Download cerebral and gastric histamine system is altered after portocaval shunt

JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2001, 52, 4, 657—670
www.jpp.krakow.pl
W. A. FOGEL, K. A. MICHELSEN*, P. PANULA*, K. SASIAK, W. ANDRZEJEWSKI
CEREBRAL AND GASTRIC HISTAMINE SYSTEM IS ALTERED
AFTER PORTOCAVAL SHUNT*
Institute of Biogenic Amines, Polish Academy of Sciences Lodz, Poland & *Department of
Biology, Abo Akademi University, Turku, Finland.
Biochemical parameters of the histamine (HA) system were examined in both rat
brain and stomach, after portocaval anastomosis (PCA). These tissues become rich in
histamine after PCA. Immunocytochemistry was used for brain histamine localisation.
In addition to increased HA concentrations, monoamine oxidase B activity increased
in both tissues. In hypothalamus HA was 15 fold; in cerebral cortex and in stomach
mucosa 2.8 and 2.5 fold of the corresponding controls, respectively. MAO B activity
was increased by approximately 50% in brain and 100% in stomach. A significant,
uneven increase in tele-methylhistamine concentration was only found in the brain. In
stomach mucosa higher histidine decarboxylase activity was found.
PCA and sham rats treated with an irreversible inhibitor of MAO B, FA-73, 0.5 mg/kg
i.p., showed 24 h later greatly reduced MAO activity and doubled t-MeHA
concentration in brain structures. The treatment had no effect on gastric mucosal
t-MeHA concentration and on urinary excretion of the t-MeHA metabolite,
N-tele-methylimidazoleacetic acid. The HA rise in the stomach of PCA rats is
associated with proliferation of histamine producing and storing cells (ECL cells) as
demonstrated by others. However, in the brain we saw no indication for increased
number of relevant cells either mast cells or neurons and our immunocytochemical
findings suggest that in PCA rat brain, histamine deposits are located exclusively in
neurons. The data indicate that the adaptative mechanisms to excessive histamine
formation are tissue specific.
K e y w o r d s: portocaval anastomosis, histamine system, brain, stomach mucosa,
tele-methylhistamine
INTRODUCTION
Histamine (HA) functions as a potent stimulant of acid secretion in the
stomach (1) and neurotransmitter/modulator in the brain (2). A local alteration
in histamine synthesis and content was suggested in the 1960s as a primary
cause of disturbed gastric functions in subjects with portocaval anastomosis
(PCA). Experimental studies with portocavally shunted rats have shown that
* Dedicated to Prof. Dr C. Maslinski on occasion of his 80th birthday.
658
higher gastric acid secretion in these animals coincided with a higher histidine
decarboxylase (HDC) activity as well as a higher histamine concentration in
stomach. Moreover, the acid hypersecretion could be attenuated by inhibiting
HDC (3). Detailed histochemical, electron microscopical and biochemical
studies (4) provided evidence that the changes in histamine system are brought
about by an increased number, size and granularity of enterochromaffin-like
(ECL) cells. ECL cells have capacity to synthesize, store and release histamine
in response to feeding or injection of pentagastrin and insulin.
Portocavally shunted rats are a suitable animal model of hepatic
encephalopathy (HE) (5) and in our studies on neurochemical alterations in the
CNS triggered by chronic liver dysfunction we have found that an enhanced
histamine synthesis occurred in brain in these animals (6, 7). Tissue histamine
deposition is a predominant and unique mechanism of metabolic adaptation for
cerebral amine neuromediators. Some lines of evidence indicate that the cells
which accumulate histamine are neurons (6, 8) but this remains to be proven.
In brain that lacks diamine oxidase released histamine is metabolised via the
methylation pathway (2). The same holds true for stomach (9). Activation of the
methylation route in the two organs in PCA rats is strongly supported by
significantly higher cerebral concentration of the intermediate metabolite,
tele-methylhistamine (t-MeHA), as well as higher urinary output of histamine
end product, N-tele-methyimidazoleacetic acid (t-MeImAA), of which major part
is of a gastric origin (10). Here we attempted to gain further insight 1/ into
regulation of HA metabolism in both brain and stomach by using FA-73 in vivo
(11), a selective, more potent than deprenyl, irreversible inhibitor of monoamine
oxidase B, for which tele-methylhistamine is an endogenous substrate (12), and
2/ into cellular location of brain histamine by employing HA immunostaining.
