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Institute for Clinical and Experimental Surgery, University of Saarland, D-66421 Homburg/Saar, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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 |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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 |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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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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).
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 |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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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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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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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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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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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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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 |
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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 |
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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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METHODS
RESULTS
DISCUSSION
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 N. Siebert, D. Cantre, C. Eipel, and B. Vollmar H2S contributes to the hepatic arterial buffer response and mediates vasorelaxation of the hepatic artery via activation of KATP channels Am J Physiol Gastrointest Liver Physiol, December 1, 2008; 295(6): G1266 - G1273. [Abstract] [Full Text] [PDF]
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 M. Hagiwara, H. Rusinek, V. S. Lee, M. Losada, M. A. Bannan, G. A. Krinsky, and B. Taouli Advanced Liver Fibrosis: Diagnosis with 3D Whole-Liver Perfusion MR Imaging--Initial Experience Radiology, March 1, 2008; 246(3): 926 - 934. [Abstract] [Full Text] [PDF]
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P. V. Pandharipande, G. A. Krinsky, H. Rusinek, and V. S. Lee Perfusion Imaging of the Liver: Current Challenges and Future Goals Radiology, March 1, 2005; 234(3): 661 - 673. [Abstract] [Full Text] [PDF]
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 S. Richter, A. Olinger, U. Hildebrandt, M. D. Menger, and B. Vollmar Loss of Physiologic Hepatic Blood Flow Control (""Hepatic Arterial Buffer Response"") During CO2-Pneumoperitoneum in the Rat Anesth. Analg., October 1, 2001; 93(4): 872 - 877. [Abstract] [Full Text] [PDF]
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) 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.
P < 0.05 vs. I.
