Departments of
1 Gastroenterology and
4 Nuclear Medicine, Nitric oxide,
prostacyclin, and glucagon have been implicated in promoting the
hyperdynamic circulatory state of portal hypertension. Recent evidence
also indicates that increased tumor necrosis factor-
splanchnic hemodynamics; nitric oxide; prostacyclin; vasodilation
SYSTEMIC AND SPLANCHNIC vasodilation is the hallmark of
the hyperdynamic circulatory state associated with portal hypertension. Decreased systemic vascular resistance leads to vascular underfilling, activation of the endogenous vasoactive systems, sodium and water retention, and blood volume expansion (1, 5). The mechanisms underlying
this systemic and splanchnic hyperemia are not completely understood,
but an excessive release of vasodilators of nonendothelial (e.g.,
glucagon) and endothelial [e.g., nitric oxide (NO),
prostacyclin] origin seems to be involved.
Among the different vasodilators, glucagon has been consistently
proposed as a firm candidate (3, 24). Serum levels of this peptide are
increased in portal hypertensive rats and in patients with cirrhosis,
and infusion of a glucagon-specific antiserum ameliorates splanchnic
hyperemia (3). In addition, administration of pharmacological doses of
somatostatin to portal hypertensive animals causes splanchnic
vasoconstriction and reverses the vascular hyposensitivity to
vasoconstrictors (24).
Recently, a growing body of evidence suggests that vasodilators derived
from the vascular endothelium, specifically NO and prostacyclin, play a
major role in the development and maintenance of the hyperdynamic
circulation (9, 12, 17, 25, 29). In these studies, it was observed that
the administration of specific inhibitors of the biosynthesis of
the vasodilator (e.g.,
L-arginine analogs,
indomethacin) attenuates the hyperdynamic circulation and vascular
hyporesponsiveness to endogenous vasoconstrictors. Moreover, increased
production of NO (measured by nitrate levels and cGMP concentration)
and of prostacyclin (measured by
6-keto-PGF1 Both vasodilators, NO and prostacyclin, are produced in the
endothelium, and they may share a common trigger stimulus for their
synthesis and release in portal hypertension (21). The endothelium is
considered an autocrine organ that regulates pressure and flow, and its
functionality is regulated by different physical or pharmacological
signals, among which proinflammatory cytokines, like tumor necrosis
factor- Specifically, the present study was undertaken to evaluate the effects
of blocking circulating TNF- Experimental Model
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
(TNF-
)
production is involved in the pathogenesis of this hemodynamic abnormality. This study was aimed at investigating in rats with portal
vein stenosis (PVS) the effects on splanchnic hemodynamics of blocking
circulating TNF-
and the factors mediating the vascular action of
this cytokine in this setting. Anti-TNF-
polyclonal antibodies or
placebo was injected into rats (n = 96) before and 4 days after PVS (short-term inhibition) and at 24 h and
4, 7, 10 days after PVS (long-term inhibition). Short-term TNF-
inhibition reduced portal venous inflow and cardiac index and increased
splanchnic and systemic resistance. Portal pressure was unchanged, but
portal-systemic shunting was decreased. After long-term TNF-
inhibition, portal venous inflow and portal pressure were unchanged,
but arterial pressure and systemic resistance rose significantly.
Anti-TNF-
PVS rats exhibited lower increments of systemic resistance
after N
-nitro-L-arginine methyl
ester and indomethacin administration and lower serum levels of
TNF-
, nitrates-nitrites, and
6-keto-PGF1
, both over the
short and the long term. Serum glucagon levels rose after long-term
inhibition. In conclusion, the specific role played by TNF-
in the
development of the hyperdynamic state of portal hypertension appears to
be mainly mediated through an increased release of nitric oxide and
prostacyclin. Maintenance of the splanchnic hyperemia after long-term
TNF-
inhibition could be due to a compensatory release of glucagon.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
levels) has been
observed in the circulation of animal models of portal hypertension and
in humans with cirrhosis (2, 11-13, 23, 28).
