Vol. 87, Issue 4, 1404-1412, October 1999
INVITED REVIEW
Presinusoidal vessels predominantly contract in response to
norepinephrine, histamine, and KCl in rabbit liver
Toshishige
Shibamoto,
Hong-Gang
Wang,
Takashige
Miyahara,
Satoshi
Tanaka,
Hisao
Haniu, and
Shozo
Koyama
Division 2, Department of Physiology, Shinshu University School
of Medicine, Matsumoto 390-8621, Japan
 |
ABSTRACT |
In rabbit
livers, it is not well known which segments of the hepatic vasculature
are predominantly contracted by various vasoconstrictors. We determined
effects of histamine, norepinephrine, and KCl on hepatic vascular
resistance distribution in isolated rabbit livers perfused via the
portal vein with 5% albumin-Krebs solution at a constant flow rate.
Hepatic capillary pressure was measured by double vascular occlusion
pressure (Pdo) and was used to determine portal (Rpv) and hepatic
venous (Rhv) resistances. A bolus injection of either histamine or
norepinephrine dose-dependently increased portal venous pressure but
not Pdo, resulting in a dose-dependent increase in Rpv and no changes
in Rhv. KCl (50 mM), when injected in anterogradely perfused livers,
contracted the presinusoidal vessels selectively with liver weight
loss. Although KCl significantly increased Rhv in retrogradely perfused
livers, the increase in Rpv by 400% of baseline predominated over the
increase in Rhv by 85% of baseline. In the retrogradely perfused
livers, KCl produced an initial liver weight loss followed by a
profound weight gain. We conclude that histamine and norepinephrine
selectively contract the presinusoidal vessels. The results on KCl
effects suggest that this selective presinusoidal constriction might be
possibly due to predominant distribution of functionally active
vascular smooth muscle in the presinusoidal vessels rather than the
hepatic vein in rabbit livers.
double vascular occlusion pressure; sinusoidal pressure; portal
vein; hepatic vascular resistance; hepatic circulation
| |
INTRODUCTION |
WE HAVE RECENTLY SHOWN, by using vascular occlusion
methods for measurement of hepatic capillary pressure, that hepatic
longitudinal vascular responsiveness differs depending on
vasoconstrictive substances in isolated perfused canine livers (20, 22,
23, 25). Either histamine (20, 22) or the thromboxane
A2 analog (22) predominantly
contracts the canine hepatic vein with resultant hepatic congestion,
whereas norepinephrine constricts both the presinusoidal vessels and
hepatic artery more vigorously than the hepatic vein, with reduction of
liver weight (20). In contrast, acetylcholine (20) and
platelet-activating factor (23) constrict both portal and hepatic veins
in a similar magnitude. However, there could be species differences in
the primary site of hepatic vasoconstriction. In isolated perfused
rabbit livers, we have recently reported that endothelin-1 selectively
contracts the presinusoidal vessels (24). However, only a limited
number of studies have been reported to determine effects of
vasoconstrictors on rabbit hepatic vascular resistance distribution
(19).
Therefore, in the present study, we determined, by using the
double-vascular-occlusion method, the effects of histamine and norepinephrine on longitudinal vascular resistance distribution in
isolated rabbit livers perfused with 5% albumin-Krebs buffer. The
reason for adopting histamine and norepinephrine as the
vasoconstrictors in the present study was that norepinephrine
predominantly constricts the presinusoidal vessels over the hepatic
vein (3, 19, 20), whereas histamine predominantly contracts the hepatic
vein over the presinusoidal vessels in canine livers (12, 16, 20, 22).
In this study, we assumed that the distribution of vascular smooth
muscle between presinusoidal vessels and hepatic veins may play a key
role in hepatic vasoreactivity. Thus another purpose of the present
study was to determine which segment of the hepatic vasculature was
primarily contracted by KCl, which in turn could act directly on
vascular smooth muscle without mediation of receptor activation. We
used the reverse-perfusion technique to clarify more accurately the
hepatic vascular response to KCl.
