portal 
vein-ligated rats, a model with prehepatic portal 
hypertension. Arterial pressure was reduced by 
1796, but portal pressure was unaffected. Diuresis 
and natriuresis were explained in part by an in- 
crease in glomerular filtration rate; in addition, 
renal vascular resistance was significantly de- 
creased. The natriuretic response to ANF was 
slightly, but significantly, decreased in portal hy- 
pertensive rats as compared to controls (fractional 
excretion of sodium, 1.8 f 0.4 us. 2.9 f 0.3; P < 
.05). The addition of Phe-Ile-Orn-vasopressin, a 
V 1 receptor agonist, normalized arterial pressure 
but induced a significant decrease in the portal 
pressure (15 f 0.9 mm Hg base line us. 12.8 f 0.7 
combination group; P < .01). Furthermore, the 
combination of both drugs markedly potentiated 
the natriuretic effects (0.4 2 0.1 pEq/min of con- 
trol us. 10.0 f 2.3 ANF us. 32.2 f 3.3 combination 
group; P < .001). The natriuretic potentiation re- 
sulted from increments in glomerular filtration 
rate and renal blood flow. Normalization of arte- 
rial pressure may enhance the renal physiological 
effects of ANF, in this portal hypertensive model. 
COMMENTS 
Identification, characterization and synthesis of atrial 
natriuretic factor (ANF) has raised considerable interest 
regarding volume regulation in cirrhosis (1). The natri- 
HEPATOLOGY Elsewhere HEPATOLOGY 898 
uresis observed subsequent to administration of ANF is 
due to several factors, e.g. increase in glomerular filtra- 
tion rate (GFR), inhibition of tubuloglomerular feedback, 
induction of medullary “washout” and direct inhibition 
of tubular sodium reabsorption, the relative effects of 
which are difficult to determine. In addition, ANF sup- 
presses plasma concentrations of renin and aldosterone 
by inhibiting the synthesis of aldosterone and by block- 
ing the release of renin and aldosterone (1). ANF is of 
considerable therapeutic interest in cirrhosis with its 
proximal and distal tubular sodium retention and acti- 
vation of the renin-aldosterone system due to decreased, 
centrally effective, intravascular volume. 
In patients with cirrhosis, particularly those with as- 
cites, response to stimulation of endogenous release of 
ANF (2) as well as to low-dose infusion of synthetic ANF 
seems to be blunted (3). The reduced response might be 
due to alterations in the status of renal ANF receptors 
and/or to systemic and renal hemodynamic abnormali- 
ties. Several investigations support the contention that 
the decrease in mean arterial pressure following ANF 
administration in cirrhosis mediates the blunted natri- 
uresis (4-6). Following a bolus administration of 1 pg per 
kg ANF, mean arterial pressure decreased by 18 f 3 
mmHg in cirrhotic patients compared to 9 k 2 mmHg in 
control subjects (4). Thus, cirrhotic subjects with an 
activated renin-angiotensin-aldosterone system seem 
particularly sensitive to the vasodilatory effects of ANF. 
Natriuretic response of ANF (50 pg bolus followed by 50 
ng per kg.min infusion) in cirrhosis with ascites was 
more pronounced in those patients with lower basal 
plasma renin activity and plasma aldosterone concentra- 
tions (5). In contrast, patients with an activated renin- 
aldosterone system show further increase of plasma renin 
activity after ANF, concomitant with a decrease of renal 
plasma flow and of GFR, and no increase of natriuresis. 
In another study, the increase of natriuresis was in- 
versely related to changes in plasma renin activity, blood 
pressure and heart rate induced by ANF (6). Therefore, 
in cirrhotic patients with ascites, low-dose infusions of 
ANF (50 or 60 ngper kg-min) of ANF may induce greater 
natriuresis than high-dose infusions (75 or 300 ng per 
kg- min) (6). Thus, renal response to ANF administration 
may be optimized by a dosage large enough to induce 
natriuresis but small enough to avoid systemic hemody- 
namic alterations that activate compensatory responses. 
