Comp. gen. Pharmac., I973, 4, 229-25o. [Scientechnica (Publishers) Ltd.] 2~ 9

A PHYLOGENETIC STUDY ON THE OCCURRENCE A_ND

DISTRIBUTION OF HISTAMINE IN THE GASTRO-INTESTINAL

TRACT AND OTHER TISSUES OF M.~N 2M~D VARIOUS .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 bio- assay, 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 acid- secreting 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 specific function 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 nd distri- but ion of his tamine in animals have been per formed by numerous authors (for a survey see Lorenz and Werie, 1974), since Best, Dale,

* Dedicated to E. Werle for his 7oth birthday. Supported by grants of Deutsche Forschungs-

gemeinschaft (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-Koch- StraSe 8, Germany.

Dudley, and 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 e lementary analysis. For several reasons, however, it seems neces- sary, to determine and reinvestigate the his tamine contents in as m a n y tissues and species as possible : - -

i. Some methods for the de terminat ion o f histamine which were used in prior studies, were shown to have a less than satisfactory specificity, in body fluids and in certain tissues (Carlini and Green, i963; ."vtichaelson and Coffman, I967; Lorenz, Benesch, Barth,

23o LOR.ENZ AND OTHERS Comp. gen. Pharmac.

Matejka, Meyer, Kusche, Hutzel, and Werle r97o; Lorenz, Barth, Kusche, Reirnann, Schmal, Matej l~, 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 physio- logical 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 may 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 many human tissues.

3. A much greater species variability than expected was found in the distribution and cellular localization of histamine (H/dtanson, Owman, Sj6berg, and Sporrong, 197o; Lorenz and Werle, 1974). In this respect a compari- son of numerous species seemed necessary in order to find out whether there exist any regularities which may 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; Takaya , 1969). A com- parison of the pharmacological effects of histamine in various phyla and classes of the animal kingdom w~th its occurrence and dis- tribution in tissues seems to be one way to elucidate physiological functions of hista- mine. 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,

and the possibility of obtaining fresh tissues im- mediately 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 pre- pared during the months September until Decem- ber, 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 ex- ploratory 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 phy- siological 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 Han- hover), 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 accord- ing 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 231

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 was used.

For the biological determination of histamine the following drugs were used: glucose, buffers, and in- organic 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 fluori- metrically 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 modifi- cation 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 NaOH, and again ex- tracted with o" t M HCI according to Shore and others (x959). Histamine in the aqueous phase was then either determined fluorimetrically follow- ing the condensation with o-phthaldialdehyde or measured by the bioassay on the isolated atropin- ized guinea-pig ileum following the neutralization of the o.x MHC1 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, chro- matographed on Dowex 5oW-X8, and histamine was determined in the diluted eluate after conden- sation 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 inhi- bition of the contraction of the isolated guinea- pig ileum by small doses of a specific antihistaminic drug can be considered as a reliable method for the identification of histamine. Because of its

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, accor- cling 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 in- vestigated in this publication. An agreement of the ,histamine values, obtained by the different determination and isolation methods, was con- sidered 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 chroma- tography 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), Kiiken- thal and others ( x 967), and Wurrnbach (, 971 ).*

RESULTS

COMPA.RISON OF T W O FLUORh~fETRIC .~V[ETHODS FOR THE DETERMINATION OF HISTAMINE AND

IDENTIFIGATION OF HrSTAm~ m VARIOUS

TxssuE Ex'r~.~crs

The high degree of correspondence be- tween the values of two different fluorimetric assays for histamine (Table I) was considered as an argument for the identity of the sub- stance isolated from human and dog tissues with authentic histamine, especially because

* We thank Professor Fr. Seidel, Ph.D., former- lv director of the Institute of Zoology, University of Marburg/Lab. , , very, much for his advice and the support of this investigation.

~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 purifica- tion procedures were used for the fluorimetrie

LO~NZ AND o'r~zRS Corn#. grn. Pharma¢.

which were determined fluorimetrically fol- lowing Dowex chromatography, were in no case significantly different from those which were measured by bioassay. The contrac- tiom of the guinea-pig ileum elicited by the

Table L--C~m, Amsor, or THE RZSULTS OF TmZ Btrr~oL EXTRACmON METHOD AccoRDING TO SHORE AND OTHERS (1959) wrrH THos~ o? TH~ DOWEX 5 ° MZTHOD ACCORDINO TO LORZNZ AND OTHF.RS (1970)

Z~ T~nms or MAN Am) DOO

H m ' ~ m ~ CONCENTRATION (~g. ~ r g. fresh weight)

Man Dog

Tissue Butanol Dowex 5o Tissue Butanol Extraction Extraction Dowex 50

~&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

~±S.D.

