Impact of intrinsic blood flow regulation in
cirrhosis: maintenance of hepatic arterial buffer response
Sven
Richter,
Isabella
Mücke,
Michael D.
Menger, and
Brigitte
Vollmar
Institute for Clinical and Experimental Surgery, University of
Saarland, D-66421 Homburg/Saar, Germany
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ABSTRACT |
The hepatic arterial buffer
response (HABR) effectively controls total blood perfusion in normal
livers, but little is known about blood flow regulation in cirrhosis.
We therefore studied the impact of HABR on blood perfusion of cirrhotic
livers in vivo. After 8-wk CCl4 treatment to induce
cirrhosis, 18 anesthetized rats (and 18 noncirrhotic controls) were
used to simultaneously assess portal venous and hepatic arterial inflow
with miniaturized ultrasonic flow probes. Stepwise hepatic arterial
blood flow (HAF) or portal venous blood flow (PVF) reduction was
performed. Cirrhotic livers revealed a significantly reduced total
hepatic blood flow (12.3 ± 0.9 ml/min) due to markedly diminished
PVF (7.3 ± 0.8 ml/min) but slightly increased HAF (5.0 ± 0.6 ml/min) compared with noncirrhotic controls (19.0 ± 1.6, 15.2 ± 1.3, and 3.8 ± 0.4 ml/min). PVF reduction caused a
significant HABR, i.e., increase of HAF, in both normal and cirrhotic
livers; however, buffer capacity of cirrhotic livers exceeded that of
normal livers (P < 0.05) by 1.7- to 4.5-fold (PVF 80%
and 20% of baseline). Persistent PVF reduction for 1, 2, and 6 h
demonstrated constant HABR in both groups. Furthermore, HABR could be
repetitively provoked, as analyzed by intermittent PVF reduction. HAF
reduction did not induce changes of portal flow in either group.
Because PVF is reduced in cirrhosis, the maintenance of HAF and the
preserved HABR must be considered as a protective effect on overall
hepatic circulation, counteracting impaired nutritive blood supply via the portal vein.
hepatic blood flow; portal venous flow; hepatic arterial flow; hepatic arterial buffer response
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INTRODUCTION |
THE PATHOGENESIS OF
CIRRHOSIS, which is initiated by hepatocyte necrosis and an
inflammatory response with subsequent extracellular matrix deposition
(8), leads finally to distinct alterations of the hepatic
microvasculature (30). The cirrhosis-associated rarefaction of sinusoids (36, 37) and the
structural changes of sinusoidal endothelia (12,
36) result in deteriorated nutritive blood supply of the
liver, increased total hepatic vascular resistance, and, hence, portal
hypertension and portosystemic collateralization (12,
31). Although major interest has been focused on
rectifying blood flow disturbances (32), little is known
about the function of regulatory mechanisms of hepatic blood flow in
cirrhosis (11, 13, 27,
33).
Under physiological conditions, alterations of portal venous blood flow
are counteracted by flow changes of the hepatic artery, aiming at the
maintenance of total liver blood flow (14,
19). This regulatory mechanism, known as the hepatic
arterial buffer response (HABR) and apparently regulated by adenosine
(7, 15, 17, 24),
serves not only to fulfill oxygen and metabolic demands of the liver
(25) but also to control the overall metabolic well-being
of the organism by maintaining hepatic clearance and excretory function
(14, 15, 19). In hepatic
cirrhosis, altered hemodynamics crucially deteriorate tissue
oxygenation and liver function, and although the significance of
hepatic arterial blood flow in various pathophysiological conditions
has become evident (11, 20, 23,
34), the role of HABR in cirrhosis has not been
extensively examined. Therefore, the aim of our study was to analyze
the control of liver blood flow in cirrhotic rat livers with specific
regard to the existence, persistence, and repeatability of HABR.
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METHODS |
Cirrhosis model.
Experiments were performed in accordance with German legislation on
protection of animals and the Guide for the Care and Use of
Laboratory Animals (Institute of Laboratory Animal Resources, National Research Council).
Thirty-six Sprague-Dawley rats of either sex (body wt 301 ± 13 g; Charles River, Wiga, Sulzfeld, Germany) were divided into two groups. In group 1 (n = 18),
animals were given phenobarbital sodium (35 mg/dl) in drinking water,
and beginning 3 days later cirrhosis was induced by subcutaneous
injection with 0.15 ml CCl4/100 g body wt (Merck,
Darmstadt, Germany) in equal volumes of olive oil twice a week over a
time period of 8 wk, as previously described (36,
37). Group 2 (n = 18) consisted
of control animals receiving neither CCl4-olive oil
injections nor phenobarbital sodium. All animals were kept on a
standard dark-light cycle and were fed ad libitum with a stock pellet diet.