MATERIAL AND METHODS
All procedures strictly followed the Polish legislation concerning animal
experiments and were approved by the local animal ethics committee.
Adult male rats of two strains Wistar and Lewis (body weight 250—300g)
were used.
Surgery
End-to-side portocaval anastomosis was performed according to the method
of Lee and Fisher (13). Sham-operated animals underwent laparotomy and
occlusion of the portal vein for 10 min. Following surgery, rats were housed in
wire mesh cages with a 12h light/dark cycle, light off at 7 p.m., and had free
access to food and water.
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Treatment
An irreversible inhibitor of MAO B, N-(2-propynyl)-2-(5-benzyloxyindol)
methylamine, FA-73 (11) was a gift from Prof. M.Unzeta, Autonomus
University of Barcelona, Spain, and was given as a single intraperitoneal
injection in a dose of 0.5 mg/kg to Lewis rats of both PCA (n = 5) and sham
(n = 5) groups, 6 months after surgery. The respective control counterparts (5
per group) received physiological saline (1.0 ml/kg i.p.).
Urine (24 h output) was collected between 48h—24 h before MAO inhibitor
and again for 24 h after the drug was administered.
Urine collection was performed by placing rats individually in metabolic
cages, where they had free access to tap water and feed.
Sample preparation and biochemical analyses
Rats were sacrificed by guillotine decapitation. Weight of whole body and
of some organs were recorded. From the brain hypothalamus and cerebral
cortex were dissected. The stomach was opened along long curvature and
cleaned in cold saline, blotted, weighed and the gastric mucosa was scrapped
off. All tissue samples were immediately frozen in liquid nitrogen and kept at
–70°C until assayed.
Cerebral histidine decarboxylase activity and histamine concentration were
assayed radioenzymatically according to Taylor and Snyder (14) employing
partially purified histamine N-methyltransferase from rat kidney (15). Gastric
mucosa histidine decarboxylase activity was assayed with 1-carboxy
14
C-L-histidine (16) whereas the tissue histamine concentration was determined
by a fluorometric procedure after isolation on a small Cellex P column as
described elsewhere (6).
MAO-A and MAO-B activities were estimated in tissue homogenates with
radioassays (17) employing serotonin (final conc. 200 mM) or beta-phenylethylamine (final conc. 20 mM) and specific inhibitors deprenyl and clorgyline (0.3
mM each), respectively. N-tele-methylhistamine was analysed by GC/MS as
bis-heptafluorobutyryl derivative, with N-tele-D3-methylhistamine as an internal
standard (18). Urinary N-tele-methylimidazoleacetic acid was converted to its
isopropylester and determined by HPLC with UV detection; N-tele-ethyl-imidazoleacetic acid was an internal standard. With the same HPLC separation
procedure urine creatinine concentration was determined enabling the expression
of excreted t-MeImAA in both mg/24h and mmol /mol creatinine (19).
Immunocytochemical study of histamine containing cells in the PCA rat brain
In situ brain perfusion with 4% 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide in 0.1 M sodium phosphate buffer, pH 7.0, (PB) was performed
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on anesthesized rats as described elsewhere (20, 21). The brains were removed,
immersed in the same fixative overnight and thereafter in 20% sucrose in PB
overnight. Cryosections (20 mm or 40 mm) were washed in phosphate buffered
saline (PBS) containing 0.25% Triton X-100 (PBS-T) and incubated overnight
with the rabbit anti-histamine antiserum 19C (22) diluted 1:1000 in PBS-T
containing 1% normal goat serum. After a subsequent wash in PBS-T the 20
mm sections were incubated with FITC-conjugated swine anti-rabbit IgG
(DAKO, Copenhagen, Denmark) diluted 1:40. They were then used for
fluorescence microscopic studies. The 40 mm sections were treated similarly
with the exception that the FITC-conjugated IgG was exchanged for Alexa 568
goat anti-rabbit IgG diluted 1:500 and the sections were used for confocal
microscopic studies. A whole brain was stained according to the latter protocol
with the exception that 1% DMSO was included in the primary incubation and
that the incubations lasted two nights each and the final wash overnight. The
sections and the whole brain were then rinsed with PBS and mounted with
glycerol-saline (1:1) (1% DABCO was added to the whole brain mounting
medium to decrease fading) and then examined with a LEICA TCS SP
confocal microscope coupled to an ArKr-laser. The fluorophore was excited at
568 nm and fluorescence emission between 580 and 660 nm was recorded. The
sections were scanned at several depths and maximum projection-images were
made out of the data. The data were processed with LEICA TCS NT software.