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

2"7±x'I 0.5±0. 3

x.t±o. 3 0.8±0.2 I'O

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

2.8±0.8 o.6~o" 4

i-4±o. 5 0-9 ±0"3 I ' i

Kidney Ureter U r i n ~ bladder Muscles

Masscter

Sternomasmid Triceps braehii Extensors dig~torum Deltoid Intercostal lZectus External oblique Psoas Autochthonous back

muscles Glutcus maximus Biceps femoris Semiumdinosus Gastrocncmius Diaphragm

2"3 30"8

7.I

In the case of human tmues, only i--8 organs were obtained from the

i. 3 2"!

l' 7 2"] 1"4 ]'8 3-0 I- 9 3"4 I" 7 I. 7

2"4 2.8 i. 9 3'3 7"0

2- 4 32"5 6.2

I ' I 2"0 I" 7 I" 7 ]'3 I'O 2" 7 I" 5 3"0 I" 7 2. 3

2"3 2" 3 1"8 2" 9 6" 5

same individual; in dogs each tissue of one series from the same anim~d. In man n = 2- 4, in dogs . = 2. For further conditiom see Methods.

determination of histamine in organs of pigs and guinea-pigs (butanol extraction, ion- exchange chromatography, and a combina- tion of both methods), no significant differ- ences between the histamine concentrations of these tissues could be observed (Lorenz and others, 197~ ).

The 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 iso- lated 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 HISTAMINE IN MAN AND ANIMALS 233

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 human tissues investigated. The highest

concentrations were found in lungs, stomach, and intestinum, the lowest in kidney, subcu- taneous connective tissue, and muscles. In several tissues, which showed pathologic~ alterations (Meckel's diverticulum, adeno- carcinoma of the rectum, and adenoma of the

Table [Z.--HIsTAMINE CONCZNTRATIONS OF HUMA,~ Tmsuzs

Tmsvz

Gastro-int~stinal Tract Gastric mucosa

Fundus Corpus Antrum

Duodenum Jejunum Ileum Appendix Meckel's diverticulum Colon (ascending) Sigma Rectum

Adcnocarcinoma • Ampulla

L i ~) e r Gall-bladder Pancreas

Head Tail

Mcsente~

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)

4 19 J5 3 6 8

I

5 t3 I1

I

2 33

2

5 3 2

4 6

°1

HI~rAMINE CONCENTILATION (gg. per g.)

~--S.D. 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

1"2--2"2

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 investi- gated. For further conditiom see Methods.

24-x=17"6

1"2

I" 9 2. 5 6- 4 7"6~2"7 2-8=1.8 o.4±o'x

4"8±3-4 8.1~3"7

0.8±0"5 0. 9 2"0=0"4 1-2~o-9 7.2 z.8~o.8

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

5"9±I '6 ~'7±o'4 1.7mo- 4

0"~--2"0

I "7-7"9 4. t - i i .5

5-5-io.7 I "4-4"5 0.2--o. 5

12"6-66-0

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-t 973, 4 H I S T A M I N E I N . M A N A N D A N I M A L S 235

pros ta te ) , r e l a t ive ly high h i s t amine contents were measu red . I n the gas t ro - in tes t ina l t rac t the h i s t amine concen t r a t i on decreased f rom oral to abora l . T h e sca t te r ing of the hist- a m i n e values f rom ind iv idua l to i nd iv idua l was especia l ly la rge in this o rgan system as c o m p a r e d wi th o ther tissues.

Histamine Concentrations in Tissues of Various Other Mammals (Table III)

H i s t a m i n e cou ld be found in al l m a m m a l - i an tissues, bu t cons ide rab le differences occur red f rom tissue to tissue. H i s t a m i n e concen t ra t ions be low z gg. pe r g. were m e a s u r e d in only a few organs , such as the

Table [ V . ~ H I S T A M I N E CONC~'NTRATIONS O F S I N G L E Tmu~,s or SP~ctxx. INTEREST I N VARIOUS S P E C I E S i

SPEcms Tmsvz AND HISTAMINE CONC1~I'CI'~-XTION ([.I.g. per g.)