Surgical procedure.
After overnight fasting with free access to tap water, animals were
anesthetized with pentobarbital sodium (50 mg/kg body wt ip; Narcoren,
Braun, Melsungen, Germany), and supplemental doses (5 mg/kg body wt ip)
were given during the experiment as required. Tracheotomy was performed
to facilitate spontaneous breathing, and the animals were placed in a
supine position on a heating pad maintaining body temperature at
36-37°C. Catheters (PE-50, 0.58-mm ID; Portex, Hythe, UK) were
placed in the right carotid artery and jugular vein for continuous
monitoring of mean arterial blood pressure (MAP) and for fluid
substitution. After transverse laparotomy, microsurgical preparation
for assessment of liver blood flow was performed similar to the method
described by Lautt et al. (17) in cats. An ultrasonic
perivascular flow probe (0.5 V; Transonic Systems, Ithaca, NY) was
placed around the celiac artery, and all other branches including the
splenic artery, the left gastric artery, and the gastroduodenal artery were ligated, so that all blood entering the hepatic artery was derived
from the celiac artery. Likewise, a second flow probe (1.5 R; Transonic
Systems) was positioned around the superior mesenteric artery, which,
after ligation of all other inlet arteries to the splanchnic system
(inferior mesenteric artery, anastomoses with rectal arteries),
conducted blood flow solely representative of the portal vein.
This experimental approach allowed simultaneous assessment of hepatic
arterial and portal venous blood flow without the risk of mechanical
obstruction or kinking of the referring vessels. An additional catheter
(PE-50, 0.28-mm ID; Portex) was inserted via the splenic vein for
continuous monitoring of portal venous blood pressure
(PVP).

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Fig. 1.
Histological section of liver tissue (Ladewig staining) after
CCl4 exposure for 8 wk. Note the dense fibrous septa
dividing the hepatic parenchyma into multiple discrete nodules.
Magnification, ×185
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Blood flow measurements.
After tourniquets (5-0 Ethibond; Ethicon, Norderstedt, Germany)
were placed around the superior mesenteric and celiac arteries, stepwise reduction of blood flow of either of the feeding vessels to
80%, 60%, 40%, and 20% of baseline values was performed with a
micromanipulator-controlled constrictor (cirrhosis, n = 6; controls, n = 6). Each individual step of portal
venous flow reduction was kept constant over a time period of 5 min for
measurement of the corresponding change in hepatic arterial blood flow
and vice versa. Heterogeneity of portal venous flow reduction was
analyzed by calculation of the coefficient of variance as standard
deviation divided by mean of the percent change of portal venous blood
flow. Flow reductions from 100% to 20% of baseline were repeated
three times in each animal, and sufficient recovery times (~15 min) between the individual measurements were allowed for regaining baseline
hemodynamics. The flow probes were connected to a flowmeter (T206
Animal Research Flowmeter, Transonic Systems), and the blood flow data
as well as MAP and PVP were recorded using a computerized data
aquisition system (Dasylab; Datalog, Mönchengladbach, Germany). For calibration of the ultrasonic flow probes, saline solution had been
perfused at standard flow rates via an aortic catheter into the
mesenteric or celiac artery in earlier in situ experiments. In addition
to the assessment of hepatic arterial and portal venous blood flow as
absolute values (ml/min), we calculated the hepatic arterial
conductance, as deduced from hepatic arterial flow per kilogram of body
weight divided by the pressure gradient between the arterial and venous
pressures (ml · min
1 · kg · mmHg).
PVP was used for the hepatic arterial conductance because PVP was
reported to be insignificantly different from hepatic sinusoidal
pressure (18). Moreover, we determined the buffer capacity
as change of hepatic arterial flow
change of portal venous
flow × 100, being aware that arterial blood pressure was not
controlled and that changes of arterial blood pressure might
potentially influence the net buffer capacity (19).
In a second set of experiments, persistence of HABR was analyzed by
portal venous flow reduction to 20% of baseline values over a total of
1, 2, and 6 h, each followed by portal venous flow restoration
(n = 3 animals with either normal or cirrhotic livers
for each time period). Additionally, repeatability of HABR was assessed
by four consecutive cycles of portal venous flow reduction to 20% of
baseline levels for 15 min with restoration of blood flow for another
15 min (n = 3 animals in each of the 2 groups).
Histopathology.