Alternatively, ANF-induced hypotension might be pre- 
vented by coadministration of vasconstrictor substances. 
Vasopressin (VP) would seem a suitable candidate with 
considerable natriuretic potential in patients with ascites 
and impaired renal function (7). 
In the study of Ganger et al. under comment, the 
effects of ANF were investigated in rats with portal 
hypertension induced by portal vein constriction. Infu- 
sion of ANF in high dose (500 ng per kg - min) induced a 
similar decrease of mean arterial pressure to that seen 
in control rats and only a small decrease in natriuresis. 
Interpretation of these data is somewhat difficult since 
no baseline renal perfusion and function values for the 
control group were provided. The second part of this 
pared the effects of an infusion of ANF (500 ng per kg. 
min) and of VP (5 ng per kg-min) individually and 
together. Indeed, the ANF-induced decrease in mean 
arterial pressure was prevented by the co-infusion of VP. 
Renal blood flow and GFR, which were only slightly 
affected by either agent alone, were increased signifi- 
cantly by the combination. The most remarkable find- 
ings were the potentiation of natriuresis and of diuresis 
by the combined infusion. Thus, in this model of portal 
hypertension, coadministration of VP with ANF over- 
came hypotension, the limiting factor for ANF adminis- 
tration, and potentiated the natriuresis and diuresis. If 
further studies in animal models confirm these findings, 
clinical trials of ANF together with vasopressin should 
be 
1. 
2. 
3. 
4. 
5. 
6. 
7. 
undertaken. 
ALEXANDER L. GERBES, M.D. 
Medizinische Klinik II 
Klinikum Grosshadern 
University of Munich 
Marchionistr. 15 
0-8000 Miinchen 70 
Federal Republic of Germany 
REFERENCES 
Gerbes AL, Arendt RM, Paumgartner G. Editorial review. Atrial 
natriuretic factor-possible implications in liver disease. J Hepatol 
Gerbes AL, Wernze H, Arendt RM, et al. Atrial natriuretic factor 
and renin-aldosterone in volume regulation of patients with cirrho- 
sis. Hepatology 1989; 9:417-422. 
Gerbes AL, Arendt RM, Stangl E, et al. Characterization of the 
ANF system in patients with cirrhosis of the liver. In: Forssman 
WG, Scheuermann DW, Alt J, eds. Functional morphology of the 
endocrine heart. Darmstadt: Steinkopff, 1988 229-234. 
Salerno F, Badalamenti S, Incerti P, et al. Renal response to atrial 
natriuretic peptide in patients with advanced liver cirrhosis. He- 
patology 1988; 8:21-26. 
Laffi G, Pinzani M, Meacci E, et al. Renal hemodynamic and 
natriuretic effects of human atrial natriuretic factor infusion in 
cirrhosis with ascites. Gastroenterology 1989; 96167-177. 
Petrillo A, Scherrer U, Gonvers J, et al. Atrial natriuretic peptide 
administered as intravenous infusion or bolus injection to patients 
with liver cirrhosis and ascites. J Cardiovasc Pharmacol 1988 
1987; 5~123-132. 
12:279-285. 
Lenz K. Hortnagl H. Drum1 W. et al. Beneficial effect of 8-ornithine - .  
vasopressin on renal dysfunction in decompensated cirrhosis. Gut 
1989 30:90-96. 
HEPATOLOGY EZsewhere CORRESPONDENCE 
ANIMAL MODELS FOR ALCOHOLIC LIVER 
DISEASE 
To the Editor: 
We agree with most of the comments made in Dr. 
Mezey’s review of the paper of Ainley et al. in HEPA- 
TOLOGY Elsewhere (Hepatology 1989; 9:904). However, 
we disagree when Dr. Mezev writes that the intragastric 
Y u 
paper provides fascinating data. The investigators com- tube feeding rat model of experimental liver disease does 


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Augmentation of the natriuretic response to atrial natriuretic factor in cirrhosis

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