Comp. gen. Pharmac., I973, 4, 229-25o. [Scientechnica (Publishers) Ltd.]
2~ 9
A PHYLOGENETIC STUDY ON THE OCCURRENCE
A_ND
D I S T R I B U T I O N O F H I S T A M I N E IN T H E G A S T R O - I N T E S T I N A L
T R A C T A N D O T H E R TISSUES O F M.~N 2M~D V A R I O U S .4~NIMALS*
W. LORENZ, E. IVL~.TEJKA, A. SCHNL~.L, W. SEIDEL, H-J. ILEINLANN,
R. U H L I G ,
AND G. M.-MNNt
Division of Experimental Surgery. and Pathological Biochemistry, Surgery Clinic of the University,
Marburg/Lahn, and Institute of Clinical Chemistry. and Clinical Biochemistry of the University,
Munich, Germany;
(Rta:eived z3 Nooember, t972 )
ABSTI~.CT
Using a specific fluorimetric and biological method, the occurrence and distribution of
histamine was investigated in man, various mammals, birds, reptiles, amphibians, bony
and cartilaginous fishes, lancelets, tunicates, echinoderms, molluscs, and crustaceans. The
anune was identified by. the fluorescence spectrum, by specific antihistaminics in the bioassay, by the comparison of the fluorimetric histamine values following three different
isolation procedures, and in some dssues also by thin-layer chromatography.
Histamine was found in all chordates in considerable concentrations with the exception
of the stomachiess carp. The distribution of histamine in the body, however, varied
largely from species to species. Only the gastric mucosa of adl vertebrates investigated was
relatively rich in histamine.
The amine was nearly uniformly distributed in amphibians and fishes, in which only the
stomach and partly the intestinum showed highdr histamine concentrations than all the
numerous other tissues investigated. The distribution of histamine, however, in mammals,
birds, and reptiles showed great variations from tissue to tissue. Organs free from histamine
were first found in fishes going backward in the phylogeny.
Because of the great variabilities in the distribution of histamine in the body of
numerous species which were studied in this investigation, only one hypothesis can be
developed with respect to a common physiological significance of histamine: there is a
selective accumulation of histamine in the gastric mucosa of all chordates possessing acidsecreting cells and a low concentration of histamine in the gastro-intestinal tract of
stomachless fishes. The gastric acid secretion is stimulated by histamine in all vertebrates
investigated, whereas in many fishes histamine has no effects on the circulation or on
smooth muscles of the gastro-intestinal tract or on the uterus. Thus, stored histamine
probably has a specificfunction in the gastric mucosa, but not a general function, such as the
regulation of ubiquitous metabolic processes or the regulation of microcircutation.
INV~.eTIOA'nONS on the occurrence a n d distrib u t i o n of histamine in animals have been
p e r f o r m e d by n u m e r o u s authors (for a survey
see L o r e n z a n d Werie, 1974), since Best, Dale,
* Dedicated to E. Werle for his 7oth birthday.
Supported by grants of Deutsche Forschungsgemeinschaft (Lo I99/z, and SFB 37 ' Restitution
und Substitution innerer Organe ').
; Requests for reprints should be sent to W.
Lorenz, Division of Experimental Surge~ and
Pathological Biochemist~, Surgery. Clinic of the
University, D-355o Marburg/Lahn, Robert-KochStraSe 8, Germany.
Dudley, a n d T h o r p e (1927) first d e m o m t r a ted the existence o f this biogenic amine in
m a m m a l i a n tissues by elementary analysis.
For several reasons, however, it seems necessary, to determine a n d reinvestigate the
histamine contents in as m a n y tissues a n d
species as possible : - i. Some methods for the determination o f
histamine which were used in prior studies,
were shown to have a less t h a n satisfactory
specificity, in b o d y fluids and in certain
tissues (Carlini a n d Green, i963; ."vtichaelson
and Coffman, I967; Lorenz, Benesch, Barth,
23o
LOR.ENZ AND OTHERS
Matejka, Meyer, Kusche, Hutzel, and Werle
r97o; Lorenz, Barth, Kusche, Reirnann,
Schmal, Matejl~, Mathias, Hutzel, and
Werle, 197I). Thus a reinvestigation about
the histamine contents of numerous tissues
should be performed with the aid of more
specific methods.
2. For several tissues, in which a physiological role of histamine is considered, no or
only very, few data are available about their
histamine concentration. Such tissues are,
for instance, the skeletal muscles and the
ureter, where histamine m a y be involved in
the functional hyperaemia (Schayer, I964) or
in the spontaneous motility (Borgstedt,
Benjamin, and Emmel, i96~). Furthermore,
nothing is known about the histamine content
of m a n y h u m a n tissues.
3. A m u c h greater species variability than
expected was found in the distribution and
cellular localization of histamine (H/dtanson,
O w m a n , Sj6berg, a n d Sporrong, 197o; Lorenz
and Werle, 1974). In this respect a comparison of numerous species seemed necessary in
order to find out whether there exist any
regularities which m a y be helpful in studies
on the physiological role of histamine in
animals.
4. Only few phylogenetic investigations
have been performed on the occurrence and
distribution of histamine in animal tissues
(Ungar, Ungar, and Parrot, 1.937; Mettrick
and Telford, 1965 ; Reite, 1965; Lorenz,
Schauer, Heitland, Matejka, and Werle,
1969; Reite, 1969a; T a k a y a , 1969). A comparison of the pharmacological effects of
histamine in various phyla and classes of the
animal kingdom w~th its occurrence and distribution in tissues seems to be one way to
elucidate physiological functions of histamine. Such functions have been discussed
especially frequently in the gastro-intestinal
tract which therefore was intensively studied
in this investigation.
MATERIALS AND METHODS
~-.ATZRIAL.S
Animals and Tissues
The election of species was influenced by several
factors, the most important of which were aspects
of systematic zoology, frequent use of the species in
physiological or pharmacological investigations,
Comp. gen. Pharmac.
and the possibility of obtaining fresh tissues immediately after the death of the animals.
With the exception of the human tissues which
were collected throughout the whole year, the
organs of all other species investigated were prepared during the months September until December, since according to Reite and Davis (i97o)
seasonal changes of the mast cell density, can occur
in the tissues. Furthermore, the tissues of the
various species were obtained from three different
places: those of man, dog, Mastomys, and rabbit
from Marburg (central Germany); those of the
cartilaginous fishes and of all the species which are
lower in the phylogeny than the elasmobranch
fishes, from Naples, Italy; ~ and those of all the
remaining species from Munich (southern
Germany).
The human tissues were withdrawn as exploratory excisions during the operations at the
Surger3" Clinic of Marburg. By microscopical
control all tissues were found to be normal and
healthv. Histamine release in man by the
anaestiaetics used (thiopentone, suxamethonium,
fluothane, N..O) and by the stress during the
operation can be considered as minimum (Lorenz,
Doenicke, Meyer, Reimann, Kusche, Barth,
Geesing, Hutzel, and Weissenbacher, x972;
Seidel, Lorenz, Doenicke, Mann, and Uhlig,
1973). Thus, the argument of Kumar, Laddu,
Lahiri, and Sanyal (1968), that the withdrawal of
tissues during operations may not guarantee physiological histamine contents, cannot be accepted
for our tissue samples.
The organs from pigs (Deutsches veredeltes
Landschwein), cattle (H0henfleckvieh), and sheep
(Deutsches schwarzk6pfiges Fleischschaf) were
obtained in the slaughter-house immediately after
the death of the animals; those from the pheasants
during the hunt; those from dogs (Deutscher
Sch~ferhund), foxes, miniature pigs (Zucht Hanhover), and rabbits (New Zealand) after
anaesthesia with pentobarbitone (I o-35 rag. per kg.
i.v.) and bleeding. The tissues from guinea-pigs
(laboratory. strain), rats (Wistar), and Mast~mys
na/a/eas/s were withdrawn after anaesthesia with
ether; those from birds, repdles and frogs after
decapitation. The fishes were sacrificed by blows
on the head and bleeding; the molluscs and
crustaceans by dividing central nerve-cords according to Ktikenthal, Matthes, and Renner (1967).
The dissection of the animals was performed
according to Ellenberger and Baum (I91a),
Kiikenthal, and others (1967) , and Koch (i97o).
Only adult animals were used.
All tissues were frozen by CO= snow immediately
after the withdrawal, were stored at --2o ° C. for
maximally 4 weeks, and then assayed for their
histamine concentration.
" We thank Dr. Rocca and Dr. Martin. from
the Stazione Zoologica in Naples, vet-,"much for
their advice and support in this investigation.
