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Histamine release from Weibel-Palade bodies of toad aortas induced by endothelin-1 and sarafotoxin-S6b.

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THE ANATOMICAL RECORD 242:374-382 (1995)
Histamine Release From Weibel-Palade Bodies of Toad Aortas
Induced by Endothelin-1 and Sarafotoxin-S6b
YOSHIAKI DOI, TAKATOSHI OZAKA, MASATSUGU KATSUKI,
HIROSHI FUKUSHIGE, EIICHIRO TOYAMA, YOSUKE KANAZAWA,
KEIICHI ARASHIDANI, AND SUNAO FUJIMOTO
Departments of Anatomy (Y.D., T.O., M.K., H.F., Y.K., S.F.) and Surgery (E.T.) and
Section of Occupational Hygiene, School of Nursing and Medical Technology (K.A.),
University of Occupational and Environmental Health, School of Medicine,
Kitakyushu, Japan
ABSTRACT
Background: Endothelin-1 (ET-1) and sarafotoxin-S6b
(STX) induce a remarkable degranulation of Weibel-Palade (WP) bodies
prior to the vasocontraction of toad aortas. As WP bodies play the role of a
reservoir site of the histamine in the endothelial cells, there is the possibility that ET-1 and STX evoke the release of histamine from W P bodies of this
vessel.
Methods: Histamine concentrations were assayed by high-performance
liquid chromatography (HPLC) from the perfusate after being perfused
with a solution containing ET-1 and STX. Each vessel was fixed and embedded for conventional electron microscopy and immunoelectron microscopy using antihistamine sera.
Results: The appreciable concentrations of histamine were assayed by
HPLC from the perfusate after the toad aortas were perfused with a solution containing ET-1 and STX. The immunoelectron microscopy revealed
that histamine immunoreactive gold particles in the W P bodies remarkably
decreased in number in the treated samples when compared to the control
ones. Our immunoelectron micrographs indicated that the release of histamine from the endothelial cells occurred in association with the degranulation and the exocytosis of the W P bodies after treatment with ET-1 and
STX.
Conclusions: The present study clearly shows that ET-1 and STX induce
the histamine release from W P bodies of the toad aortas by means of HPLC
and immunoelectron microscopy. Histamine discharged from the W P bodies may be involved in the vasocontraction evoked by ET-1 and STX.
0 1995 Wiley-Liss, Inc.
Key words: Chromatography, Endothelial cell, Endothelin, Histamine, Immunoelectron microscopy, Sarafotoxin, Toad aorta, WeibelPalade body
Since Weibel and Palade (1964) first described the
membrane-bound osmiophilic granules in the rat small
artery, which are now called Weibel-Palade (WP) bodies, their nature and function have been analysed by
biochemical, physiological, and morphological approaches.
Burri and Weibel (1968) have suggested that WP
bodies may contain a “procoagulative substance,” and
it has also been revealed that WP bodies are a storage
site of the von Willebrand factor (vWf), which has an
important role in the adhesion of blood platelets to the
endothelium after vascular injuries (Wagner et al.,
1982; Kagawa and Fujimoto, 1987). GMP-140, an intracellular granule membrane protein first identified
in the platelet a-granules (Stenberg et al., 1985),is also
localized on the limiting membrane of WP bodies (Bon0 1995 WILEY-LISS, INC.
fanti et al., 1989; McEber et al., 1989). Furthermore,
Hattori et al. (1989) reported the co-existence of vWf
and GMP-140 on WP bodies by immunofluorescent microscopy.
In contrast, the involvement of WP bodies in hypertensive activities has been proposed by Bertini and
Santolaya (1970). Our previous chromatographic studies suggested the presence of histamine in WP bodies in
the endothelial cells of both the toad aortas (Fujimoto,
1982a; Fujimoto et al., 1984) and the rabbit umbilical
Received June 21, 1994; accepted December 18, 1994.
Address reprint requests to Dr. Yoshiaki Doi, Department of Anatomy, University of Occupational and Environmental Health, School
of Medicine, Kitakyushu 807, Japan.