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MATERIALS AND METHODS |
Isolated liver preparation.
Twenty rabbits, weighing 2.2 ± 0.1 (SE) kg, were anesthetized with
pentobarbital sodium (30 mg/kg iv) and mechanically ventilated with
room air. The experiments were performed in adherence to the guidelines
of the Physiological Society of Japan for the use of experimental
animals, and the protocols were approved by the Shinshu University
Animal Care Committee. The method for isolated rabbit liver preparation
was previously described (24). Catheters were placed in the left
jugular vein and in the right carotid artery. After left thoracotomy
and laparotomy, loose ligatures were placed around the hepatic artery,
portal vein, inferior vena cava, and common bile duct. At 5 min after
heparinization (500 U/kg iv), the rabbit was rapidly bled through the
carotid arterial catheter. After ligation of the aforementioned vessels
and bile duct, the liver was rapidly excised and weighed. Then, the
portal vein and vena cava were cannulated with plastic cannulas (3 mm ID), whereas the hepatic artery was ligated to simplify analysis of the
intrahepatic vascular circuit. The common bile duct was also cannulated
with polyethylene tubing. Perfusion was begun within 5 min after
excision of the liver.
The cannulated liver was suspended from an electric balance (LF-6,
Murakami Koki) and perfused via the portal vein at a constant perfusion
flow rate of 0.157 ± 0.008 l/min
(n = 15) with 200 ml of 5%
bovine albumin (Sigma Chemical) in Krebs-Henseleit buffer in a
recirculating fashion. The perfusate was maintained at 37°C by
using a water bath, and the perfusate in the reservoir was continuously
bubbled with 95% O2-5%
CO2 (inflow perfusate
PO2: 300 Torr). A bubble trap was
placed in the inflow line. Portal (Ppv) and hepatic venous (Phv)
pressures were measured through the corresponding sidearm cannula by
using pressure transducers (Gould) referenced to the level of the
portal vein at the hepatic hilus. The perfusion flow rate
(
) was measured with an electromagnetic flowmeter
(MFV 1200, Nihonkohden), and the flow probe was positioned in the
outflow line. To occlude the portal and hepatic venous lines
simultaneously for measurement of the double occlusion pressure (Pdo),
solenoid valves were placed around the perfusion tubes upstream from
the Ppv sidearm cannula and downstream from the Phv sidearm cannula.
Bile was continuously collected in a small tube suspended from the
force transducer (45196A, NEC-Sanei). The weight of the tube was
continuously measured, and the bile flow rate was expressed as grams
per minute per 100 g liver weight. The liver weight, bile flow, and
hemodynamic variables were continuously monitored and displayed on a
thermal physiograph (8K23, NEC-Sanei). Initially, an isogravimetric
state (neither weight gain nor loss) was obtained by adjusting the flow
rate and the height of the reservoir independently to maintain Ppv and
Phv at a level within the normal perfusion range, as described below.
Experimental protocol.
Hepatic hemodynamic parameters were observed for at least 20 min after
the start of perfusion, during which an isogravimetric state was
reached at a Ppv of 6-9 mmHg, a Phv of 0-2 mmHg, and a
of 0.195 ± 0.014 (SE)
l · min
1 · 100 g liver wt1
(n = 15). After the baseline
measurements were taken, the perfused livers were challenged with
either histamine, norepinephrine, or KCl. In the norepinephrine group
(n = 5), 0.33, 3.3, 33, or 330 µg,
or 3.3 mg of norepinephrine were injected as a bolus into the portal
line and attained the final perfusate concentration of 0.01, 0.1, 1, 10, or 100 µM, respectively. In the histamine group
(n = 5), 0.37, 3.7, 37, 110, or 370 µg, or 3.7 mg of histamine were injected as a bolus into the portal line and
attained the final perfusate concentration of 0.01, 0.1, 1, 10, 30, or
100 µM, respectively. In the KCl group
(n = 5), KCl was injected as a bolus
into the portal line and attained the final perfusate concentration of
50 mM. In the retrograde perfusion KCl group (n = 5), the liver was perfused
retrogradely from the hepatic vein, and KCl was injected into the
inflow (hepatic venous) line to attain the final perfusate
concentration of 10, 25, and 50 mM. The volume of each agent injected
was adjusted to <1 ml.