Samples of liver tissue were fixed in 4% phosphate-buffered formalin
for 2-3 days and embedded in paraffin. Sections (5 µm) were cut
and mounted on poly-L-lysine slides for trichrome staining (Ladewig) to assess cirrhosis-associated collagen deposition.
Statistical analysis.
All values are expressed as means ± SE. After the assumption of
normality and homogeneity of variance across groups was proven, differences between groups were calculated using the unpaired Student's t-test (shown only in text to ensure clarity of
figures). Differences between the individual occlusion steps within a
group were assessed by one-way ANOVA (overall differences) followed by
the Student-Newman-Keuls method (pairwise multiple comparisons). Overall statistical significance was set at P < 0.05. Statistics were performed using the software package SigmaStat (SPSS,
Chicago, IL).
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RESULTS |
Rats treated with CCl4 for 8 wk revealed a
macroscopically nodular liver surface, a significant (P < 0.01) gain in liver weight (4.98 ± 0.13 g/100 g body wt vs.
3.22 ± 0.12 g/100 g body wt in controls), and histological signs
of micronodular cirrhosis, i.e., dense fibrous septa dividing the
hepatic parenchyma into multiple discrete nodules (Fig.
1). However, ascites and pronounced portosytemic collateralization were not evident.
In control animals, total liver blood flow showed values of 19.0 ± 1.6 ml/min with a portal venous blood flow of 15.2 ± 1.3 ml/min and a hepatic arterial flow of 3.8 ± 0.4 ml/min. In
cirrhotic animals, total liver blood flow was found to be significantly reduced (12.3 ± 0.9 ml/min; P < 0.01 vs.
controls) because of markedly diminished portal venous flow (7.3 ± 0.8 ml/min; P < 0.01 vs. controls), whereas hepatic
arterial flow increased (5.0 ± 0.6 ml/min) comparably to that of
noncirrhotic controls. Thus the ratio of portal venous to hepatic
arterial blood flow of 79.8% to 20.2% under control conditions
changed to 59.3% to 40.7% in cirrhosis.
Stepwise reduction of portal venous blood flow initiated a pronounced
and immediate HABR, i.e., an increase in hepatic arterial flow in both
groups (Fig. 2). Concomitantly, hepatic
arterial conductance increased progressively but without significant
differences between the groups (Table 1).
Repetition of the stepwise portal venous flow reduction did not
influence the kinetics of the onset or the degree of HABR (Table
2). The degree of portal venous flow
reduction did not vary markedly within the individual experiments or
between the groups, as indicated by the quite low and almost unchanged
coefficient of variance of percent change in portal venous blood flow
(Table 3).

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Fig. 2.
Hepatic arterial blood flow ( ) in cirrhotic
(A) and control (B) livers after reduction of
portal venous blood flow ( ) to 80% (II), 60% (III),
40% (IV), and 20% (V) of baseline (I). Values are means ± SE
for triplicate measurements/animal (n = 6).
§P < 0.05 vs. I, II, III, IV;
#P < 0.05 vs. I, II, III;
*P < 0.05 vs. I, II.
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Table 1.
Hepatic arterial conductance and buffer capacity during consecutive
reductions of portal venous blood flow
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Table 3.
Coefficient of variance (relative dispersion) of percent changes of
portal venous blood flow during consecutive reductions of portal venous
blood flow
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Flow reduction of the hepatic artery did not influence portal venous
blood flow (Fig. 3). Repetition of
stepwise flow reduction of hepatic arterial flow was also not
associated with any significant change of portal venous blood flow in
either of the two groups (data not shown). MAP of cirrhotic animals did
not differ from that of noncirrhotic controls. Interestingly, reduction
of portal venous blood flow to 20% resulted in a significant increase
of MAP of ~10-15% in both groups (Fig.
4), whereas reduction of hepatic arterial
blood flow did not induce changes in MAP (Fig.
5). PVP was only slightly (although
significantly, P < 0.05) higher in cirrhotic animals
and remained almost unchanged by either hepatic arterial or portal
venous flow reduction (Figs. 4 and 5).

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Fig. 3.
Portal venous blood flow ( ) in cirrhotic
(A) and control (B) livers after reduction of
hepatic arterial blood flow ( ) to 80% (II), 60% (III), 40%
(IV), and 20% (V) of baseline (I). Values are means ± SE for
triplicate measurements/animal (n = 6).
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Fig. 4.
Mean arterial ( ) and portal venous
( ) blood pressure during portal venous blood flow
reduction to 80% (II), 60% (III), 40% (IV), and 20% (V) of baseline
(I) in cirrhotic (A) and control (B) livers.