Dog

Fox

.Miniature pig

Sheep

Rabbi t

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 : ~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

i , , i ,i i i i i i

Mean values±S.D. All tissues in the whole series were obtained from the same animal. The proximal part of the intestinum means the first m., the distal one the last m. For further conditions see Table llI and Methods.

T a b l # V . ~ H I S T A M I N E C O N C ' q ~ N T R ~ T I O N S I N VARIOUS MUSCI..ZS OF TI.-I]~ Doo

Tlssuz

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

I"IIsTAMIN~ CONCgNTRATION (lag. per g.)

~4.S.D.

1"94,I"2 2"74-2"2 2-24-0"8 2"omi'3 2"5=['9 1.9±o.8 3-2=2.2 2 " 5 : r ' 7

2.7=2.2 2"x=~'5 2 " I = I ' 2

2"74.x- 3 2"34.x'I 2.3=x.2 2 .8±I .4

i2 . I4 .4 . 7

Extreme Values

0-8-4.2 ] "o-7"3 i "o-3"6 o.7-3-8 0.7-..6-3 0"9-2 "9 0"8-7"7 0.8-5-0

i "o-7"3

i. i-5.2 0"9-4"6 i .o-- 5. t

0"9-3.8 o-3-4-i o"3-5"o 5 "8"-I 7"4

Mean values from 7 animals of both sexes. For further conditions se- Table III and Methods.

236 LORENZ AND OTHERS Comp. gen. Pharma¢.

tongue, submandibular gland, and heart of the rabbit and in rat kidney. Histamine con- centrations higher than I oo pg. per g. were

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~ONS IN TmSUES oF BraDS

Trove

Crop Oesophagus, ~elow the crop Proventricutus

Mucosa Muscularis

Gizzard Mucosa Muscularis

Pyloric region Duodenum (total)

Proximal Distal

Small intestmum (total) Jejunum Ileum

Proximal Distal

Caeca Rectum Liver Gall-bladder

H~rrxm~rz CONCZ~rrRA~O~ (gg. per g.)

Chicken ( Gallus gaUus domesticua )

n = 5

37"5±I6" 3 38"3± 7"9

4x'5±t5"9 22.2± 12.1

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

~ ' x ± I x ' 4 89.8=23. 4 55"x:35"I 39"5±25"o 6-5= i. 9

37"9±~3"3

Duck Pigeon (Arias p/a-

( Columba tyrhynchos livia domestica) domestica)

n= 5 n= 4

7.2±2.8 8.5± 5-6±i. 4 8-2±

}I3"9±3"6 }9"I :

2 - 6 ± t ' 2 12.9± 2 - o m * . 2 I

-- 3"0=

2"4±I- 3 35"2± 2"9~z-3 I-9±o- 4 1.9=~.o 28.2= 2.2=0.5 28"9=

1-7=o- 5 32.4= x'4±o'2 25"9±

8.6± x'4=o'3 7"6= 2.0=0 .8 x'3±

2"2±

Goose (Anser ans~ domestic)

n = 3

2.8 0"8 6.8± 4"x

3"I II5-6= 2.I

0"7 }0-4= 0"2

I" 4 6"I= I'x 6"3 35"6m 4"8

3o'3~ o'5 49"7=12"9 21-8= 7"3 19"0± 4"5

2x'5= 8.x 22-3= 9.0

3 .6 I5"7± 5"3 °'5 4"8= 3"5 1-8 0"5± o'4 2"0 1"9± 0"2 4"5 6-2± 4"7 0"3 3"5± I'3 2.8 3o.9±16.o o. i I " 3 = 0.2 0.2 0 - 9 ± o.2

7"4 5"3

1o-6 I3-7 2"2

PancTe~ Lungs Kidney Spleen Heart Adrenals

4"8± o.I 8.8= 2"6 2-6± x.i

49"2= 3"8 6"9= 2"3

I '8=o '3 2"3= 2.9=i.o 5 . i= 2.o=1.i 2"5= 5"7=1"8 I 9"2= 1"3=o"4 o '7=

' 0 " 9 =

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 con- centradons in the dssues are situated within the range of i - i o o gg. per g.