2973, 4
HISTAMINE IN MAN AND ANIMALS
Reagents and Drugs
For the fluorimetric determination of histamine
the following reagents were used: histamine
dihydrochloride pur/~s/mum, o-phthaldialdehyde
purissiraum p.a. (rec~stailized from ligroin p.a.,
b.p. 4o-6& C.) (Fluka, Buchs), methanol,
n-heptane, inorganic acids and bases as Uvasol ®
(Merck, Darmstadt), n-butanol (chromatography
grade Riedel de Ha%n Hannover), Dowex
5oW-X8 (H ÷, mesh 200-400 ) (Serva, Heidelberg).
I f not otherwise stated, only twice-distilled water
w a s used.
For the biological determination of histamine the
following drugs were used: glucose, buffers, and inorganic salts p.a. (Merck, Darmstadt), atropine
(from the university's pharmacy.), methysergide,
antazoline (Ciba, Basle), mep.vramine maleate
(Bayer, Leverkmen), pentobarbitone (Nembutal,
Abbot. Ingelheim), acetylcholine (Hoffmann-La
Roche, Grenzaeh), serotonin creatinine sulphate
(Fluka, Buchs, Switzerland).
DETERMINATION AND IDENTIFICATION OF HISTAMINE
Determination of Hiaamim
Histamine in the tissues was measured fluorimetrically according to Shore, Burkhaltcr, and
Cohn (1959) and Lorenz, Benesch and others
(197o) and by the bioa~av according to
Guggenheim and L6fl~er (x9,6) in the modification of Bamoum and Gaddum (I935). About
85oo determinations were performed.
For the method of Shore and others (2959) and
the bioassay, the tissue pieces were homogenized
with 9 parts by volume of o. 4 M HCAO4 and
centrifuged at xSoo g. Four ml. of the supernatant
were extracted with alkaline ,-butanol, washed
with salt-saturated o'2 M N a O H , and again extracted with o" t M HCI according to Shore and
others (x959). Histamine in the aqueous phase
was then either determined fluorimetrically following the condensation with o-phthaldialdehyde or
measured by the bioassay on the isolated atropinized guinea-pig ileum following the neutralization
of the o.x M H C 1 solution with 0.2 M NaOH.
The most commonly used fluorimetric method
was that of Lorenz, Benesch, and others (I97O).
The tissues were homogenized as described above.
Four ml. of the same supernatant, which was used
for the bioassay, were adjusted to pH 6-5, chromatographed on Dowex 5oW-X8, and histamine
was determined in the diluted eluate after condensation with o-phthaldialdehyde.
Identification of Hiaamine
The identification of histamine in the different
tissues was carried out by chemical and biological
methods.
According to Carlini and Green (1963) the inhibition of the contraction of the isolated guineapig ileum by small doses of a specific antihistaminic
drug can be considered as a reliable method for
the identification of histamine. Because of its
231
simplicity we used this procedure to examine
the specificity of the assays for all tissues so far
investigated in this study. Mep.vramine (Io-~M
final concentration) and antazoline [ t o" eM, accorcling to Werle and Lorenz (t97o) ] were injected
into the bath fluid as well as methysergide ( t o - ' M )
as a specific antagonist to serotonin. Furthermore,
the results of the fluorimetric method of Shore and
others (x959) were compared with those of the
assay of Lorenz, Benesch, and others (,97o) in
tissues of man, dogs, pigs, and guinea-pigs. The
results of the fluorimetric determination after
chromatography on Dowex 50 were compared
with those of the bio-assay for all tissues so far investigated in this publication. An agreement of
the ,histamine values, obtained by the different
determination and isolation methods, was considered as a further argument for the identity of
the substance isolated from the tissues with
authentic histamine, which was always added
to tissue extracts for the determination of the
recovery,.
Following the purification procedure according
to Lorenz and others (i972), the tissue extracts
from pig stomach and ileum were compared with
authentic histamine using thin-layer chromato.graph y in 8 different solvent systems (cf. Lorenz and
others, i97i ). Finally-, the fluorescence spectra of
authentic histamine were compared with those of
tissue extracts from numerous tissues of man, dogs,
pigs., sheep, rats, mad guinea-pigs after chromatography on Dowex 5 o, as already reported
(Lorenz, Benesch, and others, i97o ; Lorenz and
others, 297I ).
The histamine content of the tissues was
expressed in jag. histamine dihydrochloride per g.
fresh weight. The statistical calculations were
carried out with the aid of a desk computer
(Programma Io2, Olivetti, Italy). The zoological
classification of the animals was performed
according to Storer and Usinger (z965), Kiikenthal and others ( x967), and Wurrnbach (, 971 ).*
RESULTS
COMPA.RISON OF T W O FLUORh~fETRIC .~V[ETHODS
FOR THE DETERMINATION OF HISTAMINE AND
IDENTIFIGATION OF H r S T A m ~ m VARIOUS
TxssuE Ex'r~.~crs
T h e high degree o f correspondence between the values of two different fluorimetric
assays for histamine (Table I) was considered
as an argument for the identity of the substance isolated from h u m a n and dog tissues
with authentic histamine, especially because
* We thank Professor Fr. Seidel, Ph.D., formerlv director of the Institute of Zoology, University
of Marburg/Lab.,, very, much for his advice and
the support of this investigation.
LO~NZ AND o'r~zRS
~3 2
the high specificity of the ion-exchange
method in tissues had been demonstrated
(Lorenz, Barth, and Werle, I97o; Lorenz and
others, 1971 ). Even if three different purification procedures were used for the fluorimetrie
Corn#. grn. Pharma¢.
which were determined fluorimetrically following Dowex chromatography, were in no
case significantly different from those which
were measured by bioassay. The contractiom of the guinea-pig ileum elicited by the
Table L--C~m, Amsor, or THE RZSULTS OF TmZ Btrr~oL E X T R A C m O N M E T H O D AccoRDING TO SHORE
AND OTHERS (1959) wrrH THos~ o? TH~ D O W E X 5 ° M Z T H O D ACCORDINO TO LORZNZ AND OTHF.RS (1970)
Z~ T ~ n m s or M A N Am) D O O
Hm'~m~
CONCENTRATION (~g. ~ r
g. fresh
weight)
Man
Tissue
~&stric muco~..
corpus
&ntrum
Jejunum
Ileum
Colon (ascending)
Sigma
Rectum
Mesentery
Pancreas
Lungs
Thyroid gland
Muscle
Abdominal rectus
External oblique
Fat, subcutaneous
umbilical
anal
mesenteric
Dog
Butanol
Extraction
Dowex 5o
t9.o±6.8
t4"2±5"I
x4.3±i-t
15"9±5"I
9"o±3.1
8"4
5"9±2"4
I.4
4.I±t.8
x2"3±3"8
o'4mo'I
20.2±8.8
t4"6~4"5
t2"3±2"2
I4"8~6" 4
8.I±]. 4
7"8
5.8=x. 9
I. 7
3.5±1-6
~4"4~4"3
o.4±o.i
2"7±x'I
0.5±0. 3
2.8±0.8
o.6~o" 4
x.t±o. 3
0.8±0.2
i-4±o. 5
0-9 ±0"3
I'O
I'i
Tissue
Kidney
Ureter
U r i n ~ bladder
Muscles
Masscter
Butanol
Extraction
Dowex 50
2"3
30"8
7.I
2-4
32"5
6.2
i. 3
l' 7
2"]
I'I
2"0
I" 7
I" 7
1"4
]'3
2"!
Sternomasmid
Triceps braehii
Extensors dig~torum
Deltoid
Intercostal
lZectus
External oblique
Psoas
Autochthonous back
muscles
Glutcus maximus
Biceps femoris
Semiumdinosus
Gastrocncmius
Diaphragm
]'8
3-0
I-9
3"4
I'O
2"7
I"5
3"0
I" 7
I" 7
I. 7
2.3
2"4
2.8
i. 9
3'3
7"0
2"3
2"3
1"8
2"9
6"5
~±S.D. In the case of human tmues, only i--8 organs were obtained from the same individual; in
dogs each tissue of one series from the same anim~d.
In m a n n = 2-4, in dogs . = 2. For further
conditiom see Methods.
determination of histamine in organs of pigs
and guinea-pigs (butanol extraction, ionexchange chromatography, and a combination of both methods), no significant differences between the histamine concentrations
of these tissues could be observed (Lorenz
and others, 197~ ).
T h e fluorescence spectra of the substances
isolated from tissues of man, dogs, pigs,
sheep, rats, and guinea-pigs, all corresponded
to those of authentic histamine. In all tissues
investigated the histamine concentrations,
tissue extracts and by authentic histamine
were comp}etely abolished by mepyramine
and antazoline, but not by methysergide and
atropine, which totally blocked the equivalent
contractions of the gut induced by serotonin
and acetylcholine. Thus, the substances isolated from the tissues seemed to be sufficiently
identified as histamine.
Only in the extracts of pig stomach and
ileum was histamine identified by thin-layer
chromatograph'),, as already reported (Lorenz
and others, 197 I).