Values are means ± SE for triplicate measurements/animal
(n = 6). §P < 0.05 vs. I,
II, III, IV; #P < 0.05 vs. I, II, III;
*P < 0.05 vs. I, II; P < 0.05 vs. I.
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Fig. 5.
Mean arterial ( ) and portal venous
( ) blood pressure during hepatic arterial blood flow
reduction to 80% (II), 60% (III), 40% (IV), and 20% (V) of baseline
(I) in cirrhotic (A) and control livers (B).
Values are means ± SE for triplicate measurements/animal
(n = 6).
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Although portal venous flow reduction to 20% could not be thoroughly
compensated for by HABR, the decrease of total liver blood flow was
less pronounced in cirrhotic animals [
2.1 ml/min (
20.1%) vs.
8.5 ml/min (
44.9%) in controls; Fig.
6]. Although the absolute value of HABR
in cirrhosis is, on average, very similar to that in controls, the
proportionate increase in hepatic arterial flow is strikingly augmented
in cirrhosis. This is further reflected by the significantly higher
buffer capacity in cirrhotic animals compared with controls (Table 1).

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Fig. 6.
Total liver blood flow in cirrhotic (A) and control
(B) livers with the contributing fractions of portal venous
(open bars) and hepatic arterial (solid bars) blood flow under either
baseline conditions (plain bars) or conditions of portal venous blood
flow reduction to 20% (hatched bars). Values are means ± SE; n = 6.
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Portal venous flow reduction for 1, 2, or 6 h to 20% of baseline
values demonstrated a constant HABR in both cirrhotic and control
animals (Figs. 7 and
8). During the whole experimental time
period, neither significant changes of blood flow (Figs. 7 and 8) nor
changes in MAP and PVP (data not shown) occurred, thus indicating
persistence of the intrinsic hepatic blood flow regulation over
prolonged periods of compromised portal venous perfusion. Strikingly,
reestablishment of portal venous perfusion resulted in immediate (<10
min) return of hepatic arterial blood flow, regardless of the duration
of HABR (1, 2, or 6 h; Figs. 7 and 8).

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Fig. 7.
Persistence of hepatic arterial buffer response (HABR),
i.e., increase of hepatic arterial blood flow ( ), in cirrhotic
livers for 1 (A), 2 (B), and 6 (C) h of portal
venous blood flow reduction to 20% ( ). Values are
means ± SE; n = 3 for each time period.
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Fig. 8.
Persistence of HABR, i.e., increase of hepatic arterial
blood flow ( ) in control livers for 1 (A), 2 (B), and 6 (C) h of portal venous blood flow
reduction to 20% ( ). Values are means ± SE;
n = 3 for each time period.
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Intermittent reduction of portal vein flow to 20% with intermediate
restoration of baseline flow conditions showed that HABR could be
repetitively provoked in both experimental groups (Fig. 9). Blood flow reduction was always
accompanied by a slight decrease of PVP and an increase of MAP (Fig.
10). These changes were more pronounced
than in stepwise flow reduction (Fig. 4), and fluctuation in MAP due to
reduction and restoration of portal blood flow was significantly more
pronounced in cirrhotic livers (Fig. 10A) than in controls
(Fig. 10B).

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Fig. 9.
Repeatability of HABR, i.e., increase of hepatic arterial
blood flow ( ) during consecutive portal venous blood flow
reduction to 20% ( ) for 15 min and restoration of
baseline flow conditions for 15 min in cirrhotic (A) and
control (B) livers. Values are means ± SE;
n = 3.
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Fig. 10.
Mean arterial ( ) and portal venous
( ) blood pressure during repetitive reduction of portal
venous blood flow for 15 min and restoration to baseline flow
conditions for 15 min in cirrhotic (A) and control
(B) livers. Values are means ± SE; n = 3.
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DISCUSSION |
A number of studies have been performed to analyze physiological
control mechanisms of hepatic blood flow (2,
7, 14, 17, 19,
22, 26, 28). However, the
significance of dual blood supply of the liver in various pathological
states is still poorly understood (10, 16) or
even neglected (4, 35). Although it is well
known that major blood flow disturbances within the hepatic
microcirculation occur in liver cirrhosis, only a few studies have
addressed the role of hepatic arterial perfusion (5,
11, 13, 20, 23,
33).