(TNF-
), play a prominent role (21). This cytokine
stimulates the synthesis of NO and prostacyclin and could be the
stimulus for the production of the two endothelium-derived vasodilators
in portal hypertension (10). In fact, recent data point to the
increased production of TNF-
having a role in the vasodilation
associated with portal hypertension. Cirrhotic patients with no signs
of infection show increased blood levels of TNF-
, and their
mononuclear cells exhibit an augmented in vitro synthesis of this
cytokine (6, 15). Blood levels of TNF-
are also increased in portal
vein stenosis (PVS) rats, and blockade of circulating TNF-
or
selective inhibition of its synthesis in these animals ameliorates
portal hypertension (19, 20). The factors responsible for the vascular
effects of TNF-
in portal hypertension have not yet been elucidated,
nor have the consequences of inhibiting this cytokine on splanchnic
hemodynamics and on the development of portal-systemic shunting.
by short- and long-term injection of
specific antibodies on the functionality of the endothelium and the
possible consequences in splanchnic hemodynamics in PVS rats.
Simultaneously, we have analyzed changes in the serum levels of
glucagon as an additional pathway potentially implicated in the
pathogenesis of the hyperdynamic circulatory state.
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
Portal hypertension was induced by PVS in 96 animals according to a previously reported method (5). The splanchnic and systemic hyperdynamic circulatory state that complicates portal hypertension develops in this model in a predictable, short period of time (5). Briefly, the portal vein was isolated and a calibrated stenosis was performed with a single 3-0 silk ligature around a 20-gauge blunt-tipped needle. The needle was then removed, and the portal vein was allowed to reexpand. The viscera were placed back into the abdomen, which was closed in two layers with suture, and antibiotic ointment was applied to the surgical wound.
Experimental Studies
Study I: Effects of anti-TNF- on regional blood
flows, cardiac output, and portal-systemic shunting.
While the rats were under ketamine anesthesia, the right femoral artery
was cannulated with polyethylene (PE) 50 tubing (Portex, Técnicas
Médicas, Barcelona, Spain). A similar catheter was advanced
through the right carotid artery into the left ventricle under pressure
monitoring. The position of the catheter was checked by the presence of
a ventricular pressure pattern. Thereafter, the abdomen was opened via
a lower midline incision, and the superior mesenteric vein was
cannulated via an ileocolic tributary. The abdomen was closed in one
layer, and the circulation was allowed to stabilize for at least 20 min
before definitive pressure measurements were performed. Mean arterial
pressure and mean portal venous pressure were measured, respectively,
through the femoral artery and portal vein catheters that were
connected to quartz transducers, and blood pressures were registered
using a multichannel recorder (model 5241, Lectromed Holding).
Transducers were calibrated daily and placed at point
zero, which was established at 1 cm above the operating table.
Study II: Effects of anti-TNF- on the biological
actions of NO.
Under ketamine anesthesia, the right femoral artery, the ileocolic
vein, and the right femoral vein were cannulated with PE-50 tubing to
monitor mean arterial pressure and portal pressure and to infuse drugs,
respectively. Cardiac output was measured by thermodilution, as
previously described (1). Briefly, a thermistor was placed in the
aortic arch just distal to the aortic valve, and the thermal indicator
(100 µl of 5% dextrose in water) was injected into the right atrium
through a PE-50 catheter. The aortic and injectate thermistors were
connected to a cardiac output computer (Columbus Instruments, Columbus,
OH), which measures the blood and injectate temperatures and calculates
the thermal dilution curve. Each cardiac output value was obtained from
the arithmetic mean of three thermodilution curves. Cardiac index
(ml · min
1 · 100 g
1) was calculated as cardiac output per 100 g body wt.
Systemic vascular resistance
(mmHg · min · 100 g · ml
1) was calculated from mean
arterial pressure divided by cardiac index.
Study III: Effects of anti-TNF- on serum levels of
TNF, nitrates and nitrites, and
6-keto-PGF1
and on the
biological actions of prostacyclin.
