Download Effect of Two Models of Portal Hypertension on

Clinical Science (1985) 68,23-28
23
Effect of two models of portal hypertension on splanchnic
organ blood flow in the rat
D . LEBREC
AND
L. BLANCHET
Unite' de Recherches de Physiopathologie He'patique (INSERMJ, H6pital Beaujon, Clichy, France
(Received 9 February/3 June 1984; accepted 3 July 1984)
Summary
1. Splanchnic organ blood flow and cardiac
output were measured by the microsphere method
in fasted rats with prehepatic portal hypertension
due to portal vein stenosis, in rats with intrahepatic portal hypertension due to bile duct
ligation, and in unoperated normal rats.
2 . Portal venous pressure was higher in both
groups of portal hypertensive rats than in normal
rats. Cardiac output was significantly higher in
portal hypertensive rats than in normal rats.
3. In rats with portal vein stenosis, splanchnic
blood flow was higher than in controls. This
increase was caused by increased perfusion of all
organs drained by the portal vein, and by increased
hepatic arterial blood flow. In rats with bile duct
ligation, splanchnic blood flow was not significantly higher than in normal rats: haemoperfusion
of all organs contributing to the portal circulation
decreased, whereas hepatic arterial blood flow
increased. As cardiac output rose similarly, the
differences observed between the two types of
portal hypertension depend mainly on the difference in distribution of flow within the splanchnic
bed.
Key words: blood flow, liver, portal hypertension.
Introduction
An increase in portal venous pressure is associated
with changes in systemic haemodynamics [l-31. In
patients with portal hypertension, no method is
currently available to measure blood flow in
splanchnic organs individually. The purpose of this
Correspondence: Dr D. Lebrec, INSERM U 24,
Hapita1 Beaujon, 921 18 Clichy, France.
investigation was to study changes in splanchnic
blood flow, by using the microsphere method, in
rats with prehepatic portal hypertension due to
portal vein stenosis and intrahepatic portal hypertension due to bile duct ligation.
Methods
Animals
Three groups of adult male rats (Charles River,
Saint-Aubin-L&Elbeuf, France), initially weighing
200-250 g, were studied: ten with portal hypertension due to portal vein stenosis, ten with portal
hypertension due to bile duct ligation and ten
control animals.
Portal vein stenosis
To induce prehepatic portal hypertension,
partial portal vein ligation was performed according to the method of Halvorsen & Myking [4].
Under ether anaesthesia, the portal vein was
exposed by median laparotomy. A polyethylene
catheter of 0.96 mm outside diameter (Biotrol
Pharma, Paris, France) was placed beside the
portal vein. A ligature between the bifurcation of
the portal vein and the junction of splenic and
mesenteric veins was tied around both the catheter
and the portal vein; the catheter was immediately
removed and the abdominal incision closed.
Bile duct ligation
To induce intrahepatic portal hypertension,
ligature of the common bile duct was performed
according to the method of Franco et al. [S].
Under ether anaesthesia, the common bile duct
was exposed by median laparotomy and occluded
by double ligature with a non-resorbable suture
24
D, Lebrec and L. Blanchet
(7-0 silk). The first tie was below the junction of
the hepatic ducts, and the second was above the
entrance of the pancreatic ducts. The common bile
duct was then resected between the two ligatures
and the abdominal incision closed. Two to 4 weeks
after bile duct ligation, marked jaundice and mild
ascites developed. Secondary biliary cirrhosis due
to chronic bile duct ligation [5] was histologically
confirmed in these rats.
Haemodynamic measurements
Haemodynamic studies were performed 3
weeks after partial portal vein ligation and 4 weeks
after bile duct ligation. All rats then weighed 300350 g (after ligation of the bile duct, rats slightly
decreased their weight and then return to normal).
Rats were fasted 18 h before the haemodynamic
study but were given water ad libitum. Haemodynamic studies were performed under pentobarbital anaesthesia (5 mg/100 g body wt. intraperitoneally); rats were fixed in a supine position;
rectal temperature was maintained at 38'C.