In the present study, we demonstrated reduced total liver blood flow
caused by reduced portal venous perfusion in cirrhosis while hepatic
arterial blood flow was maintained. PVP was significantly elevated when
compared with controls and fulfilled the criteria of portal
hypertension (31). However, we did not observe excessive portal hypertension or manifest ascites as observed by others using
different modes and models of cirrhosis induction (5, 6, 27, 32). The lack of
excessive portal hypertension might be explained by the reduction or
even elimination of hyperdynamic circulation on pentobarbital
anesthesia (4, 21, 31). This view is further supported by our findings of normal MAP values in
cirrhotic animals.
HABR has been examined in pigs (1, 9), dogs
(11), sheep (34), and cats (7,
14, 15, 17, 19,
22). However, because one of the aims of our study was to
set up a cirrhosis model in the rat that allows for measurement of
hepatic blood flow, we adopted the technique described by Lautt et al.
(17) with minor modifications. Although the use of
perivascular flow probes has been regarded as technically difficult in
the rat (29), transonic flowmeters have been proven to be
accurate and highly reproducible (38). Therefore, the
blood flow values obtained in the present study are consistent with
those reported by others using flowmeters (38),
microspheres (5, 21, 31), or
clearance techniques (29).
The magnitude or efficiency of the buffer response varies widely
depending on the technique used and the condition of the animal. In the
context of variability of acute HABR under experimental conditions,
Lautt (14) reported that HABR is generally greater at the
early part of an experiment, and in some animals it became completely
ineffective within 2 h of recording. Moreover, inasmuch as
anesthesia might already have initiated some buffer response, we cannot
exclude potential basal activation, although pentobarbital was reported
not to influence HABR (19). In addition, to record hepatic
arterial blood flow, the currently used methodology requires splenectomy, which would be expected to reduce portal flow and further
activate the buffer response. The present methodology might
underestimate the buffer capacity, but it allows us to evaluate the
principle of hepatic artery responsiveness.
In addition to the classic concept of HABR, a reciprocal relationship
between hepatic arterial and portal venous blood flow has also been
proposed (3); this, however, was not observed in the
present study. In addition, our results do not confirm the findings of
Ayuse et al. (1) demonstrating that flow changes in the
hepatic artery affect PVP.
Stepwise reduction of portal venous flow revealed a completely
maintained HABR in cirrhosis, although it could be speculated that HABR
had already been activated under these pathological conditions and
might therefore be limited in extent. However, the enormous buffer
capacity, with highest values between 50% and 60% in cirrhotic
animals, indicates the maintenance of a remarkable potential of the
hepatic artery to counteract reduced portal venous blood flow.
To our knowledge, no study has investigated the maintenance of HABR
over prolonged time periods. We were able to demonstrate a constant
HABR over a 6-h period of portal venous flow reduction in both normal
and cirrhotic animals. These findings, together with the sustained
repeatability of the buffer response, demonstrate the maintenance of
HABR and underline the significance of this regulatory mechanism,
particularly under the pathological conditions of cirrhosis.
Our results show that the degree of HABR in either cirrhotic or normal
livers could not thoroughly compensate for diminished portal venous
blood flow and maintain total liver blood flow. However, we show for
the first time that the absolute reduction of total liver blood flow
was less pronounced in cirrhotic than in control livers, because the
proportionate increase of hepatic arterial flow is strikingly augmented
in cirrhosis. Normally, the portal vein provides the major blood supply
of oxygen to the liver (24). In cirrhosis, the change of
the ratio of portal venous to hepatic arterial blood flow in favor of
the hepatic artery may sustain oxygen delivery and exert a protective
effect on organ function and integrity (25).
In conclusion, we established a reliable rat cirrhosis model that
allows measurement of hepatic arterial and portal venous blood flow as
well as mean arterial and portal venous blood pressure over
experimental periods up to 6 h. Because portal venous blood flow
is reduced in cirrhosis, the maintenance of hepatic arterial blood flow
and the preserved HABR probably represent a beneficial mechanism for
hepatic circulation, thereby counteracting impaired nutritive blood
supply of the cirrhotic liver.
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ACKNOWLEDGEMENTS |
This study was supported by grants from the Deutsche
Forschungsgemeinschaft (DFG) (Me 900/1-3 and 900/1-4) and the
Wilhelm Sander Stiftung (no. 93.019.2). B. Vollmar is the recipient of a Heisenberg-Stipendium (Vo 450/6-1) from the DFG (Bonn-Bad
Godesberg, Germany).
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FOOTNOTES |
Address for reprint requests and other correspondence: B. Vollmar, Inst. for Clinical and Experimental Surgery, Univ. of
Saarland, 66421 Homburg/Saar, Germany (E-mail:
exbvol{at}med-rz.uni-sb.de).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 22 November 1999; accepted in final form 17 February 2000.
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