1973, 4
H I S T A M I N E IN MAN A N D ANIMALS
HXSTAMmE C O N C E N T R A T I O N S IN M A M M A L I A N
Tzssuxs
Histamine Concentrations in Human Tissues
( Table H)
Histamine "was detected in all 34
h u m a n tissues investigated. T h e highest
233
concentrations were found in lungs, stomach,
and intestinum, the lowest in kidney, subcutaneous connective tissue, and muscles. In
several tissues, which showed p a t h o l o g i c ~
alterations (Meckel's diverticulum, adenocarcinoma of the rectum, and a d e n o m a of the
Table [Z.--HIsTAMINE CONCZNTRATIONS OF HUMA,~ Tmsuzs
HI~rAMINE CONCENTILATION(gg. per g.)
Tmsvz
~--S.D.
Gastro-int~stinal Tract
Gastric mucosa
Fundus
Corpus
Antrum
Duodenum
Jejunum
4
19
J5
3
6
Ileum
Appendix
Meckel's diverticulum
Colon (ascending)
Sigma
Rectum
Adcnocarcinoma
• Ampulla
5
t3
L i ~)e r
33
8
I
I1
I
2
Gall-bladder
2
Pancreas
Head
Tail
Mcsente~
5
3
lh~a~ining Tissues
Lungs
Kidney
Parenchyma
Capsula
Pelvis
Ureter
Prostate (adenoma)
Spleen
Thyroid gland
Skin
Abdominal
Anal
Subcutaneous fat
Abdomen
Anal
.~,-m
Mesenteric fat
M a m m ~ gland
Muscte (rectus)
2
z3-6±5"6
z7"o~8"6
8"5~3"4
m.4±8-2
zo'5±y2
z5"6~5" 4
38"I
8"5~5"5
7-i±3. 9
7-2m4.I
2I' 7
6"8
3"9=2"6
6"3
Extreme Values
6.1-t8. 9
5"o-39"o
3-5-t3-o
5"o-~6"2
6.o-i4- 3
8-3-25.o
3-3-i8.4
2"3-13"2
x-a-I2"8
I'6-16'6
5"9±I'6
~'7±o'4
1.7mo- 4
1"2--2"2
24-x=17"6
12"6-66-0
1"2
I"9
2. 5
6-4
7"6~2"7
o.4±o'x
5-5-io.7
I"4-4"5
0.2--o.5
4"8±3-4
8.1~3"7
4.t-ii.5
2-8=1.8
4
6
°1
0.8±0"5
0. 9
2"0=0"4
1-2~o-9
7.2
z.8~o.8
I "7-7"9
0"~--2"0
I "5-2"3
o.3-,2.6
0"8- 3"t
Mean values of tissues which were obtained in a total number of z-.-8 from
the same individual. From intestinal tissues, the whole wall was investigated. For further conditiom see Methods.
4 5 " 5 + 7 .8
4='ok: 6.~
r7"9 l: 3"6
63- 7 -p~3.r
35'3 :[- 9"5
3 = ' 8 ~ 6.0
~4"5 :t: ~ i .~
=O= t 15
1=7~:4o
69"3 :E'z4" 7
= =5 :J: it{
=45-]-~6
83"4:t: =6"8
7='6 t:~l.3
3=-~ :t: 8-8
38.3 {- i6-o
4"ll I- o- 7
= I "4 :t: 3"6
63"8 :k 45"4
=.l t- 0.8
'z"'9 1:=0"5
13"4 :t: 3 9
4"~ :t: ='6
18-5 l 7"o
6=-~ I: =o'9
~ r . r ~ 14,6
14"o I 2"3
9 0 t o'4
3 I'0:ll I3"6
3'6 1 ="~
54 "o I- ~6"5
3"4 I- o-~
3o'3:1:1l'6
=5'7 F o'9
3"3-E o-8
3
~9"3 :t: I o.~
7 ~ f ;'5
53"5.-}- =4 .2
n~
~3"3:1: ~'o
7
Fox
( VIdpes
vulpes )
I~.4-[: y o
a=
familiar=s)
l)og
( C'anis lup,s
6. 9
5"4
4"5
5 "=
6"'z
3"41
='5
=4";J: 7 .6
=-II :~
44'8 t
'z°'3 :1:
=7"4 [
~9'6 I
=5o'4:E 66"7
99"7 [: ~6"5
,)2"o E 49"o
14o-o :[ 13"0
~34"o t 7"11
191l:t:54
;~7 "~ [:53
=r~l'3 :t ~3
73"3 :[ 4~'5
r='4:~ TIt
56"6 ~: 9"o
4"1 t- o-I}
36"5 :t =6"5
33"~ 1 I o 7
4.~.1 o-6
75"3 t ;~'4
4"° A: ~'3
=4"~F =~z-o
(S.s scrafa
domestk,s )
n=5
l,andrace Pig
3"9
4
5 .o
7"o
'~'3
3"~
I 3'6
7"o:E ='6
I.'=
=98 t:36
3"3 t: o'2
15.9 J: 6. 5
~ ' 4 : 1 : 3 .8
= 1"3 +- 3"9
~-8 I: o'5
59"9}
63"6 J:
4o'~ :t:
~"'3 t:
I l l ::j: R l
t5; L'z5
=33 t H
74 .6 _t: 'z~'8
.qo.~ t: 7'8
34"0 :[ 5-8
~'~'7 ~ ~'4
5'5 E =3
5 .0 [- a'3
34"7-I- 5"6
= I.= k
"-
--~
Miniature
Pig
-I'O
5"7t1"2
79"8 y =2.9
3"5 t: 0-8
=3"9£ 3 .0
25"°:t- 5"5
=7"I =F I'7
3 4 " 4 k 7 "o
45"3 t: 5"o
13"8 :[ 6" 5
lh-o l-= ~-6
46.0 -[ 7"5
43 .6 J: 3"9
3 o'o I 5"8
=~8-6 }_34'4
6'1 :[: I'O i
6"6-=I l.o
2.1 l: =.o
54 8 ..t: '~ " 5
47"7=t- 8.=
6 . 4 { ~.~
4"7 t: t.~
3"7-t- ~'=
~'8 -I_ t.6
77t
1"5
8-8 I- 3 6
8"8 E 4"'~
='=
='=
='~-t
=5"4:t: 4 .0
29"5 E 5"0
3,'3:1 ~ ~'8
--
Cattle
"B "r" "
U as p ~nr. g ent,s
.
,
]ronlo.lllS )
"n=6
='5 1:
~'= :~ o" 3
4 "O-t:
a
Sheep
( Ovis aries
•
.aries)
=5
l' 4
2 "0
1.6
3"3
4"9
3"3
4'8
5-2
2"3-1- =.l}
o'9:l: o-r
=='5
0"7
15"7
o.6
1.3:l: 0.6
=6"9 E
1"5J
47"9t
2.4~
=~'3 ti
4"4E
9 "l F
6"3t:
3"9:t.
5"5[
7"6 I:
7"6:1:
'~'3:1:
IO'O t
I'O~- O'2
1.3+ O ' 2 .
=6
o'2
3"3 t_( o'4
H ' 5 E 6'3
31.o-E 4-ll
42"6 : l = 1"2
o'8t:
--
7"7 t: 3 "=
9 9 t: ~'3
7"o:[
=3.~ J: ~.6
9"7~- ~'=
8'~ :t: ='9
3 5 8 ~: 5"0
6-~ A: 3"o
~4"3~ 4'5
=8-o :[: 3"7
=3"4~ ~.8
~8"4 A: 0"3
='4 :L o. 5
7"7-J: 1"8
o'8"1: (|-e2
Rat
( Rattus
rattus)
.=at
o'B]: o 3
Rabbit
( Orwtolagus
- . "
cuntad.s)
c
n=.~
I
}1"3 1o"3
5".3 k_o'2
....
--
9.o:1-o.9
2'3 1:o'7
2"= t:u' 7
='5 t: "4°
~'7:t:o" 9
5"o:E ='o
3"a : E ='4
= "9 t o ' 6
4"3 k ° ' 4
3-8 1:o- 7
8-9 t-5. 4
I'7 :to'8
3"3 :t- o"8
4"0 t ='9
r 3 ' o J 7"1
nalalensis)
I Nalal rat
I (Mastoids
7"4J ~"I
4"9 ~: ='~
24"= 1:4'I
31"5:1. 5"4
~'6 t o'7
4"5 t o.O
5 8 t: 1'4
7 8 ]:2"4
r~.7 -l- =-9
=2"5~ 1"4
=6"8~:5"=
H ' o L2"6
=~'4 :I:= "9
=o.'z £ i- 4
7"4 it: o'I}
4"~ 1:o'6
8 . . _L t "3
6"o:t: I" 5
.:
(Carla)
4t
Guinea-pig
Mean valu(~ -I S.I). T h e upper part of file oesophagus reached from the l l h a r y n x to tile bifurcation of tile trachea, tile lower part from this pnlnt to tile
cardla, h* Ihe slomnch only the mu('nsa was invesligatcd ill all sl~x:ies , with the ext'ellth,I o[ rats, A,la.llomys, alld guinea-Pigs, whereas in the gul the whole wall
was ',;ludw(I. All lissues in tIle whole series were ol}lahwd Ih,l* Ihc sainc animal.