HISTAMINE RELEASE FROM WP BODIES
375
Fig. 1. The endothelial cells (EC) contain an abundance of WP bodies (arrows), and the perfusion with
an OR-2 solution only does not result in any significant ultrastructural changes such as swelling and
degranulation of WP bodies. X 15,000.
vein (Fujimoto e t al., 1982b). After treatment with
compound 48/80, a liberator of histamine, WP bodies of
the toad aortas show a remarkable degranulation, and
a n appreciable concentration of histamine was assayed
from the perfusate (Fujimoto et al., 1984). This suggests that WP bodies are a storage site of histamine.
Moreover, Ueda et al. (1992) revealed a simultaneous
localization of histamine and vWf on WP bodies of the
human umbilical vein using double-labeling immunoelectron microscopy.
Recently, endothelin (ET) was purified from the medium of cultured endothelial cells and has been reported to possess a potent vasoconstrictive activity
(Yanagisawa et al., 1988). ET consists of three isopeptides, ET-1, ET-2, and ET-3 (Inoue et al., 1989), and
these peptides have a close similarity in amino acid
residues and in biological actions to sarafotoxins (STX)
purified from snake venom (Takasaki et al., 1988;
Kloog et al., 1988; Hirata et al., 1989). Among these
peptides, ET-1 and STX-S6b induce vasocontraction to
both endothelium-preserved and denuded toad aortas
and evoke a remarkable degranulation of the WP bodies before the onset of the endothelium-dependent amplification of the vasocontraction (Doi and Fujimoto,
1993). This indicates that some vasocontractive components, such as histamine, may be released from the WP
bodies in association with degranulation of the WP
bodies induced by ET-1 and STX-S6b and that in turn
may amplify the vasocontraction. But to date, there
have been no available biochemical or morphological
studies describing the release of histamine from WP
bodies induced by these peptides.
On these grounds, the present study was designed to
clarify by means of high performance liquid chromatography (HPLC) and immunoelectron microscopy the
question of whether ET-1 and STX-S6b actually induce
the release of histamine from WP bodies of the toad
aortas.
MATERIALS AND METHODS
Tissue Preparation
Isolated toad abdominal aortas, 0.8 mm-1.0 mm in
diameter, were cleaned of all surrounding connective
tissue and cut into 15-mm-long specimens. A 22G (diameter: 0.7 mm) stainless-steel canule was inserted
into the proximal end of the vascular lumen and then
connected to a minipump (Perista SJ-121S, Atto, Tokyo, Japan). A balanced salt solution for frogs (OR-2
solution, composition in millimolar concentration:
NaCl 82.5, KC1 2.5, CaC1,.2H,O 1.0, MgC1,.6H20 1.0,
Na,HP04-2H,0 1.0, Hepes 5.0, pH: 7.6) was passed
through each vessel at a constant flow (1.0 ml/min) by
the minipump for 5 min in order to remove the blood
cells and plasma. After being perfused with the solution, each vessel was divided into three groups: the
control group was perfused with a n OR-2 solution only,
the ET-1 perfused group was given a solution containing ET-1 (Sigma Chemical Co., St. Louis, MO) (10-'M),
and the STX perfused group was given a solution containing STX-S6b (Peptide Institute, Osaka, Japan)
376
Y. DO1 ET AL.
Fiq 2. In the vessels perfused with a solution containing ET-1
(10- M, 10 m i d , a marked indentation of the internal elastic lamina
(IL) is observed. Swollen WP bodies with a wide peripheral halo and
decreasing electron density (WP), large intracellular vacuoles (LV),
and extrusion of their contents in a manner of exocytosis both to the
apical and basal sides of the endothelial cells (arrows) are observed. x
13,000.
(lO-'M). Each group was perfused with a 10 ml of the
above mentioned solutions with a constant flow (1.0
ml/min), and the perfusate was collected from the other
end.
For immunoelectron microscopy, the vessels of each
group were fixed in a periodate-lysine-paraformaldehyde solution (composition: 0.01 M NI04-0.075 M
lysine-2% paraformaldehyde in 0.0375 M phosphate
buffer, pH: 6.2) (Mclean and Nakane, 1974) for 6 h r at
4°C. After dehydration in graded concentrations of ethanol, specimens were embedded in Lowicryl K4M (Polaron Equipment, Watford, UK), and polymerized at
4°C with a n ultraviolet polymerizer (Dosaka EM, Kyoto, Japan).