The values shown in Tables If, III demon- strate 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 hista- mine.

There ,*-as no tissue found in mammals which showed in all species investigated a relatively high histamine concentration. Al- ways one or two exceptions could be detected, such as the gastric mucosa of sheep or 31asto- mrs, the intestinurn of rabbits, rats, or Mastomys, and the lungs of rats, which had

x973, 4 HISTAMINE IN ~ N AaND ANIMALS 237

only a med ium histamine content. Tissues with relatively low histamine concentrations in all species were kidney and heart ventricle. Organs with a histamine content, which

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'rRAmONS IN Tmstms m, R.ZPTm~S

j e junulTt Ileum Colon Liver Pancreas Trachea Lungs • Spleen Kidney. Heart

T1sstn~

HISTAMINl~ CONL'~'CrRATION ([,tg. per g.)

European Pond Turtle ( Emys orbicularis )

Caspian Pond Turtle ( Clemmys caspica )

Oesophagus 4" 7 Stomach

Fundus 9" i Corpus I o. i Antrum 4"5

Duodenum o" 7 0. 5 0. 4 o. 9 i. 3 3-1 2"2 2" 3

18"7 4"7 4"9

Abdominal muscles 0. 9 Abdominal skin

f

Mean values from two female animals, m __. means conditions see Methods.

I6. 3

12"I 1 1"2

3"3 4"4 4-'2

5"6 18-8 15"9 Io.7 r3" 4

352"0 12"8

17" 7 3"6

Gecko ( Tarento&

mauritanica )

I7-6

18- 3 15.6 I5"6 6"8 2"I 6. 5

I5.6 io. 4

8.0 t2- 4 6~-4 t4. 3 21-7

' not investigated '. For further

showed great species differences, were the submandibular gland, liver, spleen, and thyroid gland. General ly there was a con- siderable species var iab 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 mammals , in addition to those described in Table III, the histamine concen- trations of those tissues were part icularly measured (Tables IV, V) in which a physio- logical or pathophysiological role of histamine had been considered by various investigators (for a survey see Lorenz and Werle, ~974). The histamine content of striated muscles in the dog showed only small variations within the same individual, but considerable differ- ences 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, hista- mine could be detected, but its distribution varied considerably from organ to organ. The 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 concen- trations were regularly found in the pancreas, the kidney, and in three species also in the hear t . .as in mammals the histamine content of the gut decreased from oral to aboral.

In some organs of the pheasants (Pha.6mms colchicus colchieus) the following histamine con- tents were determined (~,, n ~ 2, Jag. per g.): crop t "9, oesophagus below the crop 2-4, fun- dic 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 mammal i an organs (which may 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 mammal i an 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 may not be representative for all amphibians, but have to be considered clearly as an exception among the other vertebrates studied until now.

Histamine Concentrations in Tissues of Reptiles ( Table VII)

In the three reptilian species histamine was found in all tissues investigated, but its distri- bution varied from organ to organ. The

Histamine Concentrations in Tissues of the Bony Fishes. ( Table IX)

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 CONC~ONS I~ Tissues or Tree FROO (Rana pipiens)

I -hs ' r~n~ Cowr~NT H w r ~ n ~ CowrZNT Txss~ (~tg. per g.) TmsuE (~tg. per g.)

Roof of the pharynx

Oesophagus Stomach Jejunum Ileum Colon Liver

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

Lungs Heart Kidney Testis Epididymis M. quadratu$ femoris M. gastrocnemius

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). On the average, the histamine concentrations of reptilian tissues are in the same order of magnitude as in mammals and birds.

Histamine Concentrations in Tissues of the Frog ( Rana pipiens) ( Table VIII)

As in mammals , birds, and reptiles, hista- mine was detected in all tissues which were studied in the frog. The 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 sub- stances 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 HISTAMINE IN MAN AND ANLMALS 239

most species and the kidney of the pike. O n l y the carp showed low histamine concentra- tions a long the whole gastro-intestinal tract,

whereas the histamine contents of the other tissues were mosdy relatively low. O n the average the his tamine concentrat ions in the

Table IX.--H~rAMn~E CONCENTRATIONS IN TUcSU~s OF Borer FmHES i i

HISTAMINE CONCENTRATION (Ng. per g.)

