Capillary diffusion capacity and tissue distribution of
pancreatic procolipase in rat
Catarina
Rippe1,
Bengt
Rippe2,3, and
Charlotte
Erlanson-Albertsson1
1 Section for Molecular
Signaling, Departments of Cell and Molecular Biology and
2 Nephrology and
3 Physiology, University of Lund,
S-221 00 Lund, Sweden
 |
ABSTRACT |
The
permeability-surface area product of procolipase and its apparent
distribution volume in rat tissues were assessed using a tissue uptake
technique. Procolipase was investigated together with
51Cr-EDTA, used as an inert
extracellular marker, and
131I-albumin, used as a plasma
volume marker. The tissue uptake of procolipase seemed to occur by
passive transport in most of the organs studied, such as in muscle,
liver, lung, adipose tissue, adrenal glands, colon, and skin. However,
throughout the gastrointestinal tract, except in the colon, there was a
high uptake of procolipase, greatly exceeding that of
51Cr-EDTA. This was especially
evident in the stomach, in which the procolipase uptake was
nonsaturable within the experimental period. Also, in the central
nervous system (CNS), there was evidence of specific, possibly
carrier-mediated, transport. These results suggest that procolipase may
have specific, conceivably receptor-mediated, transport pathways across
the microvascular endothelium in the stomach, pancreas, duodenum,
ileum, and the CNS.
tissue uptake technique; blood-brain barrier; gastrointestinal
tract; colipase
 |
INTRODUCTION |
PROCOLIPASE IS SYNTHESIZED and secreted from the
pancreas together with other pancreatic enzymes and is activated by
trypsin in the small intestine. This event cleaves the
NH2-terminal part of procolipase,
forming colipase and a pentapeptide called enterostatin. Colipase acts
in the intestine as an obligatory cofactor for lipase (3, 15). Lipase
and colipase form a 1:1 molar complex, which hydrolyzes
triacylglycerols. Enterostatin has an inhibitory effect on fat
intake in the rat (8). Junge and Leybold (13) have detected colipase in
the circulation of patients with acute pancreatitis. In healthy
individuals, Junge and Leybold (13) were unable to detect
colipase with a method having a detection limit of 0.65 nM (13).
However, recent work in our laboratory (unpublished data),
using a method with a lower detection limit (0.07 nM), indicates that
colipase/procolipase exists in the circulation of healthy individuals.
The rate of tissue uptake and the equilibrium distribution volume
(VE) of colipase in various
tissues have not been assessed previously. It is, for example, not
known whether tissue uptake in peripheral tissues or in the central
nervous system (CNS) is completely passive in nature or whether there
are active components and/or binding to the endothelium.
The aim of the present investigation was to study the uptake of
procolipase in various tissues in rat. This was achieved using 125I-procolipase together with
51Cr-EDTA as an inert small solute
reference substance and
131I-albumin as a marker for
plasma volume. Because 51Cr-EDTA
is a small solute (molecular radius ~4.7 Å), it is widely used to measure extracellular fluid volume (6). On the other hand,
albumin is a protein that does not easily pass through the capillary
walls. Therefore, it is essentially retained in the circulation and can
be used as a marker of the plasma volume. Procolipase is a small
protein with a molecular mass of 10 kDa (molecular radius ~17
Å). Hence, a tissue uptake technique (6, 24) should be ideal
to study its transcapillary transport capacity [permeability-surface area product (PS)], and this method
was used in the present study.
 |
METHODS |
Male Wistar rats weighing 267 ± 22 g were obtained from
Möllegaard (Denmark). Until the experiments were performed, the
animals had free access to food and water. Anesthesia was introduced by intraperitoneal injection of pentobarbital sodium (50 mg/kg). The tail
artery was cannulated with a polyethylene catheter (PE-50) and used for
blood pressure registration (via a pressure transducer coupled to a
polygraph; model 7B, Grass Instruments). The left carotid artery and
the left jugular vein were also cannulated with PE-50 catheters, the
former used for blood sampling and the latter for tracer injections. To
maintain a constant body temperature, the rats were placed on a heating
pad.