The histamine antiserum used does not detect L-histidine or
histidine-containing peptides as studied by dot-blot methods. Conjugates
containing L-histidine did not abolish the staining. Preadsorption with a
histamine-ovalbumin or histamine-BSA conjugate (1 mg/ml) abolished the
immunofluorescence.
Statistical analysis
The values are presented as mean ± SD. Differences between groups were
assessed with paired or unpaired t-tests as appropriate.
RESULTS
General effects of PCA
The data in Table 1 demonstrate the characteristic general effects of
portocaval shunt. Six months after the surgery shunted rats had body weight
about 35% lower than sham operated rats, even if their daily feed and fluid
intake was relatively higher. The relative liver weight (i.e. ratio of liver weight
Table 1. General effects of portocaval shunt.
Daily feed
Daily fluid
consumption, intake, ml/100g
body wt
g/100g body wt
Liver wt, g
Liver index
Liver wt/body wt
x 100, %
Stomach, g
Gastric mucosa,
g
Mucosal index,
Mucosa
wt/stomach wt
´100%
Group
Body wt, g
PCA (n = 10)
247.0 ± 43***
p < 0.0001
8.0 ± 1.7***
p = 0.0002
23.7 ± 7.7***
P < 0.0001
4.61 ± 0.99***
P < 0.0001
1.87 ± 0.22***
p = 0.0005
1.65 ± 0.16*
p = 0.0208
0.434 ± 0.07*
p = 0.0101
26.46 ± 3.74***
p = 0.0001
SHAM (n = 10)
382.0 ± 49
4.6 ± 1.3
7.9 ± 1.9
9.84 ± 1.55
2.82 ± 0.66
1.82 ± 0.15
0.344±0.06
18.86 ± 2.92
Lewis rats were 6 months after portocaval shunt (PCA) or sham operation.
Table 2. Histamine system in brain and stomach. The effect of portocaval shunt.
Organ
Tissue
Hypothalamus
Brain
Cerebral cortex
Stomach
Mucosa
HA,
nmol/g
t-MeHA,
nmol/g
HDC,
pmol/min/mg
protein
Enzyme activity, pmol/min/mg
protein
MAO A
MAO B
21.8 ± 7.2***
p < 0.001
2.51 ± 0.65*
p < 0.05
0.97 ± 0.34
1267 ± 54
780 ± 69 ***
p=0.0005
SHAM
1.44 ± 0.17
1.19 ± 0.70
1.11 ± 0.39
1202 ± 95
489 ± 73
PCA
0.84 ± 0.18***
p < 0.001
0.54 ± 0.12*
p < 0.05
0.19 ± 0.05
1353 ± 75
809 ± 160*
p = 0.0338
SHAM
0.30 ± 0.08
0.37 ± 0.02
0.17 ± 0.03
1252 ± 107
535 ± 121
PCA
1787 ± 523***
p < 0.001
1.25 ± 0.47
29.83 ± 13.64***
692 ± 108
p = 0.001
240 ± 56 **
p = 0.0031
SHAM
706 ± 168
1.24 ± 0.20
6.30 ± 1.77
103 ± 29
Group
PCA
604 ± 109
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Lewis rats 6 months after portocaval shunt (PCA) or sham operation were examined. Values are means ± SD of n=5 rats per group.
Histamine (HA) was assayed radioenzymatically (14) or spectrofluorometrically (7); tele-methylhistamine (t-MeHA) by GC/MS (18);
Histidine decarboxylase (HDC) and monoamine oxidase (MAO A and MAO B) activities by currently used isotopic procedures (14, 16, 17).