Tissue Trout Carp ( Salmo trutta Pike ( Cyprinus

f ario ) ( Esox lucius) carpio domesticus ) n---- 3 n==2 n = 3

R.oof of the pharynx o.6 ~o-~ Oesophagus 0.8 -*-0- 4 4.2 Stomach

Proximal 3"2 ± i "3 14" t 0'7 ±0"3 Medium 6.I --_ t-6 15.2 o '9~o.6 Distal 5"5 ~ i- 1 x 0-6 o-8 =o.6

Small intestinum Proximal 4"3-+-o"7 0--o 0.6 =o . I Distal 2- 3 ~o. 9 I '5 0"7 -----o'3

Rectum Proximal I "7 -z-o'6 I "6 0"7 .-4-o'3 Distal 1.44-o" 5

Liver 0"5 ___0"3 0-'4 0"4 ~ o-':' Gall-bladder I "9 ±0"9 4 .8 0"5 =:o'3 Gills 0. 7 -,-o. i I "8 0- 9 -.0. 5 .~Ar bladder I "3 ~o. x ~ o.2 =o. [ Heart

Atria 0. 5 ~0" I ] Ventricle o'7 ~o.5 ! I .o

Spleen o'7 =o'4 5"0- Kidney t -a ~o'5 x 6.6 Ovary. 0-44-0-0. 0-2

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.

Catfish ( ~ l u ~ g~n~) n ~ 2

o.2=o.x x.6 I ' ~ ± o ' 5 2.0

8"7 9"4 8"8

1- 9 I- 3

I. 3

o'8

1"2

o'3±o-I }0-8 0 " 0 - ~ 0 " I

0"9±0"5 :-i o ' 9±o '3 1"4

O

but it is known as a ' stomachless ' fish (see Wurrnbach , x 971 ). , among all species which were studied for their histamine content (Lorenz and Werle, I974) , the carp was found to be the animal poorest in histamine. T h e distr ibution of histamine in the bony fishes was fairly uniform.

Histamine Concentrations in Tissues of Cartilaginous Fishes ( Table X)

No histamine could be measured in pan- creas, rectal gland, ovars", and brain of car t i laginous fishes. T he other dssues investigated conta ined his tamine in vary ing concentrat ions. T he highest values were observed again in the gastro-intestinal tract,

tissues of carti laginous fishes are in the same order o f magn i tude as those of mammals , birds, and reptiles.

Histamine Concentrations in Tissues of Tunieates and Larme&ts

Tunica tes and lancetets are the two primi- five subphyla of the phy lum chordates. Thus , we investigated the distribution o f histamine in Branchiostoma lanceotatum. The intest inum conta ined histamine in a concent ra t ion o f 2 ~tg. per g. (tissues pooled from 20 animals), whereas the pha rynx and the rest of the body were found to be free f rom histamine. Also in two species of the tunicates, histamine could be found only in the s tomach and intest inum

to

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s re

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In

test

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Pr

oxim

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Dis

tal

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tum

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and

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reas

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ills

lt

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K

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vary

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mF.

CO

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ENTR

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(Scy

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him

ts

stdl

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4"3

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6-o

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11"2

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h M

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lus

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t I1

=

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tl.

3

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.

1973, 4 HISTAMINE IN MAN ~ N D ANIMALS 24I

(Table XI), in which relatively low histamine concentrations were measured.

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

could be found in the posterior salivary. glands, in many parts of the intesdnum, in the gills, or the ovary. The other tissues con- tained 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.

Table XI.--Hnvr..~,I~r~

TmsuEs

Branchial sac Stomach Heart Intestmum Gonad

~ONC.V.NTR.~.TIONS IN T m u m OF TUNICATES

HaSTaa~r~ CoN'r~rr (lag. per g.)

Hawcynthia Ciona intestinalis pa~llosa

0

I'8 0 0" I

0

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 condi- tions see Methods.

Table X I I . - - H ~ , ~ m CONCEtCr~.A~nOr~S n~ T~mtrv.s ov CEPHALO1PODA

T~ssu~

Posterior salivary, glands Oesophagus Stomach C a f x ~ u m Liver Intestinum Rectum Gills Heart Branchial heart Kidney Nidamental gland (NG) Accessory NG Ova~ Ink sac ' Brain '

Optical lobe Supraoesophageal lobe Suboesophageal lobe

Hxs'rAJ~n~ Co~c,,~rr~'noN (~g. per g.)