Hepatic sinusoidal pressure was measured by the double-occlusion method
(24, 25). Both the inflow and outflow lines were simultaneously and
instantaneously occluded by using the equipped solenoid valves, after
which Ppv and Phv rapidly equilibrated to a similar or identical
pressure, which was Pdo. In each experimental group, Pdo was measured
at baseline and 1, 2, 3, 6, 10, 20, and 30 min after an injection of
each agent. When low doses of agents were injected, Pdo was determined
only at maximal vasoconstriction.
The total portal-hepatic venous (Rtot), portal or presinusoidal (Rpv),
and hepatic venous (Rhv) resistance were calculated as follows
|
(1)
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|
(2)
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(3)
|
Statistics.
All results are expressed as means ± SE. Comparisons were made by
using Student's t-tests. A
P value <0.05 was considered significant.
| |
RESULTS |
Effects of histamine and norepinephrine on hepatic hemodynamics,
liver weight, and bile flow.
The initial wet liver weight measured immediately after excision was 86 ± 6 g (n = 15). Pdo at baseline
state of 15 anterogradely perfused livers was 3.7 ± 0.2 mmHg, with
Ppv of 7.3 ± 0.3 mmHg and Phv of 1.2 ± 0.2 mmHg at
of 0.195 ± 0.014 l · min1 · 100 g liver wt1. The calculated Rtot was 33.0 ± 4.1 mmHg · l1 · min1 · 100 g liver wt1. The segmental
vascular resistances of Rpv and Rhv were 20.2 ± 3.8 and 12.9 ± 1.2 mmHg · l1 · min1 · 100 g liver wt1, respectively,
and the Rhv-to-Rtot ratio (Rhv/Rtot) was 0.41 ± 0.04.
Figure 1
(left) shows a representative
example of the response to an injection of 330 µg norepinephrine (10 µM) into a perfused rabbit liver. Soon after an injection of
norepinephrine, Ppv increased from 5.3 to 14.7 mmHg, indicating that
vasoconstriction occurred. Phv at 1 mmHg was not changed because the
perfusion rate of 0.12 l/min was maintained. Capillary (sinusoidal)
pressure (i.e., Pdo) at 1 min after norepinephrine injection was 3.3 mmHg and was similar to the baseline value of 3 mmHg. Thus, after
norepinephrine, the pressure gradient between Ppv and Pdo was increased
from the baseline value of 2.3 to 11.4 mmHg, whereas the pressure
gradient between Pdo and Phv was not much changed. This finding
indicates that norepinephrine selectively increased the pressure
gradient from the portal vein to the capillary, that is, Rpv. Liver
weight was rapidly decreased after norepinephrine and began to return
toward the baseline when elevated Ppv began to decrease. The bile flow rate also decreased, along with liver weight loss and hepatic vasoconstriction. Hepatic vasoconstriction peaked within 3 min after an
injection of norepinephrine, followed by a gradual return to baseline
by 30 min after injection. The selective presinusoidal vessel
constriction, liver weight loss, and a decrease in the bile flow were
all similarly observed in the liver injected with 100 µM histamine,
as shown in Fig. 1 (right), although
the magnitude of the responses was small compared with that to 10 µM
norepinephrine (Fig. 1, left).
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Fig. 1.
Representative recording of response to injection of 330 µg
norepinephrine [10 µM
(left)] and 3.3 mg histamine
[100 µM (right)] in
perfused rabbit liver.
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Table 1 shows the summary data of Ppv, Pdo,
and Phv after norepinephrine and histamine. Ppv increased dose
dependently, with peak values of 23.9 ± 2.1 mmHg at 100 µM
norepinephrine and 12.0 ± 1.4 mmHg at 100 µM histamine. There
were no significant changes in Pdo after norepinephrine or histamine
[3.6 ± 0.3 vs. 3.9 ± 0.5 mmHg, baseline vs.
after 100 µM norepinephrine (n = 5);
3.3 ± 0.3 vs. 3.3 ± 0.4 mmHg, baseline vs. after 100 µM
histamine (n = 5)].