662
to body weight ´ 100%) was lower, however, the relative stomach weight was
higher, in PCA versus sham rats. The former reflects atrophic changes that take
place in the liver, the latter indicates that in poor nutritional state there are
compensative changes in stomach as further evidenced by mucosa thickening
(Tab. 1).
Effects of PCA on HA system in brain and stomach
Table 2 summarises the results describing histamine system parameters in
brain (hypothalamus and cerebral cortex) and in gastric mucosa of the shunted
rats, as opposed to sham operated ones. In both organs increased histamine
concentrations and monoamine oxidase form B (MAO B) activity were found.
In the hypothalamus HA was increased 15 fold; in cerebral cortex and in
stomach mucosa the increase was less and similar: 2.8 and 2.5 fold,
respectively. MAO B activity was increased by roughly 50% in brain but was
doubled in stomach. There was also a significant increase in tele-methylhistamine concentration in brain, however, not as large as that of HA. In
cerebral cortex the t-MeHA level was increased by half and in the
hypothalamus slightly exceeded 2 fold. In turn, in stomach mucosa a high,
almost 5 fold increase compared to the normal, histidine decarboxylase activity
was found.
It is interesting to note, that the concentration of t-MeHA in gastric mucosa
which was not changed upon shunting, closely resembles that found in
hypothalamus (1.24 ± 0.20 vs 1.19 ± 0.70).
Effect of MAO B inhibitor administration
A single dose of FA-73 did not influence the daily feed or fluid intake by
PCA or sham rats. As shown in Fig. 1A all rats treated with FA-73, and
sacrificed 24h later, expressed greatly reduced cerebral MAO B activity (by
80—90%) and lower by about 30% the gastric mucosa enzyme activity (Fig.1
A). In these rats, brain t-MeHA concentration (Fig.1 B) was roughly 2 fold
higher. Thus, in PCA rats with already increased cerebral t-MeHA (Tab. 2),
monoamine oxidase B inhibition caused a further tissue amine increment, so
their mean hypothalamic level was about 5 fold and cerebral cortex 3 fold of
the corresponding tissue of untreated sham operated counterpart.
No difference in t-MeHA concentration in the gastric mucosa was noted
either in PCA or sham groups.
The treatment also had no effect on t-MeHA metabolite,
N-tele-methylimidazoleacetic acid urinary excretion (Fig. 1 C). However, in
663
MAO-B activity,
% untreated
100
A
HTH
CCx
75
Gastric mucosa
50
25
0
SHAM+FA73
†-MeHA,
% untreated
400
B
HTH
CCx
300
Gastric mucosa
200
100
0
SHAM+FA73
200
C
*
PCA+FA73
20
**
**
**
100
10
0
untreated
PCA
SHAM
mg/24h
FA 73 treated
0
†-MeImAA, excretion
(mmol/mol creatinine)
†-MeImAA, excretion
(mg/24h)
PCA+FA73
PCA
SHAM
*p<0.05 ** p<0.01 vs corresponding sham
Fig. 1. The effect of irreversible inhibitor MAO B ( FA-73, 0.5 mg/kg i.p. – 24h) on panel A: monoamine
oxidase B activity; panel B: tele-methylhistamine concentration in brain parts and stomach mucosa and panel
C: urinary excretion of tele-methylimidazoleacetic acid by portocavally shunted (PCA) and sham operated
(SHAM) rats 6 months after surgery. The means ± SD are given. The results in Fig. 1 A & B are expressed
as % of untreated counterparts. For absolute values refer to Tab. 2.
664
agreement with the earlier study (10), the daily output of t-MeImAA by PCA
rats was 3—5 fold that of sham rats.
It should be stressed that in the dose employed, the compound FA-73
exerted no effect on MAO A activity in any examined tissue. Likewise, it did
not affect tissue histamine concentration or HDC activity.