I l l Pigs, m i n l a t u . : pigs, sheq), eallle, rabbit, rats, Maslomv~, a n d gulnca-pigs, all a n i m a l s were femalc, in dng a u d fi~xes of both sexes. Frail= tile illlesliiRini o f
the bigger all=reals, a 5-g- piece of lissuc was r e n l o w d per m., a n d all the pieces from jej.num, ileum, a n d colon were i)~uded. Also fi'om the liver of the bigger
animals 6 II ifieres of llssue were w i t h d r a w n Ii'nm various sites ol the I)arcnchyma a n d eapsula and were i)o.le(I. F'or furlher conditions .lee Mell.xls.
* In ~alth" a n d sheep the a l a ) m a s u m was investigated, in rats the glam]ular par! of Ihc stomach.
] In rats, ]tlaslon~s, a n d guinea-pigs, the tissues fi'.m l| animals were F,Doh-d.
n = N u m h e r of a n h n a l s or animal groups (when pooled tissue was used).
1.ungs
Kidney
Spleen
Thymus
T h y r o i d gland
Al~lomlnal skin
lteart
Ah'ium
Vl'nlride
Remahling "l issues
Liver
(hil-lda(hlrr
Pancreas
Re¢llun
I)uodenunl
.lej,,I.II,,
Ileum
Cae(:u0n
O)hn
AIItrlllll
Corplls
Suhmandibular
gland
Parolid gland
Palatine tonsil
( )CS.l*hagus
Upper part
I.~wer par!
SIolnadl
Fun(lus
"rOIlglll'
Gast.,intestinal Trad
"l'=ssl~
Ihs'rAMINE CONCENTRATIONS (pg. } e r g.)
Table HI.--|~l~l'AUINIg ( ~ N ( ] E N T R ^ T I O N S IN TJ$OF.s OF V ^ R I O U S I~4AMMAI.S
I0
-t973, 4
HISTAMINE
IN
.MAN
AND
ANIMALS
235
Histamine Concentrations in Tissues of Various
Other Mammals (Table III)
p r o s t a t e ) , r e l a t i v e l y high h i s t a m i n e c o n t e n t s
w e r e m e a s u r e d . I n the g a s t r o - i n t e s t i n a l t r a c t
the h i s t a m i n e c o n c e n t r a t i o n d e c r e a s e d from
oral to a b o r a l . T h e s c a t t e r i n g o f the hista m i n e values from i n d i v i d u a l to i n d i v i d u a l
was especially l a r g e in this o r g a n system as
c o m p a r e d w i t h o t h e r tissues.
H i s t a m i n e c o u l d be f o u n d in all m a m m a l i a n tissues, b u t c o n s i d e r a b l e differences
o c c u r r e d from tissue to tissue. H i s t a m i n e
c o n c e n t r a t i o n s b e l o w z gg. p e r g. were
m e a s u r e d in o n l y a few organs, such as the
Table
Tmu~,s or SP~ctxx. INTEREST
CONC~'NTRATIONS
[V.~HISTAMINE
SINGLE
IN
i
VARIOUS
SPECIES
Tmsvz AND HISTAMINE CONC1~I'CI'~-XTION([.I.g. per g.)
SPEcms
Dog
Liver capsula: 45.14.I7.u, parenchyma: 38"34.I6-o; ureter: 21.t--xo.o;
urinary, bladder: 4"9 " t. 7; testis :- t .2 = o . 4; epididymis: 36.44-12"4
Diaphragm: 4"44-2"8; duodenum, upper part: 63.7='23-2, lower part:
Fox
~9.8=5. 3
Soft palate: 12"9 4" t "3 ; diaphragm: [ 8.6--_ 3.8 ; jejunum, proximal: 246 4. 18,
distal: 1964.28; ileum, proximal: 2t44.15, distal: i444,28
Rumen, ventral : 2-5 ±o-3, dorsal : 4-2 4,o'7 ; reticulum: 3"3 ----t "4; duodenum,
first part: 23-4-,-2.6, second part: 47"7--8"~, third part: 62.7--'25.7;
jejunum, proximal: 47'74,8"I, medium: 5I"o___r2"2, distal: 28-4=16.7;
liver capsula: 12.4 ~- I "9, parenchyma: 7"7 = t "5 ; lymph node: i "5
Diaphragm: x.o--_+_l.2; appendix: x i.94.7.6; adrenals: T-r-*-o.4; m. gluteus
maximus: i-2-4-o.5; m. sternomastoid: x-~--o.9; m. masseter: o . 5 ± o - I ;
ureter: o - 9 _ o . 8 ; urinary, bladder: x.o--o.2; corpus uteri: 0.8 4-0-2; ovary:
0 - 9 . o . 3 ; fallopian tube: o'64.o-2
.Miniature pig
Sheep
Rabbit
i
OF
,
,
i
,i
i i
i
i
i
M e a n values±S.D. All tissuesin the whole series were obtained from the same animal. The proximal
part of the intestinum means the firstm., the distal one the last m. For further conditions see Table llI
and Methods.
Tabl#
V.~HISTAMINE
CONC'q~NTR~TIONS
IN
VARIOUS MUSCI..ZS OF
TI.-I]~
Doo
I"IIsTAMIN~ CONCgNTRATION (lag.per g.)
Tlssuz
~4.S.D.
Masseter
Laryngeal muscles
Sternomastoid
Deltoid
Intercostal muscles
Abdominal rectus
External oblique
Psoas
Autochlhonous back
muscles
Extensors digitorum
Triceps brachii
Biceps femoris
Gluteus rnaximus
Semitendinosns
Gastrocnemius
Diaphragm
1"94,I"2
2"74-2"2
2-24-0"8
2"omi'3
2"5=['9
1.9±o.8
Extreme Values
0-8-4.2
] "o-7"3
i "o-3"6
3-2=2.2
2"5:r'7
o.7-3-8
0.7-..6-3
0"9-2 "9
0"8-7"7
0.8-5-0
2.7=2.2
2"x=~'5
i "o-7"3
i. i-5.2
2"I=I'2
0"9-4"6
2"74.x- 3
2"34.x'I
2.3=x.2
2.8±I.4
i2.I4.4. 7
i .o--5. t
0"9-3.8
o-3-4-i
o"3-5"o
5 "8"-I7"4
M e a n values from 7 animals of both sexes. For further conditions se-
Table III and Methods.
236
LORENZ
AND
tongue, submandibular gland, and heart of
the rabbit and in rat kidney. Histamine concentrations higher than I oo pg. per g. were
Comp. gen. Pharma¢.
OTHERS
than oo gig. per g. On the other hand, there
are animals with high histamine contents in
numerous tissues, such as dogs, foxes, and
Table VI.--HmTAMU~Z CONCZNTRA~ONSIN TmSUESoF BraDS
H~rrxm~rz CONCZ~rrRA~O~ (gg. per g.)
Trove
Pigeon
(Gallus gaUus
domesticua)
(Columba
livia domestica)
Caeca
Rectum
Liver
Gall-bladder
PancTe~
Lungs
Kidney
Spleen
Heart
Adrenals
tyrhynchos
domestica)
Goose
(Anser ans~
domestic)
n= 3
n= 5
n= 4
37"5±I6" 3
38"3± 7"9
7.2±2.8
5-6±i. 4
8.5± 2.8
8-2± 0"8
6.8± 4"x
4x'5±t5"9
22.2± 12.1
}I3"9±3"6
} 9 " I : 3"I
II5-6= 2.I
2-9± I. 3
i I - o = 9"9
21"9= 2"9
3~'3± 7"8
29"5± 6"4
36"x± 5"7
62"3±33"4
~'9±,4"6
2-6±t'2
2-om*.2
0"7
I"4
3"0=
35"2± 6"3
n=
Crop
Oesophagus, ~elow the crop
Proventricutus
Mucosa
Muscularis
Gizzard
Mucosa
Muscularis
Pyloric region
Duodenum (total)
Proximal
Distal
Small intestmum (total)
Jejunum
Ileum
Proximal
Distal
Duck
(Arias p/a-
Chicken
5
~'x±Ix'4
89.8=23. 4
55"x:35"I
39"5±25"o
6-5= i. 9
37"9±~3"3
4"8± o.I
8.8= 2"6
2-6± x.i
49"2= 3"8
6"9= 2"3
12.9±
I
--
2"4±I- 3
2"9~z-3
I-9±o-4
1.9=~.o
2.2=0.5
28.2= 7"4
28"9= 5"3
1-7=o- 5
x'4±o'2
x'4=o'3
2.0=0.8
I'8=o'3
2.9=i.o
2.o=1.i
5"7=1"8
1"3=o"4
I
'
32.4= 1o-6
25"9± I3-7
8.6± 2"2
7"6= 3.6
x'3± °'5
2"2± 1-8
2"3= 2"0
5 . i = 4"5
2"5= 0"3
9"2= 2.8
o ' 7 = o.i
0"9=
0.2
}0-4= 0"2
6"I= I'x
35"6m 4"8
3o'3~ o'5
49"7=12"9
21-8= 7"3
19"0± 4"5
2x'5= 8.x
2 2 - 3 = 9.0
I5"7± 5"3
4"8= 3"5
0"5± o'4
1"9± 0"2
6-2± 4"7
3"5± I'3
3o.9±16.o
I " 3 = 0.2
0 - 9 ± o.2
Mean values ± S.D. All tissues m the whole series were obtained from the same animal, which is
true for all following tables. All individuals were female. Proximal means the proximal hall distal the
distal one. For further conditions see Methods.