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Table 1.
Changes in portal venous pressure, double-occlusion pressure, and
hepatic venous pressure after injection of norepinephrine,
histamine, or KCl in isolated perfused rabbit livers
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Figure 2 shows the peak changes in Rpv,
Rhv, Rhv/Rtot ratio, and liver weight after injection of
norepinephrine. In livers injected with norepinephrine, Rpv increased
in a dose-dependent manner at 0.1-100 µM, reaching the maximum
level of 408 ± 33% of baseline at 100 µM. In contrast, Rhv did
not change significantly even at the highest concentration of 100 µM
norepinephrine, and therefore the Rhv/Rtot ratio decreased to 39 ± 2% of the baseline values.
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Fig. 2.
Peak changes in portal (Rpv) and hepatic (Rhv) venous resistances,
hepatic venous-to-total hepatic venous resistance ratio (Rhv/Rtot), and
liver weight at concentrations of 0.01-100 µM norepinephrine as
expressed by percentage of baseline.
* P < 0.05 from baseline.
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Figure 3 shows the peak changes in Rpv,
Rhv, Rhv/Rtot ratio, and liver weight after injection of histamine. In
response to histamine, Rpv significantly increased at 1 µM, reaching
the maximum level of 197 ± 9% of the baseline at 100 µM. In
contrast, Rhv did not change significantly at concentrations ranging
from 0.01 to 100 µM. Therefore, the Rhv/Rtot ratio decreased to 64 ± 3% of the baseline values at 100 µM histamine.
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Fig. 3.
Peak changes in Rpv, Rhv, Rhv/Rtot, and liver weight at concentrations
of 0.01-100 µM histamine as expressed by percentage of baseline.
* P < 0.05 from baseline.
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Liver weight was decreased dose dependently after either norepinephrine
or histamine (Figs. 2 and 3). The maximum liver weight loss was 12.9 ± 2.4 g/100 g liver wt at 10 µM norepinephrine, and 3.6 ± 0.5 g/100 g liver wt at 100 µM histamine. The bile flow rate was 0.05 ± 0.01 g · min1 · 100 g liver wt1
(n = 10) at baseline and was
transiently decreased concomitantly with liver weight loss after
injection of norepinephrine or histamine. Table
2 shows the summary data of changes in bile
flow. Norepinephrine reduced the bile flow dose dependently to 63 ± 11% of baseline at 0.1 µM, 56 ± 10% at 1 µM, 21 ± 11% at
10 µM, and 11 ± 5% at 100 µM. Histamine also decreased the
bile flow to 56 ± 16% of baseline at 100 µM.
Effects of KCl on hepatic hemodynamics, liver weight, and bile flow.
We studied the effect of KCl on hepatic vascular resistance
distribution to determine the distribution of effective smooth muscle
by directly stimulating vascular smooth muscle with KCl. Figure
4 shows a representative recording of the
hepatic vascular response to 50 mM KCl in an anterogradely perfused
liver. KCl caused presinusoidal constriction, as characterized by an
increase in Ppv without changes in Pdo. This KCl-induced
vasoconstriction was accompanied by decreases in liver weight and bile
flow rate. This response was similar to that to histamine and
norepinephrine. Figure 5 shows
representative recordings of a retrogradely perfused liver injected
with 10, 25, and 50 mM KCl. At low concentrations of 10 and 25 mM, KCl
did not change either Ppv or Pdo but produced transient liver weight
loss. An injection of the same volume of saline did not cause any
changes in liver weight or pressures (data not shown). At the highest
concentration of 50 mM KCl, Pdo was increased along with an increase in
the inflow pressure of Phv during the retrograde perfusion. Liver
weight showed a biphasic response, as characterized by an initial liver
weight loss followed by a progressive weight gain.