Labeling procedures.
Procolipase was labeled with 125I
using the chloramine-T method (10). The reaction mixture contained 10 µg porcine procolipase (15), 130 MBq
125I, and 2 µg
chloramine-T and was incubated for 5 min on ice.
125I-procolipase was separated
from free 125I on a PD-10 Sephadex
G-25 M column (Pharmacia, Uppsala, Sweden). 51Cr-EDTA was purchased from
Amersham and 131I-albumin from
Kjeller. Before each experiment,
131I-albumin and
125I-procolipase were purified
from free iodine, using centrifugal filtration (Microcon 30 and
Microcon 10, Amicon).
Experimental procedures.
Three groups of animals were used in the experiment, as indicated in
Table 1. One group
(group A)
was given 125I-procolipase and
51Cr-EDTA simultaneously, using
51Cr-EDTA as an extracellular
marker. Another group (group
B) was administered with
125I-procolipase together with
131I-albumin to evaluate the
plasma volume in the tissue simultaneously with the uptake of
procolipase. The last group (group
C) was given 131I-albumin alone for
complementary information on albumin distribution. We gave ~70 kBq
125I-procolipase as a bolus dose
together with either ~70 kBq
131I-albumin
(group B) or
~50 kBq 51Cr-EDTA
(group A).
Simultaneously, an infusion of the tracers diluted in physiological
saline was given (3 ml/h) to maintain the plasma concentration of the
injected tracers constant over time. The infusion contained either
125I-procolipase alone or
125I-procolipase and
51Cr-EDTA. Because albumin is
largely retained in the circulation and disappears at ~12-17%/h
(23, 28), there is no obvious need for any infusion of the protein.
Blood samples (25 µl) were collected at 1, 3, 5, 8, 16, 25, 40, 60, 80, 120, and 160 min after tracer infusion. The blood was transferred
into tubes and counted in the gamma counter. Before and during the
experiment, hematocrit (50 µl) was measured to convert blood
concentration to plasma concentration. The animals were killed at 3, 8, 25, 40, 80, and 160 min by an intravenous injection of saturated KCl. The following tissues were dissected: biceps femoris muscle,
gastrocnemius muscle, tibialis anterior muscle, stomach, pancreas,
ileum, duodenum, colon, lung, liver, adrenal glands, skin, adipose
tissue, and brain (cerebrum and cerebellum). All tissues were
immediately collected in tarred test tubes, weighed, and counted in a
gamma counter. The number of animals in each experimental group and the
body weights are shown in Table 1.
Calculations.
The average plasma concentration was calculated by fitting the plasma
concentration curve as a function of time to an arbitrary mathematical
function, which was integrated to get the area under the curve (AUC).
To calculate the tissue uptake, the accumulated amount of tracer in the
tissue [counts per minute (cpm)/g] was divided by the
average plasma concentration of tracer (cpm/ml) obtained from the AUC,
to yield the "plasma equivalent" space. This space was then
followed as a function of time. The plasma equivalent space for a
molecule as large as albumin can with a small error be regarded as the
intravascular distribution volume (V0). Thus a blood-rich organ
will have a large albumin space, which should be accounted for. The
tracer plasma equivalent space as a function of time can be described
as
|
(1)
|
where
V0 represents the distribution
volume of tracer at time 0, which, in
the absence of endothelial binding, equals the regional plasma volume.
The intercept with the y-axis of the
albumin space vs. time curve was used as
V0 in the equation above.
VE is the equilibration
distribution volume, which is usually attained after 30-60 min for
small molecules, such as 51Cr-EDTA
and inulin (11). PS represents the permeability-surface area
product, i.e., the capillary diffusion capacity of solute. If the
transport is limited by the plasma flow, i.e., when PS exceeds flow (Q)
by a factor of 3 (6), we have the equation
|
(2)
|
where
k approximates to
Q/VE (12).
Statistics.
The plasma equivalent space vs. time curve was assessed by fitting the
experimental data V(t) to
Eq. 1, using nonlinear least-squares regression analysis (Microcal Origin 4.0, Microcal Software). The
values for the parameters VE and
PS are given with their respective standard errors.
 |
RESULTS |
Plasma concentration curves of tracers.