detected only in the gastro-intestinal tract and
partly in the lungs of dogs, pigs, and cattle.
Thus, about 9 ° per cent of all histamine concentradons in the dssues are situated within
the range of i - i o o gg. per g.
The values shown in Tables If, III demonstrate that there is no mammalian species
which is really poor in histamine, since in one
or several tissues of every, species histamine
concentrations can be found which are more
pigs, whereas in rabbits and Mastomys natalen.
s/s many organs are relatively poor in histamine.
There ,*-as no tissue found in mammals
which showed in all species investigated a
relatively high histamine concentration. Always one or two exceptions could be detected,
such as the gastric mucosa of sheep or 31astomrs, the intestinurn of rabbits, rats, or
Mastomys, and the lungs of rats, which had
HISTAMINE IN ~ N
x973, 4
only a m e d i u m histamine content. Tissues
with relatively low histamine concentrations
in all species were kidney a n d heart ventricle.
Organs with a histamine content, which
AaND ANIMALS
237
e.g., by d-tubocurarine (Macintosh and
Paton, x949), can cause pathophysiological
reactions in an animal of a very different
degree.
Table VII.--Hm'r.~,M~NE CONCa~N'rRAmONSIN Tmstms m, R.ZPTm~S
HISTAMINl~ CONL'~'CrRATION ([,tg.
T1sstn~
per
g.)
Gecko
European Pond Turtle
Caspian Pond Turtle
(Clemmys caspica)
( Tarento&
mauritanica )
4"7
I6. 3
I7-6
9" i
I o. i
4"5
o"7
0. 5
0. 4
o. 9
i. 3
3-1
12"I
1 1"2
18-3
15.6
I5"6
6"8
(Emys orbicularis)
Oesophagus
Stomach
Fundus
Corpus
Antrum
Duodenum
j ejunulTt
Ileum
Colon
Liver
Pancreas
Trachea
Lungs
•Spleen
2"2
2" 3
18"7
4"7
4"9
0. 9
Kidney.
Heart
Abdominal muscles
3"3
4"4
4-'2
5"6
18-8
15"9
Io.7
r3"4
352"0
12"8
17"7
3"6
2"I
6. 5
I5.6
io. 4
8.0
t2- 4
6~-4
t4. 3
21-7
Abdominal skin
f
Mean values from two female animals, m __. means ' not investigated '. For further
conditions see Methods.
showed great species differences, were the
s u b m a n d i b u l a r gland, liver, spleen, and
thyroid gland. Generally there was a considerable species v a r i a b i l i ~ of the histamine
concentration in tissues.
In the gastro-intesdnal tract of all species
the histamine content decreased from oral to
aboral.
In several m a m m a l s , in addition to those
described in Table III, the histamine concentrations of those tissues were particularly
measured (Tables IV, V) in which a physiological or pathophysiological role of histamine
h a d been considered by various investigators
(for a survey see Lorenz and Werle, ~974).
T h e histamine content of striated muscles in
the dog showed only small variations within
the same individual, but considerable differences within the same species (Table V).
Thus, histamine release from these muscles,
Histamine Coru:entrations in Tissues of Birds
( Table VI)
In all tissues of the birds investigated,
which belong to three different orders, histamine could be detected, but its distribution
varied considerably from organ to organ. T h e
highest histamine contents were measured in
the mucosa of the glandular part of the
stomach (proventriculus). In threespeeies high
levels were also found in the small intestinum
and spleen. Relatively low histamine concentrations were regularly found in the pancreas,
the kidney, and in three species also in the
heart..as in m a m m a l s the histamine content
of the gut decreased from oral to aboral.
In some organs of the pheasants (Pha.6mms
colchicus colchieus) the following histamine contents were determined (~,, n ~ 2, Jag. per g.):
crop t "9, oesophagus below the crop 2-4, fundic region of the proventriculus x3.6, gizzard
"38
LORENZ
AND
OTHERS
Comp. gen. Pharmac.
2.o_, pyloric region of the proventriculus 0.4,
livei 2.6.
Although in no tissue of the birds studied
could as high histamine concentrations be
measured as in some m a m m a l i a n organs
(which m a y be a casual event, owing to the
election of the species), on the average the
histamine values of the avian tissues were in
the same range of concentrations as those of
m a m m a l i a n tissues.
histamine in the organs showed only small
variations, with the exception of the upper
part of the gastro-intestinal tract, which was
relatively rich in histamine. Generally, the
histamine content of the frog tissues was low
as compared with that of the other species
investigated. These findings m a y not be
representative for all amphibians, but have to
be considered clearly as an exception a m o n g
the other vertebrates studied until now.
Histamine Concentrations in Tissues of Reptiles
( Table VII)
Histamine Concentrations in Tissues of the Bony
Fishes. ( Table IX)
In the three reptilian species histamine was
found in all tissues investigated, but its distribution varied from organ to organ. T h e
For the first time no histamine could be
detected in a tissue of an animal. Despite the
high sensitivity of the fluorimetric method,
Table VIII.--Hxs'ra.~mz C O N C ~ O N S
Txss~
Roof of the
pharynx
Oesophagus
Stomach
Jejunum
Ileum
Colon
Liver
I~ Tissues or Tree FROO (Rana pipiens)
I-hs'r~n~ Cowr~NT
(~tg. per g.)
3.6±x.2
2"7±0" 9
2-6±0.8
1"2±0"2
I'o~o'2
0.6±0.3
o-6±o.3
TmsuE
Lungs
Heart
Kidney
Testis
Epididymis
M. quadratu$ femoris
M. gastrocnemius
H w r ~ n ~ CowrZNT
(~tg. per g.)
0.8±0"3
0,7±0-2
I'I~O'I
o-4±o-~
0-6±0.2
o.4±o.x
o-3±o.I
Mean values ~ S.D. from 3 experiments, in each case the tissues from 5 male animals were
pooled. For further conditions see Methods.
highest histamine concentrations were found
in the spleen and in the corpus region of the
stomach, but only low histamine contents
were determined in the intestinum. Since a
high histamine concentration of the spleen
was measured both in reptiles and in birds,
this finding could be a further argument for a
close affinity, of these two classes in the phylum
chordata (Sauropsides). O n the average, the
histamine concentrations of reptilian tissues
are in the same order of magnitude as in
m a m m a l s and birds.
Histamine Concentrations in Tissues of the Frog
(Rana pipiens) ( Table VIII)
As in mammals, birds, and reptiles, histamine was detected in all tissues which were
studied in the frog. T h e distribution of
which was used as combined method under
conditions as for the determination of plasma
histamine (Lorenz, Reimann, Barth, Kusche,
Meyer, Doenicke, and Hutzel, 1972a ) and
was capable of measuring a o. 5 ng. histamine
per g. tissue, no histamine could be measured
in the tissue extracts o f the carp o v a l ' .
Furthermore, authentic histamine added to
the ovary, extracts showed the same recovery
as that which was combined with other tissue
homogermtes. Thus, the presence of substances interfering with both the fluorimetric
and the biological assay of histamine could be
excluded.
Generally the organs of bony fishes, which
belonged to three different orders of the class
Osteichty. es, were relatively poor in histamine,
with the exception of the gastric mucosa of
I973, 4
H I S T A M I N E IN MAN A N D ANLMALS
most species a n d the kidney of the pike. O n l y
the carp showed low histamine concentrations along the whole gastro-intestinal tract,
239
whereas the histamine contents of the other
tissues were m o s d y relatively low. O n the
average the histamine concentrations in the
Table IX.--H~rAMn~E CONCENTRATIONSIN TUcSU~sOF Borer FmHES
i
i
HISTAMINE CONCENTRATION (Ng. per g.)