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Fig. 4.
Representative recording of response to injection of KCl (50 mM) in
anterogradely perfused rabbit liver.
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Fig. 5.
Representative recording of response to injection of KCl (10, 25, and
50 mM; left,
middle, and
right, respectively) in retrogradely
perfused rabbit liver.
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As shown in Table 1, after 50 mM KCl in anterogradely perfused livers,
Ppv was increased from baseline of 8.5 ± 0.4 mmHg to the peak
values of 20.3 ± 2.2 mmHg, but Pdo did not significantly change
(3.9 ± 0.2 vs. 4.0 ± 0.3 mmHg, baseline vs. after KCl). In
contrast, in retrogradely perfused livers, 50 mM KCl caused significant
increases in Phv (the inflow pressure) from the baseline of 8.3 ± 0.4 to 22.4 ± 2.0 mmHg and in Pdo from the baseline of 4.8 ± 0.1 to 16.7 ± 2.0 mmHg. In this retrograde perfusion KCl group,
neither 10 nor 25 mM KCl caused no significant increases in Phv, Ppv,
or Pdo.
Figure 6 shows the summary data for Rpv,
Rhv, Rhv/Rtot ratio, and liver weight in both the KCl and retrograde
perfusion KCl groups. In anterogradely perfused livers injected with
KCl, Rpv was increased but Rhv did not change significantly, with a
resultant decrease in the Rhv/Rtot ratio. In retrogradely perfused
livers, 10 and 25 mM KCl did not significantly increase either Rpv or Rhv. However, at the highest concentration of 50 mM KCl, Rhv was significantly increased by 85% of baseline, although Rpv was increased by a much greater magnitude to 500% of baseline. Figure 6
(bottom right) shows the response of
liver weight to KCl. In retrogradely perfused livers, a dose-dependent
liver weight loss was observed within an initial 1 min, but the
subsequent weight gain occurred only at the highest dose of 50 mM KCl.
In anterogradely perfused liver injected with 50 mM KCl, liver weight
progressively decreased. As shown in Table 2, in response to 50 mM KCl,
the bile flow rate decreased to 22 ± 14% of baseline in
anterogradely perfused livers and to 73 ± 17% in retrogradely
perfused livers.
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Fig. 6.
Peak changes in Rpv, Rhv, Rhv/Rtot, and liver weight after injection of
KCl (10, 25, and 50 mM) with retrograde perfusion (open bars) and 50 mM
KCl injection with anterograde perfusion (solid bars). In liver weight
gain panel (bottom right),
left column shows initial 1-min change and
right column the maximal change
6-10 min after injection.
* P < 0.05 from baseline.
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DISCUSSION |
Hepatic vasoconstriction sites in dog livers differ depending on
vasoactive substances (12, 16, 20, 22, 23). In fact, histamine
predominantly contracts the canine hepatic vein (12, 16, 20, 22),
whereas norepinephrine primarily contracts the presinusoidal vessels
rather than the hepatic vein (3, 19, 20). There could be species
differences in hepatic vascular responsiveness. In the present study,
we determined effects of histamine and norepinephrine on hepatic
vascular resistance distribution in rabbit livers.
Vasoreactivity to vasoactive substances will depend on the receptor
density, the ability to transmit the stimulus message, and the quantity
of effective smooth muscle at the effective site. Thus the role of
functional vascular smooth muscle in vasoconstrictive responses was
estimated by measuring the longitudinal distribution of the resistance
increase induced by KCl. In these experiments, Rtot was assigned to Rpv
and Rhv by measuring Pdo as hepatic capillary pressure. A bolus
injection of either histamine or norepinephrine caused a dose-dependent
increase in Rpv, but no changes in Rhv. KCl (50 mM), when injected
portally, increased Rpv almost exclusively, whereas the same dose of
KCl injected into the hepatic vein in retrogradely perfused livers
caused small but definite hepatic venous constriction concomitant with
marked portal contraction. This finding suggests that functional smooth
muscle may exist in much greater quantity in the presinusoidal vessels
than in the hepatic veins in rabbit livers. Thus the present results
suggest that histamine and norepinephrine selectively contract the
presinusoidal vessels, which may be ascribed, at least in part, to
predominant distribution of functionally active vascular smooth muscle
in the presinusoidal vessels rather than the hepatic veins.