Under ketamine anesthesia, animals were instrumented as in
study II. Animals were allowed to
stabilize, and 1.2 ml of blood were withdrawn and centrifuged; the
serum was divided into aliquots that were frozen at
80°C
until assay. Mean arterial pressure and cardiac index were then
measured at baseline and 30 min after a bolus injection of indomethacin
(5 mg/kg; Sigma Chemical). The dose of indomethacin was previously
calculated to cause a 25% reduction in the serum levels of
6-keto-PGF1
. TNF-
was
measured in serum using a commercially available ultrasensitive ELISA
(Biosource International, Camarillo, CA). The sensitivity of this
bioassay was 0.7 pg/ml, and the intra- and interassay coefficients of
variation were 3.1 and 5.1%, respectively. Nitrates and nitrites were
measured in serum by a colorimetric method based on the Griess reaction (Cayman Chemical, Ann Arbor, MI). Glucagon immunoreactivity was measured using a 30K antiserum in serum samples containing
EDTA and 1,000 units kallikrein trypsin inhibitor.
6-Keto-PGF1
was isolated by
HPLC on a reverse octadecyl silica column (Nove Pak, Water Associates,
Mildford, MA) using an isocratic solvent system composed of
triethylamine-formic buffer (pH 3.0) and acetonitrile (2:1, vol/vol) at
a flow rate of 0.8 ml/min. The concentration of
6-keto-PGF1
in the fraction
after HPLC was determined by RIA (Amersham International,
Buckinghamshire, UK). In each animal, the total duration of the
experiment was ~50 min.
Experimental Protocols in PVS Rats
Circulating TNF-In protocol 1 (short-term inhibition
of TNF-), 48 PVS animals were divided into two groups to receive
anti-TNF-
or placebo. In this protocol, anti-TNF-
or placebo was
injected, respectively, 6 h before and 4 days after induction of portal
hypertension. In protocol 2 (long-term
inhibition of TNF-
), 48 PVS rats were also divided into two
experimental groups to receive anti-TNF-
or placebo, which, in this
case, was injected 24 h and 4, 7, 10 days after induction of portal
hypertension. In both protocols, the experimental studies were
performed the day after the last injection of anti-TNF-
or placebo.
Three sets of 16 animals were used in each protocol for use in the
three experimental studies: measurement of regional blood flows and
cardiac output (study I),
calculation of dose-response curve to
L-NAME (study
II), and measurement of serum levels of TNF-
,
nitrates and nitrites,
6-keto-PGF1
, and glucagon
(study III).
Anti-TNF- or placebo was injected into the jugular vein with a
30-gauge needle. The intravascular character of the injection was
ensured by reflux of venous blood into the syringe. The dose of
anti-TNF-
was chosen in a series of preliminary experiments in PVS
rats. The timing of anti-TNF-
administration was chosen with the
consideration that the median serum half-life of this antibody is 40.1 h and that neutralizing levels remain in serum until 5 days after
injection (8). In protocol 1,
anti-TNF-
was injected before surgery to ensure the presence of
circulating TNF-
antibodies at the time of induction of portal hypertension.
Experimental Studies and Protocols in Nonportal Hypertensive Rats
To discard the possible hemodynamic effect of anti-TNF-Statistics
Results are expressed as means ± SE. Statistical analysis was performed using the unpaired Student's t-test, with Bonferroni correction for multiple comparisons as appropriate. Linear regression analysis was performed for selected variables. Statistical significance was set at P < 0.05. ![]() |
RESULTS |
---|
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---|
Five days after induction of portal hypertension, rats receiving
placebo had developed the hemodynamic features of a hyperdynamic circulatory state as well as a significant amount of portal-systemic shunting. PVS rats had higher portal pressure (13.5 ± 0.2 vs. 6.1 ± 0.9 mmHg, P < 0.01) and portal
venous inflow (8.9 ± 0.8 vs. 4.1 ± 0.5 ml · min1 · 100 g
1, P < 0.05) and
lower splanchnic arteriolar resistance than Sham rats (11.3 ± 1 vs. 29.9 ± 4 mmHg · min · 100 g · ml
1,
P < 0.01). Compared with Sham rats,
placebo PVS animals showed significantly lower mean arterial pressure
(102 ± 2 vs. 121 ± 8 mmHg,
P < 0.01), higher cardiac index
(33.4 ± 3 vs. 27.8 ± 2 ml · min
1 · 100 g
1, P < 0.05), and
lower systemic vascular resistance (3.37 ± 0.3 vs. 4.63 ± 0.8 mmHg · min · 100 g · ml
1,
P < 0.05). Hematocrit was
significantly lower in PVS rats treated with placebo than in Sham
animals (38.3 ± 0.8 vs. 42.3 ± 0.4%, P < 0.01). These significant
differences in splanchnic and systemic hemodynamics between Sham and
portal hypertensive rats at day 5 were
also observed at day 11 after the
induction of portal hypertension.