Brain histamine location; non-neuronal versus neuronal compartment
Wistar rats, 4—9 weeks after the surgery were examined. There was no
significant difference in HA-immunoreactivity between 4-week and 2-month
PCA. The representative results of immunocytochemical study on cellular
histamine location in brain are shown in Figs 2 and 3. Mast cells were not
observed in any brain areas other than lateral thalamus and median eminence
and following portocaval shunt neither their number was changed nor intensity
Fig. 2. Histamine-immunoreactivity in the PCA rat one month after operation and sham-operated rat brain. A)
A view of a coronal section of the caudolateral hypothalamus of PCA rat shows several large varicosities. B)
The corresponding sham-operated animal displays a fairly high density of normal histaminergic nerve. Scale
bars = 100 mm.
of HA immunostaining was different (not shown). This was in contrast to the
neuronal fibre histamine immunofluorescence in PCA rats, which was
evidently more intense in several brain areas. On the other hand, the
occurrence and density of histamine immunoreactive neurons and nerve fibres
was essentially the same for PCA and sham animals (Figs 2, 3). In PCA rat
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Fig. 3. Confocal microscopy maximum projection images of HA-stained hypothalamus of rats that have been
subjected to portocaval shunt for four to nine weeks. A) An overview of the posterior hypothalamus in
coronal plane. Two of the characteristic large cisternae are marked with arrows. B) A higher magnification
image of an area corresponding to the lower right corner in A showing the morphology of three objects with
high accumulations of HA-immunoreactivity and a few short fiber sections. C) A horizontal overview of the
caudolateral hypothalamic surface shows numerous intensely HA-immunofluorescent large varicosities and
one intensely HA-immunofluorescent neuronal cell body (arrow). Scale bars in A, C = 100 mm, B = 10 mm.
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brain unusually large varicosities and cisternae intensely immunoreactive for
histamine, formations that were never seen in control rat brain, were observed
in hypothalamus (Fig. 2) and in other areas f.ex. amygdala, substantia nigra
and cerebral cortex. The histamine immunofluorescence was elevated not only
in the fibers. An elevation, although one not as obvious, could also be seen in
the cell bodies of histaminergic neurons (Fig. 3) but the contribution of the
fibers to the total histamine immunofluorescence was significantly higher in
PCA rats as compared to normal ones. Confocal microscopy indicated that the
histamine-containing cisternae were irregular in shape and size (Fig. 3).
DISCUSSION
We have confirmed here that portocaval shunt in the rat is associated with
an enhanced histamine synthesis in brain and gastric mucosa resulting in the
high tissue amine concentration. In brain it is related to better HDC saturation
with L-histidine (6); in stomach it is due to ECL cell proliferation (4).
Intensified HA synthesis raises the question concerning counteracting
adaptational mechanism(s). Under normal conditions, in brain, histamine
released from histaminergic nerve terminals or varicose fibers is methylated
mainly in postsynaptic or extrasynaptic neurons (23, 24) although astrocytes
also appear to contain histamine N-methyltransferase (25, 26). In stomach,
released histamine is taken up and methylated by oxyntic cells (27).
GC/MS analysis revealed that in PCA rats the concentration of the
methylation product, tele-methylhistamine, increases, only in brain and not in
the stomach (Tab. 2).
In the brain tele-methylhistamine is an endogenous substrate of monoamine
oxidase B (12, 28). In peripheral tissues, the common belief is that both,
monoamine oxidase and diamine oxidase can degrade t-MeHA (9, 29).
Interestingly, monoamine oxidase B activity was significantly higher in brain
as well as in stomach in the portocavally shunted rats (Tab. 2), suggesting that
the adaptive rise in the enzyme protein could be induced by the higher t-MeHA
substrate supply. However, the suicidal MAO B inhibitor which was
administered to test this concept, evoked an increase in tele-methylhistamine
concentration only in brain. The effect was the same for the shunted and sham
operated rats (Fig. 1B). It should be noted however that the inhibitory effect of
FA-73 on MAO B activity was much higher for the brain than for stomach
mucosa (Fig. 1A), the difference probably related to the enzyme turnover rate,
which is much slower for the brain than for peripheral tissues (30). Thus, the
remaining activity (ca 70% control) could still be high enough to maintain
metabolism; the urinary excretion of the histamine end product,
tele-methylimidazoleacetic acid was not significantly affected by the treatment
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(Fig. 1C). Alternatively, diamine oxidase (31) may be responsible for the
oxidative deamination of t-MeHA to t-MeImAA.