Our laboratory has recently shown, by measuring the capillary pressure
with the use of the triple-vascular-occlusion method (20) and the
double-occlusion method (25) in isolated canine livers, that
postsinusoidal vascular resistance comprises approximately one-half of
total liver vascular resistance. In the subsequent study,
we have shown, using the same vascular occlusion method, that 59% of
Rtot exists in the presinusoidal vessels and 41% in the hepatic vein
at resting state of isolated rabbit liver. This finding was confirmed
by the present study and is consistent with the results obtained by
using a micropipette servo-null pressure measurement technique in in
vivo rabbit liver (3, 14, 15, 19). Thus these results suggest that the
portal venule and presinusoidal vasculature are the dominant resistant
sites in rabbit livers. On the basis of the present results in both the
KCl and the retrograde perfusion KCl groups, it is suggested that
vascular smooth muscle may be more abundantly distributed in the portal
than the hepatic veins, which may explain in part why the presinusoidal
vessels provide a predominant resistance in rabbit livers.
In the present study, the dose of histamine required to produce
significant hepatic vasoconstriction was 1 µM. This dose of histamine
(1 µM) is identical to that used to contract the isolated rabbit
portal vein (4, 10). The responsiveness of rabbit hepatic vessels to
histamine seems to be weak compared with that of norepinephrine,
because the lower concentration of 0.1 µM norepinephrine can induce
significant hepatic vasoconstriction, as shown in Fig. 2. In addition,
100 µM histamine increased Rtot only two times baseline, whereas with
the same dose of norepinephrine the increase was four times baseline.
We have clearly shown that histamine-induced hepatic vasoconstriction
occurs almost exclusively in the presinusoidal vessels in rabbit
livers. This result contrasts with the well-established concept that histamine predominantly contracts the hepatic vein rather
than the presinusoidal vessels in dogs (12, 16). We believe that part
of the explanation lies in species differences in the distribution of
functional smooth muscle in the hepatic vessels. However, differences
in receptor distribution, density, and affinity between these two
species certainly have a role in the response to histamine. Indeed, the
histamine-induced hepatic venoconstriction is not observed in the cat
(6) or rat (9). On the other hand, Rothe and Maass-Moreno (19) have
recently reported, measuring the hepatic venular pressure with
micropipettes in in vivo anesthetized rabbits, that histamine at the
portal venular blood concentration of 11 µmol/l significantly
increases hepatic venular pressure and outflow resistance. They also
estimated changes in liver volume by recording changes in lobe
thickness, using a variable differential transformer, and showed that
histamine passively induces hepatic engorgement (19). This finding is not in agreement with the present result. The reason for this discrepancy is not known, but the different preparation might account
for it. Indeed, in isolated portally and hepatic arterially perfused
rabbit liver, histamine at a concentration higher than 1 µM increases
Rpv and hepatic arterial resistance dose dependently but did not
increase liver weight at all (17). However, Greenway and Lautt (7)
asserted that the isolated perfused rat livers are unsuitable for
studying hepatic hemodynamics with respect to distribution of flows and
O2 supply. The limitations of
using isolated perfused rabbit livers might be similar to those of the isolated perfused rat livers.
It is well known that norepinephrine causes a reduction in liver blood
volume in cats (6), dogs (2, 20), and rabbits (19). In addition, Rothe
and colleagues, using the micropipette servo-null pressure measurement
technique, have recently demonstrated that the increase in Rpv is much
more than that of Rhv in dogs (3), rats (3), and rabbits during
norepinephrine infusion (19). We confirmed that a similar response to
norepinephrine occurs in isolated rabbit livers. Furthermore, this
norepinephrine-induced increase in hepatic vascular resistance is
caused almost exclusively by portal venular constriction.