Splanchnic organ blood flow was measured by
using the microsphere method peviously described
[6-91. Under pentobarbital anaesthesia, the right
common carotid artery was cannulated with a
catheter of 0.70 mm outside diameter (William
Cook Europe, ApS, Soborg, Denmark). The
catheter was advanced into the left ventricle; its
position was demonstrated by a left ventricular
pressure curve and verified at autopsy. The left
common carotid artery was then cannulated with a
catheter of 0.96 mm outside diameter (Biotrol
Pharma, Paris, France). This catheter was used
for monitoring heart rate and arterial pressure
(Telco, Gentilly, France) and for taking the
reference blood sample (see below). Each catheter
was flushed with 50 i.u. of heparin. Microspheres
(15 f 3 pm diameter; sp. activity, 10 mCi/g; New
England Nuclear, Boston, MA, U.A.S.), labelled
with 14'Ce, were suspended in 10% glucose, and
dispersed in an ultrasonic disintegrator (MSE,
Scientific Instruments, Crawley, U.K.) for 10 min
before injection. A 0.1 ml suspension of approx.
60 000 microspheres was injected into the left
ventricle over 15 s; the catheter was then flushed
with 0.5 ml of saline (154 mmol of NaC1/1).
Starting 5 s before microsphere injection, the
reference blood sample was withdrawn through
the left carotid artery catheter, at a rate of 0.8
ml/min, for a period of 60 s (Syringe infusion
withdrawal pump; Sage Instruments, Cambridge,
MA, U.S.A.). The number of microspheres
collected in this sample ranged from 400 to 600.
After portal venous pressure measurement (see
below), animals were killed by injection of 25 mg
of pentobarbital. The stomach, intestine, colon,
mesentery-pancreas (because of the difficulty in
detaching all pancreas fragments of the mesentery
in the rat, these organs were not divided), and liver
were dissected, washed, dried with a compress,
weighed, and placed in counting tubes. The
amount of injected radioactivity was calculated
from the difference between initial and residual
radioactivity in the syringe. Radioactivity of the
syringe, reference blood sample and removed
organs was counted (c.p,m.) by gamma scintillation
(Picker Nuclear Intertech, U.S.A.). The number
of microspheres collected in the organs ranged
from 400 to 12000. Distribution of cardiac
output to various organs was calculated from the
ratio of organ radioactivity to injected radioactivity. Organ perfusion was calculated according
to the following formula: organ blood flow
(ml/min) = (organ radioactivity/injected radioactivity x cardiac output) (ml/min). Cardiac output
was calculated from the following formula: cardiac
output (ml/min) = (injected radioactivity/reference
blood sample radioactivity) x 0.8 (ml/min).
Microsphere mixing was considered adequate
because differences between right and left renal
blood flow measurements [ 101 were insignificant.
Arterial pressure was unaffected by left ventricular
catheterization, by withdrawal of reference blood
samples, o r by microspheres (except for a transient
fall during injection).
Within 5 min after microsphere injection
median laparotomy was performed to measure
portal venous pressure. A polyethylene catheter
(0.7 mm outside diameter; William Cook Europe,
ApS, Soborg, Denmark) was inserted into the
junction of two small ileal veins and gently advanced into the portal vein. The correct position
of the catheter was visually checked through the
portal vein wall. Portal venous pressure was
measured with the catheter and recorded on a
square-wave electromagnetic manometer (Telco,
Gentilly, France). The zero reference level was
aligned with the right atrium. The adequacy of
portal catheterization for pressure measurement
was confirmed by rapid response of the tracing
and easy aspiration of blood.
Statistical analysis
The values are expressed as means+ 1 SD. The
Wilcoxon test for unpaired samples was used for
statistical comparisons.
Results
The mean values for arterial pressure were not
significantly different in the three groups [110+
8 mmHg (mean ~ S D )in normal rats; 107 f 1 4
Splanchnic blood flow in portal hypertensive rats
mmHg and 98 k 9 mmHg in rats with portal hypertension due to portal vein stenosis and bile duct
ligation, respectively].