For conventional electron microscopy, the vessels
were fixed in 2% paraformaldehyde-2.5% glutaraldehyde in 0.1 M phosphate buffer for 2 h r a t 4°C and
postfixed in 1% osmium tetroxide in the same buffer for
2 h r a t 4°C. After dehydration in graded concentrations
of acetone, the specimens were embedded in epoxy
resin. Ultrathin sections were stained with 5% uranyl
acetate for 6 min and lead citrate for 4 min and examined in a JEM 1200 EX electron microscope.
lution, and the histamine was extracted by n-butanol.
Then the n-butanol fraction was added to benzene, and
the histamine in this fraction was extracted by 0.1 M
HC1. HC1-extracted histamine fraction was added to 1
M NaOH and o-phthalaldehyde (OPT). To stop this reaction, 0.45 M H,S04 was added after 4 min.
The OPT-histamine complex was separated and determined by a reversed phase high performance liquid
chromatograph (Hitachi 650-LC) equipped with a spectrofluorometer. The peak of OPT-histamine of each
sample solution was identified by comparing the retention time of the standard OPT-histamine, and the histamine concentration was determined by a calibration
curve from the peak area of the standard OPT-histamine. The recovery of histamine by this method was
103.1 +- 4.9% (mean S.D., n = 4 ) .
Histamine Determination
For histamine determination, 4 ml of each perfusate
was used; 5 M NaOH and NaCl were added to the so-
*
lmmunoelectron Microscopy
All procedures were done at room temperature. U1trathin sections of Lowicryl-embedded specimens were
collected on uncoated 150-mesh nickel grids and placed
for 15 min on drops of 1.0%egg albumin (EA) in phosphate-buffered saline (PBS) to absorb nonspecific proteins.
Sections were incubated for 2 h r with rabbit antihistamine serum (Chemicon International, Los Angeles,
CAI, which consisted of whole rabbit serum, diluted a t
HISTAMINE RELEASE FROM WP BODIES
377
F i t 3.In the vessels perfused with a solution containing STX-S6b
(10- M, 10 rnin), some WP bodies are also altered in a similar manner
to ET-1.Swollen WP bodies with a wide peripheral halo and decreasing electron density (WP), large intracellular vacuoles (LV), and the
extrusion of their contents to the apical sides of the endothelial cells
(arrows) are observed. A marked indentation of the internal elastic
lamina (IL) is also seen. x 14,000.
1:400 in 0.1% EA-PBS. After rinsing them in PBS, the
grids were reacted to goat antirabbit IgG-coated 15 nm
colloidal gold (Ultra Biosols, Liverpool, UK), diluted at
1 : l O O in 0.1% EA-PBS for 1 hr, washed in PBS, and
washed again in distilled water. The sections were finally stained with 5% uranyl acetate for 3 min and
examined in a JEM 1200EX electron microscope.
The specificity of the immunolabelings was confirmed by replacing the antisera with either normal
rabbit sera diluted a t 1:400 in 0.1% EA-PBS or PBS.
RESULTS
Cytological Observations
Quantitative Analysis of Immuno-gold Particles
Quantitative analyses as to the mean Weibel-Palade
(WP) body area, the number of gold particles per mean
WP body area, and the number of gold particles per 1.0
pm2 WP body area were carried out with a n imageanalysing device (Nikon Cosmosome IS) from immunoelectron micrographs of randomly selected endothelial
cells of the control group (12 cells from 4 vessels), the
ET-1 perfused group (7 cells from 3 vessels), and the
STX perfused group (11cells from 4 vessels). Statistical
comparisons between data from the control group and
the drug perfused group were made using Student's
t-test for unpaired comparisons.
The endothelial cells contain a n abundance of WP
bodies, and the perfusion with a n OR-2 solution only
does not result in any significant ultrastructural
changes such as swelling and degranulation of the WP
bodies (Fig. 1).
In the vessels perfused with a solution containing
ET-1 (1OP8M,10 rnin), some of the WP bodies are altered. These alterations include a decrease in electron
density, swelling with a wide peripheral halo between
a n osmiophilic dense core and the limiting membrane,
formation of large intracellular vacuoles, contacts of
the altered WP bodies with the plasma membrane, and
extrusion of their contents in a manner suggestive of
exocytosis both to the apical and basal sides of the endothelial cells (Fig. 2). However, there are considerable
variations in these changes from cell to cell: in some
endothelial cells, most WP bodies are remarkably altered, whereas almost all WP bodies remain intact in
the other cells (Fig. 2). The internal elastic lamina covering the squeezed endothelium occasionally becomes
deeply infolded (Fig. 2).