Cuttlefish

n ----2-3

0

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

0"8 4.0 I- 5 0-8

Octopus ( Oaopus vulgar'is)

n ~ 2 - 3

O

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

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 OTHERS Comp. gen. Pharmac.

In three species of the echinoderms only a few tissues were studied for their histamine concentration. In the sea-urchin (Paracentro- tus 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.

DISCUSSION The reasons for such an extensive study on

the occurrence and distribution of histamine in the animal kingdom, which were: named in the introduction, have now to be discussed in more detail.

I. I t 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 Crab ( Palinur~ vulgaris ) ( Carcinus maenas )

n - ~ 3 r t = ~ 2

Cardia o.4_+o. S Stomach o.6±o.3 2o.4 Liver 4"8 ± 3"6 x 80

o-4=o.2 70 5"6=2"t 5"3 0- 3 =0-2 ~ 5 °

0

7"8±3-x 4o0 0

m ~3o

i i 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.

Intestinum Gills Heart Antenna Eyestalk Mandibular muscles Seminal vesicle

(n = 2, organs pooled from Io animals), whereas in the sea cucumber (Holothuria tubu- losa) the intestinum contained i. 4. gg. hista- mine 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 (Car- cinus maenas) all tissues investigated contained histamine. The 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 compared 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 com- monly used histamine assays; i.e., the fluori- metric method of Shore and others (I959) and the biological determination on the isolated guinea-pig ileum according to Bar- soum and G a d d u m (1935) , have recently arisen (Michaetson and Coffman, i967; Aures, Davidson, and H~tkanson, x969; Waton, I97I). The 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 HISTAMINE IN .MAN AND ANIMALS 243

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 accu- racy of the bio-assay and the fluorimetric methods for determination of histamine can- not exist any longer. Only in the case of tissues with extremely low histamine concen- trations, 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 hist- amine content.

This is specially true for human tissues: histamine concentrations have been deter- mined 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), Kumar and others (i 968), Anion and Sayre (7969), and Lorenz, Benesch, and others (797o), and only Kumar and others (I968) measured hist- amine in a greater number of individuals (n ---- 68). Thus, we were eager partly to close the gaps in our knowledge about the distribu- tion 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

more in animal experiments, it seemed sig- nificant to obtain data about the distribution of histamine in these animals.

In organs or tissues in which pharmaco- logical actions of histamine were observed, the endogenous histamine concentration was con- sidered to be important--besides other para- me te r s - fo r the evaluation of physiological or pathophysiological functions of histamine. Pharmacological effects of histamine with pos- sible 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 hist- amine (e.g., Rocha e Silva, I966). Quite recently Reite ( 1972) compiled the literature about the pharmacological actions of hist- amine in animals lower than mammals. Some of these effects, which started our investi- gations 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 hypo- theses.

3. The species variability, relating to the distribution and localization of histamine in tissues is much greater than has been assumed untilnow. The resultsof thispublica- tion confirm those of histochemical studies (H~kanson and others, 7970 ) and of a com- prehensive 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 concentra- tion 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.

to

"1 a

ble

XIV

.--T

I.~

SUE

S o

f L

OW

ER

VE

RT

EB

RA

TE

S T

IIA

N ~

'~A

MM

AI.

S, I

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.II

ON

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ASI

S O

F P

llA

RM

AC

OL

OG

I(:A

I. A

CT

ION

S A

IhI

~'SI

OLO

~;W

AI..

O

R P

AT

IIO

PII

YS

IOI.

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ICA

L R

OI.