Inhibition of TNF- in Sham Rats
|
Short-Term Inhibition of TNF- (protocol 1)
|
|
PVS animals receiving anti-TNF- had significantly higher mean
arterial pressure (114 ± 2 mmHg, P < 0.01), lower cardiac index (24.8 ± 1 ml · min
1 · 100 g
1, P < 0.05), and higher systemic vascular resistance (4.9 ± 0.4 mmHg · min · 100 g · ml
1,
P < 0.05) than those treated with
placebo (Table 2). The values of these parameters in anti-TNF-
PVS
rats were not significantly different from those in Sham rats. The
hematocrit value in PVS rats receiving anti-TNF-
was 41.2 ± 0.3%, significantly higher (P < 0.01) than in placebo PVS rats but similar to that of the Sham rats.
In both groups of PVS rats and in Sham animals, inhibition of NO by
L-NAME administration resulted
in dose-dependent increases in mean arterial pressure and systemic
vascular resistance and dose-dependent decreases in cardiac index. At
every dose of the inhibitor, the absolute increases of mean arterial
pressure and systemic vascular resistance were higher in placebo PVS
rats than in anti-TNF- PVS and Sham animals (Fig.
1A),
with differences statistically significant from the 6 mg/kg dose on.
L-NAME did not affect portal
pressure in either group.
|
In PVS animals treated with placebo, indomethacin induced a
significantly greater (P < 0.05)
increment in systemic vascular resistance than that observed in
anti-TNF- PVS and Sham rats (Fig.
2A).
|
Serum values of TNF-, nitrates and nitrites, and
6-keto-PGF1
were significantly
lower in anti-TNF-
PVS than in placebo PVS rats (Table
4). Both placebo PVS and anti-TNF-
PVS
rats showed similar serum levels of glucagon.
|
Long-Term Inhibition of TNF- (protocol 2)
L-NAME infusion caused
dose-dependent increases in mean arterial pressure and in systemic
vascular resistance and dose-dependent decreases in cardiac index in
both groups of PVS rats. Similar to the findings in
protocol 1, at every dose of the
inhibitor, the increments in systemic vascular resistance were
significantly higher in anti-TNF- PVS than in placebo PVS and Sham
animals from the 6 mg/kg dose on (Fig.
1B).
L-NAME did not affect portal pressure in any group.
The 5 mg/kg injection of indomethacin induced a significantly greater
(P < 0.05) increment in systemic
vascular resistance in placebo than in anti-TNF- PVS and Sham rats
(Fig. 2B).
Anti-TNF- induced a significant reduction in serum levels of
TNF-
, nitrates and nitrites, and
6-keto-PGF1
in PVS animals (Table 4). In contrast to the endothelium-derived vasodilators, the
serum glucagon concentration was significantly higher in anti-TNF-
than in placebo PVS rats.
When data of PVS animals treated over the short and long term with
TNF- or placebo were pooled together, significant correlations were
found among the mean arterial pressure and the serum levels of TNF-
(r =
0.62,
P < 0.05) and those of nitrates and
nitrites (r =
0.50,
P < 0.05).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In this study, we focused on the effects on splanchnic hemodynamics of
the blockade of circulating TNF- in portal hypertensive rats. We
have also evaluated the impact of TNF-
inhibition on the biological
actions and on the serum levels of NO and prostacyclin, two proposed
mediators of the effect of this cytokine in the vessel wall, by
assessing the vascular responsiveness to the infusion of their specific
biosynthesis inhibitors, L-NAME
and indomethacin. Simultaneously, we analyzed the pattern of changes in
the serum levels of the nonendothelial vasodilator, glucagon. This was
accomplished in two protocols: the first to study the short-term
inhibition of TNF-
in the early stages of portal hypertension and
the second to study the long-lasting effect of continued TNF-
inhibition.