Mean values of blood flow to splanchnic organs
are presented for all groups in Table 1 . In rats with
portal hypertension due to portal vein stenosis,
the total arterial flow to organs drained by the
portal vein ranged from 21.12 to 29.91 ml/min
(26.14 f 3.55 ml/min). Those with portal hypertension due to bile duct ligation ranged from 8.73
to 20.16 ml/min (14.65 f 3.39 ml/min). In the
former group, the mean value was significantly
higher than that found in normal rats, whereas
in the latter group, the mean value was significantly lower than normal (Table 1). Spanchnic
blood flow in the two groups ranged from 23.65
to 36.33 ml/min (29.82 f 3.91 ml/min) in rats
with portal vein stenosis, and from 13.52 to 27.19
ml/min (20.73 f 4.06 ml/min) in rats with bile
duct ligation; the mean value in the first group
was significantly higher than that measured in
normal rats, whereas, in the second group, the
mean value was not significantly different from
normal (Table 1).
Distribution of cardiac output to various
splanchnic organs in rats with portal hypertension
due to portal vein stenosis or bile duct ligation,
compared with normal rats, is shown in Table 2. In
rats with portal hypertension due to portal vein
stenosis, the percentage of cardiac output supply-
25
ing organs drained by the portal vein (stomach,
intestine, colon, spleen and mesentery-pancreas)
ranged from 18.87 to 32.49%,with a mean value
(25.24%) significantly higher than that found in
normal rats (20.77%). In those with portal hypertension due to bile duct ligation the distribution
of cardiac output to the portal bed ranged from
9.22 to 22.84% with a mean value (15.10%)
significantly lower than normal (Table 1).
Distribution of cardiac output to splanchnic
bed (portal venous bed and liver) in the two
groups ranged from 22.51 t o 35.53% in rats with
portal vein stenosis, and from 14.3'8 to 27.21%
in rats with bile duct ligation. In the former group,
the mean value was significantly higher than in
normal rats, whereas, in the latter group, the mean
value was not significantly different (Table 1).
Splanchnic organ blood flow expressed per g
tissue wt. in rats with portal hypertension due to
portal vein stenosis or to bile duct ligation, and in
normal rats, is summarized in Table 3. In rats with
portal vein stenosis the differences with the
control group of splanchnic organ blood flow
expressed per g tissue wt. were similar to those
expressed per ml/min except for mesentericpancreatic and hepatic blood flows (Table 3). In
rats with bile duct ligation, blood flows expressed
per g tissue wt. were different from those expressed
per ml/min except for gastric, splenic and hepatic
blood flows (Table 3).
TABLE 1. Splanchnic organ blood flow, portal venous tributary blood flow and
splanchnic blood flow in rats with portal hypertension due to portal vein stenosis or to
bile duct ligation, and in normal rats
Results are mean values f SD. Portal venous tributary blood flow is equal to the sum of
gastric, intestinal, colonic, splenic and mesenteric-pancreatic blood flows. Hepatic
blood flow is equal t o hepatic arterial blood flow. Splanchnic blood flow is equal to
the sum of portal venous tributary blood flow and hepatic arterial blood flow.
Blood flow (ml/min)
Normal
(n = 10)
Gastric
Intestinal
Colonic
Splenic
Mesenteric-pancreatic
Portal venous tributary
Hepatic
Splanchnic
0.592 0.06
1.67A 1.68
1.81 0.49
1.77 f 0.62
2.05 0.49
7.89* 1.70
1.99k0.52
19.88 k 2.02
*
*
Portal vein stenosis
(n = 10)
Bile duct ligation
(n = 10)
0.84 2 0.36 *t
17.64*4.03$§
2.12k 0.43*11
1.99* 0.43*11
3.55* 1.38**t
26.14i: 3.55tt§
3.68i 1.78s $ $
29.82k 3.91ttll
0.66f 0.24*
7.96* 2.44:
1.34* 0.55
1
. 0.53n
~
3.57* 1.18$
14.65i3.39n
6 . 0 8 2.09tt
~
20.73f4.06*
~~
*Not significantly different from normal; 1- not significantly different from bile duct ligation;
$significantlydifferentfrom normal (P< 0.01); § significantly different from bile duct ligation (P<
0.001); II significantly different from bile duct ligation (P< 0.01); 1[ significantly different from
from normal (P< 0.001); $ $ significantly different from bile duct ligation (P< 0.02).