Figure 1 shows the plasma concentration of
the radiolabeled proteins as a function of time. The plasma
concentration of 131I-albumin
decreased with a rate of 19%/h, which was slightly larger than we
expected, and was due to the equilibration with the extravascular space. For both 125I-procolipase
and 51Cr-EDTA, a decrease in
concentration was observed over the first 20 min followed by an
increase in plasma concentration that reached a stable value 40 min
after the start of tracer infusion.

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Fig. 1.
Relative plasma concentrations of tracers (means ± SE) as a
function of time. Plasma concentrations of tracers were standardized to
the given dose. 125I-procolipase
and 51Cr-EDTA were given as a
bolus dose followed by continuous infusion, whereas
131I-albumin was given as a bolus
dose only.
|
|
VE and PS.
VE and PS for the different
tissues are shown in Table 2. The rate of
51Cr-EDTA accumulation was lower
than expected for a molecule having a radius of 4.7Å,
conceivably due to blood flow limitation. Therefore only an apparent PS
(VEk)
is given for 51Cr-EDTA in Table 2.
In muscle tissue (biceps femoris, gastrocnemius, and tibialis
anterior), the uptake of procolipase seemed to be entirely passive in
nature. 51Cr-EDTA reached a
blood-tissue equilibrium (VE)
after 20-30 min, whereas
125I-procolipase, which had a much
slower uptake, achieved equilibrium first after 80-100 min (Fig.
2). Both
125I-procolipase and
51Cr-EDTA had similar
VE and their uptake rates were as
large as expected considering their different sizes assuming diffusive transport. However, the albumin space can be regarded as an indicator of the V0.

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Fig. 2.
Plasma equivalent space for
125I-procolipase,
51Cr-EDTA, and
131I-albumin as a function of time
in muscle tissue (biceps femoris muscle). Data are plotted according to
Equation 1 using nonlinear least
square regression analysis. VE,
equilibration distribution volume.
V0, intravascular distribution
volume.
|
|
Similar passive distribution patterns were achieved for colon, lung,
adrenal glands, skin, and adipose tissue (not shown). In these tissues
there was no indication of specific uptake of procolipase, even though
the VE of procolipase seemed
higher than that of 51Cr-EDTA at 180 min (shown in Table
2). However, there was no difference at 80 min.
In the liver, after a high immediate uptake into Disse's space of
51Cr-EDTA,
131I-albumin, and
125I-procolipase, the subsequent
uptake of 125I-procolipase and
51Cr-EDTA was very low, exhibiting
a clearance of 0.50 and 0.30 ml · min
1 · 100 g
1, respectively.
Figure 3 shows the plasma equivalent space
as a function of time in stomach, pancreas, duodenum, and ileum. In
these tissues, we found a much higher uptake of
125I-procolipase than of
51Cr-EDTA. This was especially
prominent in the stomach, in which a high plasma equivalent space for
125I-procolipase was detected.
Actually, 125I-procolipase did not
attain equilibrium during the experimental period, i.e, during 160 min.
The pancreas, duodenum, and ileum showed a similar tissue uptake
pattern, with a higher uptake of 125I-procolipase than of
51Cr-EDTA. In these tissues, there
was, however, indication of saturation after 160 min. The uptake of
125I-procolipase in these organs
differs from the passive behavior of procolipase in muscle, suggestive
of active transport in the gastrointestinal tract (except for the
colon).

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Fig. 3.