In portal hypertensive rats, short-term inhibition of TNF- reversed
the splanchnic and systemic vasodilation and hyperemia. Anti-TNF-
-treated PVS rats showed values of splanchnic and systemic arteriolar resistance, portal venous inflow, and cardiac index similar
to those found in Sham animals. By correcting the peripheral vasodilation, the expansion of the plasma volume associated with portal
hypertension was prevented, as indicated by a higher hematocrit in
anti-TNF-
PVS rats. The complete reverse of the splanchnic and
systemic hyperemia after short-term TNF-
inhibition suggests a key
role of this cytokine in the development of the hyperdynamic circulatory state observed in portal hypertension. The absence of
hemodynamic changes in nonportal hypertensive rats excludes an
intrinsic vascular effect of anti-TNF-
antibodies.
Besides the described hemodynamic effects, anti-TNF--treated animals
showed lower serum levels of nitrates and nitrites and of
6-keto-PGF1
, used as indexes of
NO and prostacyclin release, respectively. Likewise, blockade of
TNF-
modified the vascular response to NO synthase and
cyclooxygenase inhibition, since the relative increments in systemic
resistance caused by L-NAME and indomethacin infusion were significantly lower in portal hypertensive animals receiving anti-TNF-
. These findings are in keeping with recent experimental observations that support the contribution of these
endothelium-derived vasodilators to the splanchnic and systemic
vasodilation as well as to the gastric mucosal hyperemia of portal
hypertensive rats (4, 7, 13, 30). In addition, both TNF-
and
inducible NO synthase have been shown to be overexpressed in the
gastric mucosa of portal hypertensive rats, and the expression of the
enzyme is decreased by TNF-
-neutralizing antibodies (14). These data
indicate an increased synthesis of NO and prostacyclin in portal
hypertension and indicate that TNF-
can be the common trigger that
stimulates their synthesis. Alternatively, because the effect of
TNF-
on vascular tone may be influenced by mechanisms other than NO
and prostacyclin, such as by increases in the levels of calcitonin-gene
related peptide or by activation of potassium channels in smooth muscle
cells, the possibility of a contributory role of these factors in the
hemodynamic abnormalities observed cannot be excluded (16, 29).
The induction of both NO synthase and cyclooxygenase is not a
situation unique to portal hypertension but is shared by other inflammatory conditions, such as sepsis and rheumatoid arthritis (27).
On the other hand, NO synthase and cyclooxygenase can be stimulated by
proinflammatory cytokines other than TNF-, like interferon-
and
interleukin-1
(26). However, considering that blockade of
circulating TNF-
suppressed the activities of both enzymes, a
prominent role for these other mediators in the pathogenesis of the
hyperdynamic circulatory state of portal hypertension is unlikely.
Conversely, in the present study, the hyperdynamic circulatory state
observed 10 days after induction of portal hypertension persisted in
the splanchnic circulation, whereas it was attenuated at the systemic
level by blockade of circulating TNF-. This was shown by similar
portal venous inflow and splanchnic arteriolar resistance but lower
cardiac index and higher systemic vascular resistance in PVS rats
receiving anti-TNF-
than in those treated with placebo. These
findings further extend the results of Lopez-Talavera et al. (20) who
observed that anti-TNF-
antibodies administered at
days 11 and
13 after PVS led to decreased cardiac
index and increased systemic vascular resistance; splanchnic
hemodynamics were not assessed in this study. It could be argued that
the blockade of circulating TNF-
was inadequate in our study, but
the serum levels of TNF-
were reduced to an extent similar to that
observed in protocol 1. Moreover,
anti-TNF-
effectively inhibited the increased synthesis of NO and
prostacyclin, as shown by a reduction in the serum levels of their
metabolites and by significantly lower increments in systemic vascular
resistance after the infusion of the specific inhibitors.