In the vessels perfused with a solution containing
STX-S6b (lO-'M, 10 rnin), some WP bodies are also
378
Y. DO1 ET AL.
Fig. 4. In the vessels perfused with a solution containing STX-S6b (lO-*M, 10 min), extrusions of WP
bodies contents into both the subendothelial connective tissue and vascular lumen are frequently observed (arrows). x 15,000.
altered in a similar manner to ET-1 (Fig. 3). Extrusions
of their contents from the altered WP bodies into both
the subendothelial connective tissue and vascular lumen are frequently observed (Fig. 4).
Histamine Quantification
All the sample solutions containing ET-1 (n = 5) and
STX-S6b (n = 5) showed fluorescence peaks, which had
the same retention time as that of the standard histamine solution (Fig. 5), but those containing an OR-2
solution only (n = 5) did not show any peaks.
The histamine concentration from a solution con20.1 (pg/ml, expressed as
taining ET-1 was 151.0
S.E.M.) and that from a solution containing
means
STX-S6b was 316.2 t 111.6.
*
*
lmmunoelectron Microscopy
Control specimens perfused with an OR-2 solution
only in which the antihistamine sera were replaced by
normal rabbit sera (Fig. 6) or PBS for the negative
staining show few or no gold particles on the endothelial cells.
By immunoelectron microscopy of the endothelial
cells of control specimens, histamine immunoreactive
gold particles are preferentially localized on WP bodies
(Fig. 7 ) .The immunoreactions are also seen on the apical plasma membrane of the endothelial cells (Fig. 71,
but rarely seen on other endothelial cell organelles, on
the nonendothelial structures and on the nontissue areas of the grid.
In endothelial cells perfused with a solution containing ET-1, the immunoreactive gold particles of the WP
bodies decrease in number when compared to those perfused with an OR-2 solution only, but the immunoreactions are often observed in the cytoplasm near the
limiting membrane of degranulated WP bodies (Fig.
8A,B). The immunoreactions are seen in the vascular
lumen, especially near the degranulation sites of WP
bodies (Fig. 8C).
In endothelial cells perfused with a solution containing STX-SGb, the gold particles decrease in number
inside WP bodies as in case of the ET-1 perfusion. Some
swollen W P bodies are in contact with both apical and
basal membrane of endothelial cells where immunoreactions of histamine are often found (Fig. 9A,B). The
gold particles are seen on the limiting membrane of the
swollen WP bodies (Fig. 9A) and the subendothelial
space near the degranulated WP bodies (Fig. 9B).
Quantitative Analysis of Immuno-gold Particles
The data from quantitative analyses are illustrated
in Table 1. As shown, the mean area of WP bodies of
the ET-1 perfused group and STX perfused group significantly increase when compared to that of the control group. However, the number of gold particles labeling histamine per mean WP area and per 1.0 pm2
HISTAMINE RELEASE FROM WP BODIES
379
A
ET-1
B
STX-S6b
.-
0
Standard Histamine
2
4
6
8
(rnin]
Retention time
Fig. 5. The standard histamine solution (C) shows a histamine peak
(H). All the sample solutions containing ET-1 (A) and STX-S6b (B)
show fluorescence peaks (HI, which have the same retention time
as that of the standard histamine solution. Chromatographic conditions: Column, LiChrosorb RP18, 5 pm (150 X 4 mm, I.D.). Mobile
phase; 0.2M NaCl: CH,OH: CH,CN (60:20:20, viv, pH 3). Flow rate;
0.5 mlimin. Fluorescence detection; excitation 350 nm, emission 450
nm.
WP areas of the ET-1 perfused group and STX perfused
group significantly decrease in comparison with those
of the control group.
DISCUSSION
In our previous studies, WP bodies of the toad aortas
were remarkably degranulated after perfusion with
compound 48/80, a liberator of histamine, and an appreciable concentration of histamine was assayed from
Fig. 6. Few or no gold particles are seen in the endothelial cell (EC)
perfused with a n OR-2 solution only in which normal antihistamine
sera were replaced by normal rabbit sera for the negative staining. x
23,000.