Plasma equivalent space for procolipase ( ),
51Cr-EDTA ( ), and albumin ( )
as a function of time in stomach, pancreas, duodenum, and ileum. These
are plotted using nonlinear least square regression analysis (as in
Fig. 1), except for procolipase uptake in stomach, where a linear
regression was plotted.
|
|
There was no significant uptake across the blood-brain barrier (BBB) of
51Cr-EDTA or
131I-albumin during the
experimental period. The uptake of
125I-procolipase was, however,
considerably higher than that of
131I-albumin. The PS in cerebrum
and cerebellum was 0.052 ± 0.005 and 0.043 ± 0.009 ml · min
1 · 100 g
1, respectively. The
apparent VE for cerebrum and
cerebellum during the observation period was 2.1 ± 0.09 and 2.5 ± 0.3 ml/100 g, respectively, which was much higher than the plasma
volume (0.46 ± 0.06 and 0.89 ± 0.06 ml/100 g). This indicates a
selective transport of procolipase into the brain tissue of the rat
(Fig. 4).

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Fig. 4.
Plasma equivalent space for procolipase and albumin as a function of
time in brain. A:
cerebellum. B:
cerebrum.
|
|
 |
DISCUSSION |
We have collected data strongly suggesting that pancreatic procolipase,
when injected into the blood stream, has specific transport mechanisms
in the capillaries of the upper gastrointestinal tract, and
surprisingly, also in the brain. In the other tissues examined, e.g,
muscle tissue, the uptake of procolipase was completely passive. In the
liver, an instantaneous equilibration of
125I-procolipase,
51Cr-EDTA, and
131I-albumin occurred, probably
with Disse's space. This was followed by a slower uptake, presumably
across the interstitium, of both 125I-procolipase and
51Cr-EDTA, which could be due to
their excretion into the bile (16).
Throughout the gastrointestinal tract (the stomach, pancreas, duodenum,
and ileum), there was a much higher uptake of
125I-procolipase than of
51Cr-EDTA. Procolipase was hence
rapidly taken up to these tissues and its
VE greatly exceeded that of
51Cr-EDTA, a criteria for active
transport. Because VE
was larger for 125I-procolipase
than for 51Cr-EDTA,
125I-procolipase seemed to be
transported against a concentration gradient, although there is also a
slight possibility of tissue binding of tracer. This suggests that
there may be active transport of procolipase from the bloodstream to
the gastrointestinal tract and/or tissue binding. Fenestrated
capillaries exist throughout the gastrointestinal tract and offer a
large surface area for transport of small and large solutes but not a
reduced selectivity to macromolecules and polypeptides. This is in line
with the results of our study. There was indeed a higher uptake of
51Cr-EDTA in the gastrointestinal
tract than, for example, in muscle. However, the much higher uptake of
125I-procolipase compared with
that of 51Cr-EDTA cannot be
explained by an increased permeability of fenestrated capillaries. A
significant finding of the present study is the high amount of
125I-procolipase taken up by the
stomach. Actually, this uptake did not reach saturation within the
experimental period (160 min). Instead, there was a linear uptake as a
function of time. This again suggests that procolipase is actively
transported from the circulation to the stomach. Recently,
Sörhede et al. (25, 26) showed, with in situ hybridization and
immunohistochemical methods, that procolipase is produced in chief
cells of gastric fundus. It could be speculated that circulating
procolipase acts as a feedback signal on the production of gastric
procolipase.
A major finding of the present study was the data supporting the uptake
of procolipase across the BBB. Passive diffusion of procolipase over
the BBB is not likely to occur due to the tight junctions that
characterize BBB selectivity. Instead, a specific mechanism is
suggested to mediate the uptake of procolipase to the brain. In recent
years, receptors for peptides and other macromolecules have been
identified in isolated brain capillaries (19) and hypothesized to
mediate transcytosis. Furthermore, recent studies have indicated that
circulating peptides or proteins may undergo receptor-mediated
transport through the BBB. This has been suggested for ligands, such as
insulin (7), transferrin (9) and leptin (1). A comparison of results
with those from another study (20), in which the cerebellar uptake of a
number of proteins and polypeptides was examined, shows that the PS for
procolipase is 2.4 times higher than that for transferrin but three
times lower than for insulin (20). The influx of leptin into the brain was in the same range as for procolipase and was also saturable (1).