D. Lebrec and L . Blanchet
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TABLE 2 . Percentage of distribution of cardiac output to splanchnic organs, portal
venous tributary, and splanchnic tributary in rats with portal hypertension due to
portal vein stenosis or to bile duct ligation, and in normal rats
Results are mean values f SD.Portal venous tributary is equal to the sum of percentages
of cardiac output of the stomach, intestine, colon, spleen and mesentery-pancreas.
Liver is equal to the percentage of cardiac output of the hepatic artery. Splanchnic
tributary is equal to the sum of percentages of cardiac output of the portal venous
tributary and the liver.
Percentage of cardiac output
Normal
(n = 10)
Stomach
Intestine
Colon
Spleen
Mesentery-uancreas
Portal venobs tributary
Liver
Splanchnic tributary
0.69i 0.09
13.53 i 2.14
2.09i 0.56
2.09i0.66
2.37 f 0.57
20.77f 1.94
2.31 f 0.55
23.08f 1.90
Portal vein stenosis
(n = 10)
Bile duct ligation
0.78f0.25*t
17.17*4.60*$
2.03*0.35*11
1.90t 0.30*11
3.36f 1.237 t
25.24+4.36**$
3.63f 1.46711
28.87i 3.79ttll
0.71 f 0.27*
8.25 i 2.805
1.36i0.508
1.13 f 0.48 5
3.655 1.127
15.10i3.605
6.17i 1.87tt
21.27f 3.82*
(n = 10)
* Not significantly different from normal; t not significantly different from bile duct ligation;
(P< 0.001); 5 significantly different from normal
(P< 0.01); II significantly different from bile duct ligation (P< 0.01); ll significantly different
from normal (P< 0.02): ** significantly different from normal (P< 0.05); tt significantly
different from normal (P< 0.001).
$. significantly different from bile duct ligation
TABLE 3 . Splanchnic organ blood flow in rats with portal hypertension due to portal
vein stenosis or to bile duct ligation, and in normal rats
Results are mean values f SD. Hepatic is equal to hepatic arterial blood flow.
Blood flow (ml min-' g-' tissue wt.)
Normal
In = 10)
Gastric
Intestinal
Colonic
Splenic
Mesenteric-pancreatic
Hepatic
0.41 i 0.08
2.32f 0.47
1.67* 0.54
2.63 f 0.94
0.62i 0.24
0.21 i 0.27
Portal vein stenosis
In = 10)
0.66 f 0.23*t
3.65f 1.04*8
2.54f00.78*11
1.72 +0.30$11
0.97i 0.425t
0.52t0.41*t
Bile duct ligation
In = 10)
0.47i 0.145
1.88f 0.785
1.12f0.407
0.49t 0.32*
0.67 i 0.26$.
0.38i0.135
* Significantly different from normal (P< 0.01); t not significantly different from bile duct
ligation; $not significantly different from normal; 5 significantly different from bile duct ligation
(P< 0.01); II significantly different from bile duct ligation (P< 0.001); 11 significantly different
from normal (P< 0.05).
Mean values for cardiac output in rats with
portal hypertension due to portal vein stenosis and
in rats with portal hypertension due to bile duct
ligation were: 104.95 5 16.80 ml/min and 97.50k
6.78 ml/min, respectively. No significant difference
in cardiac output was found between these two
groups of rats, whereas the mean values for cardiac
output in these rats were significantly higher than
in normal rats (86.75 f 6.71 ml/min) (P< 0.02
and P < 0.01, respectively).
In rats with portal hypertension due t o portal
vein stenosis and in those with portal hypertension
due to bile duct ligation the mean values for portal
venous pressure were 13.85 2.0 mmHg and 13.1 k
1.8 mmHg, respectively, and were significantly
higher than those measured in normal rats (7.2 f
0.7 mmHg) (P< 0.001 in both).
Discussion
Methods used in the present study to induce portal
hypertension in the rat were previously described
[4-6, 81. The degree of portal hypertension was
similar in all cases, but mechanisms and haemo-
Splanchnic blood flow in portal hypertensive rats
dynamic effects differed between the two groups.