Fig. 7. Histamine immunoreactive gold particles are preferentially
localized on WP bodies (WP) of the endothelial cells of toad aortas
perfused with a n OR-2 solution only. The immunoreactions are also
seen on the apical plasma membrane of the endothelial cell (arrows).
x 45,000.
the perfusate using HPLC (Fujimoto, 1982; Fujimoto et
al., 1984). Also, we reported that both ET-1 and STXS6b induce ultrastructural changes of the WP bodies.
The altered WP bodies showed a decrease in electron
density, formation of the peripheral halo, fusion to each
other, which results in the formation of large intracellular vacuoles, and expulsion of their contents in a
manner of exocytosis. We found no basic inconsistencies in these changes of the altered W P bodies with
those treated with compound 48/80.
380
Y. DO1 ET AL.
toad aorta. Immunoelectron microscopy showed the release of histamine from the WP bodies in association
with their degranulation. After being perfused with
ET-1 and STX-SGb, the immunoreactive gold particles
that were localized in the WP bodies remarkably decreased in number when compared to the control group
and are often localized on and outside the limiting
membrane of the swollen WP bodies. They also exist
not only in the vascular lumen but also in the subendothelial space, especially in regions where the extracellular release of the WP bodies occurs.
These immunocytochemical findings suggest that
histamine stored in WP bodies may permeate into the
cytoplasm through the limiting membrane and are
then discharged extracellularly in association with
exocytosis of the WP bodies after treatment with ET-1
and STX-S6b. ET-1 has been recently reported to provoke the release of histamine from pulmonary mast
cells (Uchida et al., 1992) and to induce bronchoconstriction by its indirect action through the production
of some chemical mediators such as histamine in pulmonary mast cells a s well as its direct action on the
smooth muscle cells (Ninomiya et al., 1992). Our previous data (Doi and Fujimoto, 1993) indicate the existence of some vasocontractive substances in WP bodies
of the toad aortas, and the present data suggest that
histamine included in WP bodies and released from
them is one of the candidates. It is therefore reasonable
to consider that indirect action after the release of histamine may be involved in the vasocontraction of the
toad aorta induced by ET-1 and STX-S6b a s in the case
of the bronchoconstriction induced by ET-1. However,
there still remains the question whether histamine
amplifies the vasocontraction induced by ET-1 and
STX-S6b. To answer this question, it should be
confirmed that histamine and these peptides show a
synergistic action. More detailed studies, now in
progress in our laboratory, are necessary to solve this
problem.
ACKNOWLEDGMENTS
We thank Ms. Tomoko Nishino for her technical assistance, and Ms. Toyono Nobukuni for typing the
manuscript.
LITERATURE CITED
Fig. 8. In endothelial cells (ECs) perfused with a solution containing
ET-1, histamine immunoreactive gold particles of the WP bodies decrease in number when compared to those perfused with an OR-2
solution only (Fig. 71, but the immunoreactions are often observed in
the cytoplasm near the limiting membrane of degranulated WP bodies (WP) in B (high magnification view of the box in A), and in the
vascular lumen near the degranulation sites of WP bodies (arrow) in
C. A, x 23,000; B, $st 45,000; C, 35,000.
Our chromatographic study revealed that both ET-1
and STX-S6b induce the release of histamine from the
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381
HISTAMINE RELEASE FROM WP BODIES
Fig. 9. In endothelial cells perfused with a solution containing STXS6b, the gold particles decrease in number inside WP bodies as in case
of the ET-1 perfusion. Some swollen WP bodies are in contact with
both the apical and basal membrane of the endothelial cells where
immunoreactions for histamine are often found (arrowheads). The
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TABLE 1. Number of gold particles labeling histamine within Weibel-Palade bodies (mean
Control group (12 cells from 4 vessels)
ET-1 perfused group (7 cells from 3 vessels)
STX perfused group (11 cells from 4 vessels)
WP body profile
area (urn2)
0.075 0.003
0.101 0.006**
0.110 -t 0.011**
*
*
Number of gold
varticles/WP bodv
1.355 -t 0.139
0.335 0.033**
0.422 & 0.058**
f
S.E.M.)
Number of gold
aarticles/um2
19.417 2 1.782
3.754 t 0.412**
4.037 2 0.525**
**P<O.Ol, Asterisks show a statistically significant difference between the control group and the drug perfused group.
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