Tissue
R.oof of the pharynx
Oesophagus
Stomach
Proximal
Medium
Distal
Small intestinum
Proximal
Distal
Rectum
Proximal
Distal
Liver
Gall-bladder
Gills
.~Ar bladder
Trout
Carp
( Esox lucius)
n==2
o.6 ~o-~
0.8 -*-0-4
o.2=o.x
x.6
4.2
I'~±o'5
2.0
3"2 ± i "3
6.I --_ t-6
5"5 ~ i- 1
14" t
15.2
x0-6
0'7 ±0"3
o'9~o.6
o-8 =o.6
8"7
9"4
8"8
4"3-+-o"7
2-3 ~o. 9
0--o
I '5
0.6 = o . I
0"7 -----o'3
1-9
I- 3
I "7 -z-o'6
1.44-o" 5
0"5 ___0"3
I "9 ±0"9
0. 7 -,-o.i
I "6
0"7 .-4-o'3
I. 3
0-'4
4 .8
I"8
0"4 ~ o-':'
0"5 =:o'3
0-9 -.0. 5
o'8
I"3 ~ o . x
~
o.2 = o .
Pike
(Cyprinus
carpiodomesticus)
n= 3
Catfish
(~ l u ~
g~n~)
(Salmo trutta
f ario )
n---- 3
[
n~2
1"2
Heart
Atria
Ventricle
Spleen
Kidney
Ovary.
0.5 ~0" I
o'7 ~ o . 5
o'7 = o ' 4
t -a ~ o ' 5
0-44-0-0.
]
! I .o
5"0x6.6
0-2
o'3±o-I
}0-8
0"0-~0"I
0"9±0"5
o'9±o'3
:-i
1"4
O
Mean values ~ S.D., only female animals were tested. " Stomach ' in carps means
the widening of the gut following the oesophagus, which immediately follows the gills.
For further conditions see Methods.
but it is k n o w n as a ' stomachless ' fish (see
W u r r n b a c h , x971 ). , a m o n g all species which
were studied for their histamine content
(Lorenz a n d Werle, I974) , the carp was
f o u n d to be the animal poorest in histamine.
T h e distribution of histamine in the b o n y
fishes was fairly uniform.
Histamine Concentrations in Tissues of
Cartilaginous Fishes ( Table X )
No histamine c o u l d be m e a s u r e d in pancreas, rectal gland, ovars", a n d brain of
cartilaginous
fishes.
The
other dssues
investigated contained histamine in v a r y i n g
concentrations.
T h e highest values were
observed again in the gastro-intestinal tract,
tissues of cartilaginous fishes are in the same
order o f m a g n i t u d e as those of m a m m a l s ,
birds, a n d reptiles.
Histamine Concentrations in Tissues of Tunieates
and Larme&ts
Tunicates a n d lancetets are the two primifive s u b p h y l a of the p h y l u m chordates. Thus,
we investigated the distribution o f histamine
in Branchiostoma lanceotatum. T h e intestinum
contained histamine in a concentration o f
2 ~tg. per g. (tissues pooled from 20 animals),
whereas the p h a r y n x a n d the rest of the b o d y
were found to be free from histamine. Also in
two species of the tunicates, histamine could
be found only in the s t o m a c h a n d intestinum
O
O
o.4i
o
o'6t
o'5t
1.4±
2"5t
O
0"2
0' 4
0-8
0-2
0.2
R2-2t 3"0
2 , ' 7 ~ 2"9
9 . 8 t 8-2
6 - o t 3"7
9 " 9 t 5 .6
17-4~1o" 7
4 " 3 t 3"2
Cat Shark
(Scylliorhimts
stdlariQ
O
2-6t1"1
o-7to.2
o'5~o-2
;'4to" 4
,-oto-5
O
3"8ii'4
o
i-4to. 9
O
2-oto. 9
='7to" 4
O'2tO'1
2.oti.8
O
o'9to-8
0
0
9"!
0" 3
4"2
0
0"2
To
0"2
0"2
11"2t7-!
3"5to"6
I-8ti'6
1"2to'3
2"0
~'5t1"6
}3 " o t ~ ' 2
7"3
}5 . 2 t l . 3
i 3"0
n :=2
}7"4t2"6
3
Oxynotus
cenlrina
3"8t2"J
I1 =
Smooth l)ogfish
Mmtelus
mustelgt
5"1t2"4
Dogfish
(Seylliorhinus
caniada)
n= 3
(~+ARTiI.AI'IINOIJ8FISlIES
HIs'rAmmF. CONCENTRATION(lag. per g.)
X . - - I | I S T A M I N E ~ONCENTRA'rlONS IN "|'ISSUES OF
Mean values 1 S.I)., only female animals were investigated. For further conditions see Methods.
Oesophagus--cardia region
Stomach
Fundus
Corpus
Pylorus region
Intestinum
Proximal
Distal
Rectum
Rectal gland
Liver
Pancreas
(;ills
lteart
Kidney
Spleen
Ovary
Brain
TISUE
Table
o-5~o.2
o.5to" 4
o.5~o- 3
O'!~O'1
O
O'l~O'l
3"5i2"1
o-6~o'2
}2 . 7 t 2 . 4
6"6t4"5
Nail Ray
( Raft
clavata)
n= 3
3
o"51o"3
t.lto. 4
n-51o-i
o'5to"2
~-8t1-1
3.2tl- 5
I-2to. 7
o.4to-I
5"5~o-3
4-8il-3
7"6~5- 5
n ~
Star Ray
( Raja
radiata)
to
t~
0
1"4
0
O
H I S T A M I N E IN MAN ~ N D A N I M A L S
1973, 4
(Table XI), in which relatively low histamine
concentrations were measured.
could be found in the posterior salivary.
glands, in many parts of the intesdnum, in
the gills, or the ovary. The other tissues contained variable concentrations of histamine.
In octopus the highest values were found in
the nerve ganglia around the pharyrm, which
may be considered as a primitive brain,
whereas in sepia the liver showed the highest
histamine concentration.
Histamine Concentrations in Tissues of ,~,lolluscs
and Echinoderms
From the phylum Mollusca, two highly
developed species, sepia and octopus, were
investigated for their histamine content in
various tissues (Table .YII). No histamine
Table XI.--Hnvr..~,I~r~
24I
~ONC.V.NTR.~.TIONS IN
Tmum
OF
TUNICATES
HaSTaa~r~ CoN'r~rr (lag. per g.)
TmsuEs
Ciona intestinalis
Branchial sac
Stomach
Heart
Intestmum
Gonad
0
I'8
0
0"I
0
Hawcynthia
pa~llosa
O
1"2
0
0.4
0
Mean values from 2 experiments. For each determination
the tissues of Io-z 5 animals were pooled. For further conditions see Methods.
Table X I I . - - H ~ , ~ m
CONCEtCr~.A~nOr~Sn~ T~mtrv.s ov CEPHALO1PODA
Hxs'rAJ~n~ Co~c,,~rr~'noN (~g. per g.)
T~ssu~
Cuttlefish
n ----2-3
Posterior salivary, glands
Oesophagus
Stomach
Cafx~um
Liver
Intestinum
Rectum
Gills
Heart
Branchial heart
Kidney
Nidamental gland (NG)
Accessory NG
Ova~
Ink sac
' Brain '
Optical lobe
Supraoesophageal lobe
Suboesophageal lobe
Octopus
(Oaopus vulgar'is)
0
n ~2-
3
O
I" 4
5.5~.5
7.4~3.8
13.1±6.2
4.3~3-o
I'I
4"7±2"0
4.o~2.6
o'3±oq
O
0.3±0"2
o.5~o.i
O
O
2.9~2.3
3"6~2"4
o.7~o-2
0"8
4.0
I-5
0-8
O
5.7~1.8
2"2~o'9
1"6~o'5
Mean values -v- S.D. from 2-3 experiments. The tissues of io female
animals were pooled. For further conditions see Methods.
242
LORENZ
AND
In three species of the echinoderms only a
few tissues were studied for their histamine
concentration. In the sea-urchin (Paracentrotus lividus) the gut contained 2.2 lag. per g. (n
---- 2, organs pooled from io animals). In the
brittle star (Ophiura exturata) the central
gastro-intestinal tract showed 2 5 lag. per g.,
the hepatic caeca in the arms 7"4 ~tg. per g.
Comp. gen. Pharmac.
OTHERS
DISCUSSION
T h e reasons for such an extensive study on
the occurrence and distribution of histamine
in the animal kingdom, which were: n a m e d in
the introduction, have now to be discussed in
more detail.
I. It seemed necessary to reinvestigate the
histamine content of numerous organs and
Table XIII.--HrsrAMmZ CONC"r~TR.'~ONS ir~ Tmv,,s or Cavsr^cz^m
i
HmTxmr~z CONCZr~Tt~AaaON(l~g. per g.)