In rats with portal vein stenosis, portal hypertension is of so-called ‘prehepatic’ type: the liver is
normal, neither liver failure nor liver fibrosis
occurs, and, as shown by others, portosystemic
collateral circulation is extensive [8, 111. In rats
with bile duct ligation, portal hypertension is of
the so-called ‘intrahepatic’ type: secondary biliary
cirrhosis develops [S] associated with manifestations of liver failure (jaundice and ascites). The
liver lesions are similar to those observed in rats
with cirrhosis induced by repeated injections of
CC14 [8]. In both types of portal hypertensive
rats, it has already been demonstrated that by
3-4 weeks of the haemodynamic study, induced
portal hypertension is constant, permanent and
stable [4, 5, 81. In the present study, haemodynamic studies were performed in fasted rats
and consequently splanchnic organ weights,
mainly the intestine, as well as splanchnic organ
blood flows markedly differ from fed animals
[121.
The two types of portal hypertension have
opposite effects on both distribution of cardiac
output to splanchnic organs and organ blood flow.
In rats with portal hypertension due to portal
vein stenosis, portal venous tributary blood flow
increased, whereas in those with portal hypertension due to bile duct ligation, this tributary
blood flow decreased. Such a discrepancy in
results was marked with intestinal, colonic and
splenic perfusion, but was minimal with gastric
and mesenteric-pancreatic flow. Changes in
splanchnic organ blood flow did not directly
depend on changes in cardiac output, which
increased in both groups, but mainly on the
distribution of cardiac output. The increase in
portal venous bed perfusion in rats with portal
vein stenosis was the sum of an increase in both
the percentage of cardiac output and the cardiac
output itself. Such effects of portal hypertension
on perfusion of splanchnic organs are not clearly
understood; induced splanchnic resistance may
differ between the two types of portal hypertension, thereby inducing various modifications
in portal venous drainage.
A sustained increase in hepatic arterial blood
flow was observed in both types of portal hypertensive rats. This effect disappeared when hepatic
arterial blood flow was expressed per g of liver
tissue, and depended mainly on an increase in the
fraction of cardiac output, rather than on a rise in
cardiac output. Changes in hepatic arterial blood
flow are related to changes in portal venous blood
flow [13]. However, the correlation between
hepatic arterial and portal venous blood flows
probably does not directly depend upon portal
27
venous tributary blood flow, but rather upon
portal liver perfusion. This perfusion is reduced in
the two types of portal hypertensive rat, since a
large amount of blood from the portal venous
tributary directly reaches the systemic tributary
through spontaneous portosystemic shunts [8,11].
The marked increase in hepatic arterial blood flow
measured in rats with portal hypertension due to
bile duct ligation has been previously reported in
the dog [14-161. This increase is nearly twice
that measured in rats with portal hypertension
due to portal vein stenosis. The difference in the
hepatic arterial blood flow in the two types of
portal hypertensive rats is unclear. In those with
bile duct ligation, total splanchnic blood flow
increased slightly, because the increase in hepatic
arterial blood flow compensated for the decrease
in portal venous tributary blood flow. However,
changes in splanchnic blood flow in these rats
were less marked than those observed in rats with
portal vein stenosis. The difference between the
two types might be related to the degree of
development of portosystemic collateral venous
circulation.
The haemodynamic changes common to both
types of portal hypertension were a sustained
elevation in portal venous pressure and an increase
in cardiac output. The increase in cardiac output
seems to be at least partially the consequence of
the rise in portal venous pressure. This effect was
recently demonstrated in rats [6, 171, and is
a common response t o portal hypertension in man
[3, 18-20]. The mechanism for increased cardiac
output is unknown, but this study suggests two
possibilities. In rats with portal vein stenosis and
wide portosystemic collateral venous circulation,
the increase in cardiac output may be due to the
opened splanchnic shunt, as in rats with arteriovenous fistulae [21]. This relationship between the
increase in cardiac output and the presence of
portosystemic shunts may be compared with that
observed in patients with portal hypertension due
to portal vein obstruction; in these patients the
liver is normal [20]. In rats with bile duct
ligation, the increase seems to be due mainly to
liver failure, a known effect in man with or
without cirrhosis [22, 231.
Acknowledgments
The authors thank Dr C. Degott for histological
examinations and Dr C. T. Nuzum and Miss C.
Girod for their help. This work was supported by
grant CRL 8 2 7 018 from the Institut National de
la Sant6 et de la Recherche MBdicale.
28
D. Lebrec and L. Blanchet
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