The concentration of tele-methylhistamine which was found in gastric
mucosa in the rat closely resembles that in hypothalamus [1.24 nmol/g, Table
2] and it is of the same order of magnitude as in porcine gastric mucosa [2.5
nmol/g] (32) or in whole stomach in mouse [2.5-4 nmol/g] (33, 34). However,
the ratios of t-MeHA to histamine in the same tissues (tMeHA = 1) show
marked differences between species, i.e. 1:570 (rat) 1:60 (pig) 1:20 (mouse). In
rat brain the corresponding ratio is almost 1:1. On this basis, it can be
concluded that in rat stomach mucosa, in contrast to the brain, only a very tiny
fraction of tele-methylhistamine is retained by the tissue and this might suggest
very limited capacity/ability of the rat gastric mucosa to store t-MeHA. In other
words, after being formed in oxyntic cell, t-MeHA leaves the stomach.
Schippert et al. (32) in pig gastric mucosa did not detect any other histamine
metabolite beyond t-MeHA. In a more recent study, it was shown that after
pentagastrin infusion in dogs, histamine and tele-methylhistamine secretion could
be followed in gastric venous plasma, suggesting that not all of the released HA
is metabolised by gastric mucosa (35). These data imply that further metabolism
of t-MeHA, unlike that of in the brain (36), takes place extragastrically. If
therefore further metabolism continues at the level of intestine, diamine oxidase
is more likely to exclusively participate in it (37, 38).
We have confirmed here the high potency of the compound FA-73 in
inhibiting cerebral MAO B in vivo (11). Thus, FA-73 in this low dose of
0.5mg/kg ip gave a similar reduction of the enzyme activity as 3 mg/kg sc
deprenyl (28). In this context, we feel obliged to add that the treatment with
FA-73 did not affect daily feed consumption either by portocavally shunted or
sham operated rats, although MAO B inhibition with deprenyl (5 mg/kg) has
been reported to be associated with reduction of gastric mucosal blood flow
and basal acid secretion in rat (39).
In the central nervous system histamine is present in neural and non-neural
pool, the second comprises mast cells and microvascular endothelial cells (2).
In portocavally shunted rats an increase in histamine concentration is invariably
found in different brain areas, raising the obvious question which cell type
stores the amine. Uneven and widely spread, this increase does not fit to mast
cell compartment engagement (40) and indeed, biochemical approaches
excluded the mast cell as the site and fully supported the concept of its
neuronal location (6, 8). Likewise, in the immunocytochemical part of our
present study we have found that mast cell number, location and their
HA-immunoreactivity in PCA and sham brain are similar. Comparison of the
images obtained for portocavally shunted and sham operated rat brain shows
clearly that characteristic histaminergic innervation was totally preserved
following shunting and the main difference was much higher intensity of
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histamine immunoreactivity and the presence of large cisternal structures in
PCA brains. In PCA rats varicose fibers expressed much more intense, bright
fluorescence and pathologic formations with accumulated histamine and
neuronal cell bodies often appeared somewhat brighter than in sham operated
animals. All these findings firmly suggest that it is neuronal compartment
which is enriched in histamine following portocaval shunt.
Portocaval shunt is associated with excessive synthesis of other amine
neurotransmitters (5, 7) however, described histamine neuronal deposition is an
unique countermechanism.
Acknowledgement. The authors would like to express their thanks to, Ms Krystyna Adach,
Zofia Grzelinska Ing. M.Sc and Ms Kuchciak for skillful technical assistance.
The study was supported by 4P05A110 16 KBN grant. PP and KAM were supported by the
Erna and Viktor Hasselblad Foundation and the Academy of Finland.
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R e c e i v e d: October 10, 2001
A c c e p t e d: October 18, 2001
Author’s address: Prof. W.A. Fogel, Institute of Biogenic Amines, Polish Academy of
Sciences, 3 Tylna St., 90-364 Lodz, Poland.
E-mail: [email protected]