In the present study, a decrease in liver weight accompanied selective
presinusoidal vessel constriction when histamine, norepinephrine, or
KCl was injected in the anterogradely perfused livers. The mechanism
for this decrease in liver weight cannot be presently clarified. A
reduction in unstressed volume of the hepatic venules or even sinusoids
will explain the reduction in volume induced by norepinephrine (7, 18).
If the area where this venoconstriction occurs has a very small total
resistance to flow, then even a large change in this minute resistance
will be negligible with respect to total resistance. This active
constriction and also Ito cell contraction might contribute to the
present blood volume reduction. Another possibility may be related to
possible heterogeneous portal venule constriction. If there was
heterogeneity in portal venule constriction among the hepatic lobules,
that is, some vessels were closed and others open, the blood volume of
sinusoids, which was distal to the closed portal venules, could be
passively reduced due to a decrease in distending pressure of the
sinusoids. Actually, in rat liver treated with norepinephrine, the
heterogeneous vasoconstriction was observed, as revealed by clear
heterogeneous dye staining of the liver, when trypan blue dye was
infused after norepinephrine infusion (1, 13).
On the other hand, in retrogradely perfused livers, KCl also caused a
dose-dependent initial weight loss. This could possibly be explained by
vasoconstriction of the inflow vessel of the hepatic vein by using
retrograde perfusion, which did not affect so much the calculated
hepatic vascular resistance. At the highest dose of 50 mM KCl, the
initial weight loss was followed by a progressive weight gain. When
sufficient vasoconstriction downstream from the compliant
microvasculature might overcome the effects of possible constriction of
the inflow vessel of the hepatic vein, the weight begins to increase
because of vascular filling and filtration.
We found that the bile flow decreased after injection of either
norepinephrine, histamine, or KCl, with elevation of Ppv. The mechanism
for this cholestasis is not known from the present study. Lenzen et al.
(13) proposed that cholestasis caused by norepinephrine is secondary to
its hemodynamic effects, on the basis of the finding that papaverine,
an unspecific vasodilator, prevented norepinephrine-induced cholestasis
and hepatic vasoconstriction in isolated rat livers. Similar findings
have been observed, in that administration of vasodilatory agents such
as a nitric oxide donor and a prostaglandin
I2 analog restored the decreased
biliary flow rate induced by a potent vasoconstrictor of endothelin-1 to normal values, along with the recovery of Ppv (11, 21).
In conclusion, we determined, measuring the hepatic capillary pressure
with the double-occlusion method, the effects of histamine, norepinephrine, and KCl on hepatic vascular resistance distribution in
isolated rabbit livers perfused with 5% albumin-Krebs solution. Histamine or norepinephrine caused a dose-dependent increase in presinusoidal vascular resistance but no changes in Rhv. There was also
a decrease in liver weight. This selective constriction of the
presinusoidal vessels seems to be due to the predominant distribution
of functionally active vascular smooth muscle in the presinusoidal
vessels rather than the hepatic vein. This assumption was based on the
observation that KCl contracted the presinusoidal vessels selectively
in the anterogradely perfused liver, although KCl significantly, but
minimally, increased the Rhv in retrogradely perfused livers. It also
should be mentioned that the present results were based on sinusoidal
pressure, which was analyzed as part of the pressure profile during the
double-occlusion maneuver, that is, an indirect measure. In the future,
further studies might be required to compare double-occlusion pressure
with microvascular pressures measured directly by micropipettes (3, 14,
19) in the same isolated liver preparation, as was performed in
isolated lungs (8).
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ACKNOWLEDGEMENTS |
This study was supported by Grant-in-Aid for Scientific Research
10557138 from the Ministry of Education, Science and Culture.
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FOOTNOTES |
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.
Address for reprint requests and other correspondence: T. Shibamoto,
Dept. of Physiology, Division 2, Shinshu Univ. School of Medicine,
Matsumoto 390-8621, Japan (E-mail:
shibamo{at}gipac.shinshu-u.ac.jp).
Received 2 November 1998; accepted in final form 11 June 1999.
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