Tmstm
Lobster
(Palinur~ vulgaris)
n-~
Cardia
Stomach
Liver
Intestinum
Gills
Heart
Antenna
Eyestalk
Mandibular muscles
Seminal vesicle
i
i
3
o.4_+o. S
o.6±o.3
4"8 ± 3"6
o-4=o.2
5"6=2"t
0-3 =0-2
Crab
(Carcinus maenas)
rt=~2
2o.4
x80
70
5"3
~5°
0
7"8±3-x
4o0
0
m
~3o
i
i
Mean value~ ± S.D. from 2-3 experiments. Tissues of the crab were
pooled from 2o mate animals, only female lobsters were used. For
further conditions see Methods.
(n = 2, organs pooled from Io animals),
whereas in the sea cucumber (Holothuria tubulosa) the intestinum contained i. 4. gg. histamine per g. tissue (n ---- 2, organs pooled from
5 animals).
Histamine Comentrations in Tissues of Crustaceans
( Table XIII)
No histamine could be found in the
antennae and in the muscles of the lobster
(Palinuru~ vulgaris), whereas in the crab (Carcinus maenas) all tissues investigated contained
histamine. T h e highest concentrations were
measured in the eyestalk, where the x-organ,
a neurosecretory organ, is localized. For this
reason, we investigated also the evestalk of the
crayfish (Astacusfluviatilis) and found there the
high histamine content of 16o ~tg. per g. (n ---2, tissues pooled from 20 animals). Thus, the
histamine concentrations in the crustacean
tissues can be considered as relatively high as
c o m p a r e d with those of most chordates.
tissues with the aid of methods th¢ specificity
of which had been demonstrated by several
chemical and biological procedures (Lorenz,
Barth, and Werle, 197o; Lorenz, Benesch,
and others, I97o; Lorenz and others, I97i ).
General doubts of the correctness of the commonly used histamine assays; i.e., the fluorimetric method of Shore and others (I959)
and the biological determination on the
isolated guinea-pig ileum according to Barsoum and G a d d u m (1935) , have recently
arisen (Michaetson and Coffman, i967;
Aures, Davidson, and H~tkanson, x969;
Waton, I97I). T h e direct comparison of the
histamine values which were obtained by the
bio-assay, the butanol extraction method, the
Dowex method, and the combined method
(Lorenz, Benesch and others, I97o; Lorenz
and others, 1971 ; this publication), by no
means justified such an assumption, however.
Furthermore, the indirect comparison of the
histamine values, which were presented by
7973, 4
H I S T A M I N E IN .MAN A N D A N I M A L S
this paper and by many other investigators
(for a survey see Lorenz and Werle, i974),
showed such a good correspondence in so
many cases that general doubts of the accuracy of the bio-assay and the fluorimetric
methods for determination of histamine cannot exist any longer. Only in the case of
tissues with extremely low histamine concentrations, such as certain nervous tissues
(Carlini and Green, i963; Kremzner and
Pfeiffer, 1966 ) and of body fluids, on principle
one should be cautious with histamine assays;
the best isolation procedure giving maximum
specificity, has to be examined for each single
case (Lorenz, Benesch and others, I97o;
Lorenz and others, 1977; Lorenz, Huhnd,
Kusche, Barth, Haubensak, Hutzel, Schmal,
Gerant, Wachter, Matejka, Hahn, and Werle,
7973; Lorenz, Reimann, and others, 1972;
Lorenz, Schmal, Reimann, Tauber, Uhlig,
Mann, Barth, Kusche, Seidal, Doenicke,
Hamelmann, and Werle, 7972 ).
2. For some of the tissues and organs, in
which a physiological or pathophysiotogical
role of histamine has been considered, no or
very, few data are known about their histamine content.
This is specially true for human tissues:
histamine concentrations have been determined mostly only in single, relatively few
organs, such as salivary, glands, stomach, liver,
lungs, kidney, thyroid gland, uterus, skin,
nervous tissue, and mastocytoma (for a survey
of the results of 64 authors see Lorenz and
Werle, 7974). A comparison of the histamine
contents of more than four organs can be read
only in the publications of Stone, Merill, and
Menechy (7955), Duner and Pernow (i96o),
Lorenz, Pfleger, and Werle (7967), K u m a r
and others (i 968), Anion and Sayre (7969),
and Lorenz, Benesch, and others (797o), and
only K u m a r and others (I968) measured histamine in a greater number of individuals (n
---- 68). Thus, we were eager partly to close
the gaps in our knowledge about the distribution of histamine in man.
. ~ far as we have found in the literature,
nothing has been published until now about
the histamine concentrations of tissues from
the miniature pig and 3dastomys natalensis.
Since these two species are used more and
243
more in animal experiments, it seemed significant to obtain data about the distribution
of histamine in these animals.
In organs or tissues in which pharmacological actions of histamine were observed, the
endogenous histamine concentration was considered to be important--besides other param e t e r s - f o r the evaluation of physiological or
pathophysiological functions of histamine.
Pharmacological effects of histamine with possible physiological relevance were investigated
in man, especially in the gastric mucosa
(Code, 1956; Lorenz and Pfleger, 1968), the
gastric muscles (Bennett and Whimey, i966),
the intestinal muscles (Bennett, I965) , and
the ureter (Borgstedt and others, 7962 ). Such
effects of histamine in other mammals can be
read in numerous reviews and books on histamine (e.g., Rocha e Silva, I966). Quite
recently Reite ( 1972) compiled the literature
about the pharmacological actions of histamine in animals lower than mammals. Some
of these effects, which started our investigations of the histamine contents in the
corresponding tissues, are shown in Table
XIV.
Since histamine was found in sufficient
amounts in all these organs (see Results), on
principle a physiological role of histamine in
these organs cannot be excluded. Thus, our
findings may stimulate further investigations
on the acceptance or rejection of these hypotheses.
3. The species variability, relating to the
distribution and localization of histamine in
tissues is much greater than has been
assumed untilnow. The resultsof thispublication confirm those of histochemical studies
(H~kanson and others, 7970 ) and of a comprehensive review (Lorenz and Werle, x974).
There was no tissue or organ in animals
which showed an absolutely or relatively high
or low histamine content in all species
investigated.
Gastric mucosa: Even the gastric mucosa, in
which a relatively high histamine concentration was regularly demonstrated, contained
only medium concentrations in sheep and
3,Iastomys. All other tissues in vertebrates
showed much greater species variability, than
the gastric mucosa.
lncrcase of the permeability
for ions
Contraction, histaminergic
Gastric mucosa
Gastric mtlcosa
Gastric inucosa
Oesophagus
Lizard
Chicken
lntestinum
Gastric nnlcosa
Turtle
Whole animal
Gaslric muscles
Striated muscle
Gastric muscles
Slimulation of secretion
Gastric nnieosa
Frog
Stimulalion of sccrction
Contraction, releasc of
acctylcholine
Release of catccholamines
Stimulation of secretinn
Stimulation of secretion
Release of acetylcholine
Increase of neuromuscular
transmission
Shock
nerves
Stimulation of secretion
Conlraction or relaxation
ltypotension or hypertension
of peripheral blood-pressure
Gastric mucosa
lntestinum
Smooth muscles of
blood-vessels
Bony fishes
Stimulation of secretion
Pi IYSIOI,OGIGAL OR
P A T I | O P I IYSIOLOGICAL FUNG'I'iON
Gastric mttcosa
TISSUE
Cartilaginous fishes
SPECIES
LITERATURE
Everett and Mann, I967
Rimff and Sewing, 197o
Bartlet and llassan, i968
Wrighl, and nthcls, I957
Wright, and othc~, i957
Cohen, Sapp, and Shaskas, 1968
Singh and Singh, 1966
Valeri and Fantin, I97O
Singh, Singh, Malhortra, and Sarna, 1961 ; Rashid, 1972
Davidson, I.emmi, and Thompson, 1966; Kasbekar, i967; Kasbekar, Ridlcy, anti Forle, 1969
Villegas, 1963
ilogben, 1967
Dreycr, 1946; von Euler and (')sthlnd, i956- 7
Schievelbein, and others, 1969; Vogel, Schievelbein, Lorenz, Werle,
and Schmal, t969; Reite, 1969a
Hogben, 1967
OR PATIIOPIIYSIOI.O(]ICAL ROI.E OF illS'FAMINE IS CONSIDERED
"1able XIV.--TI.~SUES o f LOWER VERTEBRATES TIIAN ~'~AMMAI.S, IN WlllC.II ON TIlE BASIS OF PllARMACOLOGI(:AI. ACTIONS A IhI~'SIOLO~;WAI..
g~
0~
o
N
o
I-4
to
I973, 4
H I S T A M I N E IN M A N A N D A N I M A L S
Small intestinum: The small intestinum had
a relatively high histamine concentration in
man, dogs, foxes, pigs, cattle, guinea-pigs,
chickens, ducks, geese, and carulaginous
fishes with the exception of the dogfish.