Persistence of splanchnic hyperemia despite effective long-term
blockade of circulating TNF- and adequate inhibition of NO- and
prostacyclin-mediated vasodilation suggests that, in these circumstances, splanchnic vasodilation may be supported by a
compensatory release of other vasodilators. In this regard, glucagon
levels were significantly higher in PVS rats receiving anti-TNF-
over the long-term than in those treated with placebo. It is possible to speculate that an increased synthesis of glucagon could account for
the lack of splanchnic vasoconstriction after long-term inhibition of
NO and prostacyclin biosynthesis. The increase in serum glucagon levels
may represent an adaptive response aimed at maintaining splanchnic
vasodilation in portal hypertension. The fact that, in portal
hypertension, the vasodilatory effect of glucagon predominates over the
splanchnic vascular bed may account for the persistence of hyperemia in
the splanchnic but not in the systemic circulation (3, 24). Increased
serum glucagon also contributes to the maintenance of splanchnic
hyperemia in portal hypertensive rats after continued NO inhibition
(9). In addition, it has been recently shown in the same animal model
that an enhanced vascular response to
L-NAME follows long-term
indomethacin administration, indicating a compensatory release of NO
when cyclooxygenase is chronically inhibited (7). Taken together, these
findings support the concept that the hemodynamic abnormalities that
complicate portal hypertension result from the increased activity of
different vasodilatory pathways that are coupled to maintain mesenteric hyperemia.
In our study, portal pressure was unchanged after short- and long-term
TNF- inhibition, a finding that contrasts with the results of
Lopez-Talavera et al. (20). The lack of changes in portal pressure
after short-term TNF-
inhibition despite the decrease in portal
venous inflow could be caused by the concomitant increase in
portal-collateral resistance. In portal hypertension, the collateral
circulation carries most of the blood entering the portal system and
changes in the resistance of these vessels markedly influence the
overall resistance to portal blood flow and portal pressure. In
addition, studies in an isolated portal-collateral perfused model have
shown a role of NO in modulating the resistance of this vascular bed in
portal hypertensive rats (18, 22). Therefore, increased
portal-collateral resistance after short-term TNF-
inhibition might
result from a passive decrease in the cross-sectional area of the
collateral channels secondary to lowered portal venous inflow and
active contraction of these vessels secondary to blockade of NO
synthesis. Both factors were also responsible for the decrease in the
extent of portal-systemic shunting after short-term TNF-
inhibition.
Similar results have been reported after early, continuous infusion of
N
-nitro-L-arginine
in portal hypertensive rats (18). On the other hand, splanchnic
hyperemia persisted after long-term TNF-
inhibition, thereby leaving
portal pressure unchanged. Persistence of elevated portal venous inflow
probably also accounted for the absence of changes in the extent of
portal-systemic shunting despite effective NO inhibition. This fact
highlights the concept that portal hyperemia is the most important
driving force in the development of portal-systemic shunting.
In conclusion, the results of this study support a specific role of
TNF- in promoting the systemic and splanchnic hyperdynamic circulatory state that complicates portal hypertension. The vascular effect of TNF-
in this setting seems to be mainly mediated through NO and prostacyclin.
![]() |
ACKNOWLEDGEMENTS |
---|
We are indebted to Maria-Luisa Villanueva, PhD, for glucagon determinations and to Marta Messman for editorial help.
![]() |
FOOTNOTES |
---|
This study was supported by a grant from the Fondo de Investigaciones Sanitarias (FIS 95/1292). J. Muñoz was the recipient of a grant from Comunidad Autónoma de Madrid para Formación de Personal Investigador. M. Perez-Páramo was the recipient of a grant from Fundación Lair (Lair 0317).
This study was presented in part at the 21st Annual Meeting of the American Association of the Study of the Liver, Chicago, IL, November, 1997.
Address for reprint requests and other correspondence: A. Albillos, Dept. of Medicine, Facultad de Medicina-Campus Universitario, Universidad de Alcalá, Ctra. Madrid-Barcelona, Km 33.600, 28871 Alcalá de Henares, Madrid, Spain.
Received 25 June 1998; accepted in final form 5 November 1998.
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