Although, it has been known for some time that insulin and certain
other hormones can be selectively transported across the BBB, the
present results were completely unexpected. It can only be
speculated as to why procolipase, which is present in serum in very low
concentrations, has a certain specific uptake pathway across the BBB. A
specific uptake may have implications for conditions when a large
circulating pool of pancreatic enzymes occurs, such as during acute
pancreatitis. Pancreatic proteins are normally secreted toward the
apical region but constitutive-like pathways also direct secretion
toward the basolateral membrane (5). This secretion could explain how
pancreatic proteins enter the circulation. A recent study (5) has shown
that this secretion could be increased by maximal stimulation with
CCK-8. Hence, procolipase may have some yet unknown actions in the CNS,
related to lipid metabolism or postprandial conditions after high-fat
feeding. Alternatively, procolipase in the brain may serve as a
precursor for the peptide enterostatin mediating satiety through
central mechanisms (2).
Among physiologists, active transendothelial transport of
macromolecules is a controversial issue. Several authors have
persistently argued against active transcytosis as a major mechanism of
protein transport between blood and tissue (21, 22, 27).
Their evidence is based on a large number of lymph flux analyses and
tissue uptake studies in various organs. It should, however, be pointed
out that the studies on which these conclusions were reached were all
concerned with transcapillary passage of "bulk" plasma proteins, mostly albumin, fibrinogen,
2-macroglobulin, and some
immunoglobulins. However, with regard to insulin, for
example, it was pointed out that it differed markedly in its transport
from inert probes, such as inulin, which is of equal size but has no
specific function in the human body (11). Above all, it
has been shown that insulin can strongly bind to the endothelium even
in vivo (11) and it can be transported more or less intact across the
endothelium by active mechanisms (14). With regard to procolipase, it
seemed to be specifically transported or bound to the endothelium of the upper gastrointestinal tract and the CNS, which strongly indicates specialized modes of action in these target organs.
As expected, 125I-procolipase was
taken up passively in muscle (Fig. 2). The rate of tissue
uptake was eightfold higher for
51Cr-EDTA than for
125I-procolipase. In an aqueous
solution, 51Cr-EDTA diffuses at a
3.6-fold higher rate than
125I-procolipase, depending on its
smaller size (molecular radius 4.7Å for
51Cr-EDTA vs. ~17Å for
125I-procolipase). According to
the theory of restricted diffusion through a membrane having
cylindrical pores (18), an eightfold lower transport of a
17-Å molecule compared with that of
51Cr-EDTA can be expected, if the
equivalent capillary pore radius were 75 Å (6). However,
since 51Cr-EDTA was most likely
flow limited in its transport, this pore radius is an overestimate. The
measured PS for 51Cr-EDTA in
muscle was thus only 1.2 ml · min
1 · 100 g
1, whereas the expected
value is 2-3
ml · min
1 · 100 g
1 in nonvasodilated tissue
(6, 17). From this comparison, one can calculate that plasma flow would
have been 1.1-1.2
ml · min
1 · 100 g
1 in our rats and that PS
for 51Cr-EDTA was markedly
underestimated, whereas PS for
125I-procolipase was not. Thus if
plasma flow (Q) was 1.1-1.2
ml · min
1 · 100 g
1 then PS/Q for
procolipase is ~0.13, which by being <0.33 ensures nonflow-limited
conditions (6).
In conclusion, the present study has demonstrated specific uptake of
circulating pancreatic procolipase in the gastrointestinal tract and
brain tissue of the rat. In most other tissues, the uptake was passive
according to current concepts. The specific uptake of procolipase
across the BBB is surprising and intriguing and therefore deserves
further investigation.
 |
ACKNOWLEDGEMENTS |
We are grateful to Anna Rippe (Departments of Nephrology and
Physiology, University Hospital of Lund) for excellent technical assistance.
 |
FOOTNOTES |
This work was made possible through grants from the Swedish Medical
Research Council (07094 and 08285), A. Påhlsson's Foundation, and The Swedish Nutrition Foundation.
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: C. Rippe, Section for Molecular
Signaling, Dept. of Cell and Molecular Biology, Univ. of Lund, PO Box
94, S-221 00 Lund, Sweden.
Received 23 February 1998; accepted in final form 24 July 1998.
 |
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0002-9513/98 $5.00
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