245
rodents, birds, bony fishes, and three species
of the cartilaginous fishes.
Lungs: The histamine content of the lungs
was found to be high in all mammals with the
exception of the rat (Rattus rattus) and
Table X V . - - I h d Y L A IN THE A_NIMAL KINGDOM, IN THE SPECIF~ OF W H I C H HISTAMINE HAS BE~'N DETIgCTED
No.
I
Sponges (Porifera)
o
Coelenterates (Coelenterata)
3
4
5
6
Flatworms (Plathelminthes)
Roundworms (Aschelminthes)
Segmented worms (.amnelida)
Joint-footed animals
(Arthropoda)
Molluscs (Mollusc.a)
8
9
9. I
Echinoderms (Echinodermata)
Chordates (Chordata)
Tunieates (Tunieata)
9.3.3
Lancelets (Cephaloehordata)
Vertebrates (Vertebrata)
Cyclostomes (Cyclostornata)
C~rtilaginous fishes
(Chondrichthyes)
Bony fishes (Osteichthyes)
9.3.4
Amphibians (Amphibia)
9-3-5
Reptiles (Reptilia)
9.3.6
Birds (Aves)
9.3.7
Mammals (Mammalia)
9.2
9.3
9.3-I
9.3.2
LITERATUR~
PHYLUM
Ungar and others, 1937; Ackermann and List, t 957; Mettrick
and Tdford, I965; Das, Lira, and Teh, I97t
Ungar and others, t937; Mathias, Ross, and Schachter, i958.
x96o; Mettrick and Tclford, x965
Mettrick and Telford, I965
Mettrick and Telford, z965
Ungar and others, 1937; Metuick and Telford, z965
Ungar and others, 1937; Werlc and G|eissner, 195t ; Eckert.
Paasonen, and Vartainen, 195i ; Jaques and Schachter,
1954; Kerkut and Price, t96t ; Bhoola, Calle, and Schachter,
196t ; Parsons, t962 ; Bertaccini, Neviani, and Koseghini,
t965; Mettrick and Tclford, i965
Ungar and others, t937; Erspamer and Boretti, 195t;
Bertaccini, t 96 t ; Mettrick and Telford, 1965; Huggins and
Woodruff, i968; Koseghini and Kamorino, x97o
Ungar and others, 1937; Mettrick and Telford, x965
Mettrick and Telford, x965; Lorenz and others, 1969;
Lorenz, t969
This paper
Reite, 1969a, b; Holstein, i970
Hogben, i967; Lorenz and others, r969; Lorenz, t969; Keite,
1969a, b
Keite, t965; Lorenz and others, ~969; Lorenz, t969; Keite,
1969a, b
Erspamer, Vitali, Roseghini, and Cei, I963, t964; Erspamer,
Roseghini. and Cei, I964; Reite, 1965; Davidson and
others, 1966; Cei and others, 1967; Takaya and others,
:967; Lorenz, t969; Lorenz and others, 1969; Keite, 1969a,
b; Erspamer and Cci, 197o; Erspamer, i97t
Wright and Trethewie. I956; Lorenz, t969; Lorenz and
others, i969; Reite, z969a, b; Takaya, 1969; Gabe, t97i
Misrahy, t946; Beaumariage and Lecomte, x955; Lorenz,
x969; Lorenz and others, t969; Takaya, t969; Ruoff and
Sewing, 197ob
A survey with io6 tables, see Lorenz and Werle, x974
Relatively low histamine contents were measured in sheep, rats, pigeons, tortoises, and in
all bony fishes.
Liver: The liver showed high histamine
contents in dogs, foxes, and cattle as well as
in the Caspian pond turtle and in the gecko.
L o w values were determined in man, all
the Natal rat (Mastomys natalensis). In birds
and in one species of the tortoises, the histamine concentrations in the lungs were
relatively low.
Kidney: The kidney was considered to be an
organ poor in histamine in all mammals and
birds. However, in reptiles, in the pike, and
~46
LORENZ
AND
in Oxyrmtus centrina, a cartilaginous fish, relatively high histamine contents were detected.
Spleen: The histamine concentration in the
spleen showed a considerable scatter from
species to species. It was found to be high in
birds, reptiles, and rabbits, in all other species
medium or low.
Thus, with the exception of the gastric
mucosa, there was no uniform tissue preference for the storage of histamine in any of the
species investigated. It seems very, difficult
to correlate the distribution of histamine with
a special function of this amine. However,
this kind of unequal distribution of histamine
in the tissues and species seems to contradict
the hypothesis that histamine plays a general
role in the body, e.g., as a regulator of
ubiquitous metabolic processes (Johnson,
197I ) or of the microcirculation (Waton,
I97t).
A correlation between the histamine content and a pharmacological function of histamine can so far be demonstrated only in the
gastric mucosa. Histamine stimulates the
gastric acid secretion in all mammals so far
studied (Code, I956; Lorenz and Pfleger,
i968), in birds (Ruoff and Sewing, 197oa),
reptiles (Wright, Florey, and Sanders, 1957),
amphibia (see Table XIV), as well as in bony
and cartilaginous fishes (Hogben, 1967). In
all these orders and species, histamine is
localized in the gastric mucosa in high, or in
two exceptions (sheep, Mastomys) in at least
medium concentrations. In those vertebrates,
however, which do not have a specific area
with gastric glands in the intestinal tract,
such as the stomachless bony fishes (carp,
Rutilus rutilus, Labrus berggyltra) and the cyclostome Myxine glutinosa (Reite I969b, and this
paper), only a very. low histamine concentration can be found in the whole gut. Also in
molluscs and crustaceans, in which the stomach has no digestive functions, only a low
histamine concentration was measured in
gastric tissues, whereas the liver, the common
digestive gland of these animals, was relatively rich in histamine.
The correlation between the histamine content and the pharmacological action of histamine in the gastric mucosa is naturally no
evidence for the hypothesis that histamine
OTHERS
Comp. gen. Pharmac.
may be a physiological stimulator of the
gastric acid secreuon. On the other hand, it
is again consistent with the view that histamine plays a specific role in the secreting
stomach and not an unspecific one (Johnson,
r97i; Waton, ~97I), as already mentioned.
The activation of the adenyl cyclase, for
instance, may be considered as such a physiological function of histamine (Nakajima,
Hirschowitz, and Sachs, 197 I).
4. Important hints for a physiological role
of histamine in the animal kingdom should be
expected from phylogenetic and evolutionary studies. The occurrence of histamine has
been demonstrated until now in numerous
phyla and orders of animals (Table XV).
Phylogenetic investigations on the concentration of histamine in dssues were performed
with relatively few species or with one tissue
alone, such as the skin or the gastric mucosa,
by Ungar and others (i937), Mettrick and
Telford (I965), by Erspamer's group (e.g.,
Cei, Erspamer, and Roseghini, I967), by
Reite (I969 a, b), Lorenz (i969), Lorenz and
others (I969), and Takaya (x969). A comparison of the histamine contents of numerous
tissues and organs in many species, orders,
and phyla is now possible from the data presented in this publication.
There are, however, also few evolutionary
and phylogenetic studies on the pharmacological actions of histamine on the smooth
muscles in the gut and on the circulation
(Dreyer, i946; yon Euler and Ostlund,
1956-7 ; Reite, I969 a; Schievelbein, Vogel,
Lorenz, and Schmal, 1969) as well as on the
gastric secretion (Hogben, I967). By these
authors it was shown that histamine is practically inactive on the smooth muscles and on
the circulation of cartilaginous fishes and also
many bony fishes, but not on the gastric
secretion. These findings seem to be again
an argument for a specific function of histamine in the gastric mucosa of the chordates.
As far as we know, only two authors performed phylogenedc studies on the localization of histamine in certain ceils (Reite, 1965;
Takaya, Tsuneo, and Endo, I967; Takaya,
I969). It seems ver7 remarkable that in
fishes and Amphibia histamine is not stored
in mast ceils. In the evolution, beginning
~973, 4
HISTAMINE IN MAN AND ANIMALS
with reptiles a n d birds, histamine could be
d e m o n s t r a t e d in these cells, which are
quantitatively the most i m p o r t a n t stores o f
histamine in m a m m a l s (Riley a n d West,
I953).
Unlike the findings in most o f the m a m m a l s
(H~kanson a n d others, ~97o), histamine in
the gastro-intestinal tract of o t h e r classes o f
vertebrates is therefore called ' n o n - m a s t cell
histamine '.
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Eey Word Index: Histamine, specific determination, man, chordatcs, echinoderms, molluscs,
crustace~"lns.