E O

F i

llS

'FA

MIN

E I

S C

ON

SID

ER

ED

SP

EC

IES

Car

tila

gino

us f

ishe

s

Bon

y fi

shes

Fro

g

Tur

tle

Liz

ard

Chi

cken

TISS

UE

Gas

tric

mtt

cosa

Gas

tric

muc

osa

lnte

stin

um

Sm

ooth

mus

cles

of

bloo

d-ve

ssel

s

Gas

tric

nni

eosa

Gas

tric

muc

osa

Gas

tric

mus

cles

Gas

lric

mus

cles

S

tria

ted

mus

cle

Who

le a

nim

al

Gas

tric

nnl

cosa

Gas

tric

mtl

cosa

Gas

tric

inu

cosa

O

esop

hagu

s

lnte

stin

um

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IYS

IOI,

OG

IGA

L O

R

PA

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AL

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NG

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N

Sti

mul

atio

n of

sec

reti

on

Sti

mul

atio

n of

sec

reti

on

Con

lrac

tion

or

rela

xati

on

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oten

sion

or

hype

rten

sion

of

per

iphe

ral

bloo

d-pr

essu

re

Sli

mul

atio

n of

sec

reti

on

lncr

case

of

the

perm

eabi

lity

fo

r io

ns

Con

trac

tion

, hi

stam

iner

gic

ne

rve

s R

elea

se o

f ac

etyl

chol

ine

Incr

ease

of

neur

omus

cula

r tr

ansm

issi

on

Shoc

k

Sti

mul

atio

n of

sec

reti

on

Sti

mul

atio

n of

sec

reti

nn

Sti

mul

alio

n of

sccr

ctio

n C

ontr

acti

on,

rele

asc

of

acct

ylch

olin

e R

elea

se o

f cat

ccho

lam

ines

LIT

ER

AT

UR

E

Hog

ben,

196

7

ilog

ben,

196

7 D

reyc

r, 1

946;

von

Eul

er a

nd (

')sth

lnd,

i95

6- 7

Sc

hiev

elbe

in, a

nd o

ther

s, 1

969;

Vog

el, S

chie

velb

ein,

Lor

enz,

Wer

le,

and

Sch

mal

, t9

69;

Rei

te,

1969

a

Dav

idso

n,

I.em

mi,

and

T

hom

pson

, 19

66;

Kas

beka

r,

i967

; K

as-

beka

r, R

idlc

y, a

nti

For

le,

1969

V

ille

gas,

196

3

Sin

gh,

Sin

gh,

Mal

hort

ra,

and

Sar

na,

1961

; R

ashi

d, 1

972

Sin

gh a

nd S

ingh

, 19

66

Val

eri

and

Fan

tin,

I97

O

Coh

en,

Sap

p, a

nd S

hask

as,

1968

Wri

ght,

and

oth

c~,

i957

Wri

ghl,

and

nth

cls,

I95

7

Rim

ff a

nd S

ewin

g, 1

97o

Bar

tlet

and

lla

ssan

, i9

68

Eve

rett

and

Man

n,

I967

I-4

o N

o 0~

g~

I973, 4 HISTAMINE IN MAN AND ANIMALS

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 WHICH HISTAMINE HAS BE~'N DETIgCTED

I

o

3 4 5 6

8 9 9 . I

No.

9 . 2

9.3 9.3-I 9.3.2

9.3.3

9.3.4

9-3-5

9.3.6

PHYLUM

Sponges (Porifera)

Coelenterates (Coelenterata)

Flatworms (Plathelminthes) Roundworms (Aschelminthes) Segmented worms (.amnelida) Joint-footed animals

(Arthropoda)

Molluscs (Mollusc.a)

Echinoderms (Echinodermata) Chordates (Chordata) Tunieates (Tunieata)

Lancelets (Cephaloehordata) Vertebrates (Vertebrata) Cyclostomes (Cyclostornata) C~rtilaginous fishes

(Chondrichthyes) Bony fishes (Osteichthyes)

Amphibians (Amphibia)

Reptiles (Reptilia)

Birds (Aves)

Mammals (Mammalia) 9.3.7

LITERATUR~

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 meas- ured 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. Low values were determined in man, all

the Natal rat (Mastomys natalensis). In birds and in one species of the tortoises, the hist- amine 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 OTHERS Comp. gen. Pharmac.

in Oxyrmtus centrina, a cartilaginous fish, rela- tively 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 prefer- ence 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 con- tent and a pharmacological function of hist- amine 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 cyclo- stome Myxine glutinosa (Reite I969b, and this paper), only a very. low histamine concentra- tion can be found in the whole gut. Also in molluscs and crustaceans, in which the stom- ach 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 rela- tively rich in histamine.

The correlation between the histamine con- tent and the pharmacological action of hist- amine in the gastric mucosa is naturally no evidence for the hypothesis that histamine

may be a physiological stimulator of the gastric acid secreuon. On the other hand, it is again consistent with the view that hist- amine 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 physio- logical 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 evolution- ary studies. The occurrence of histamine has been demonstrated until now in numerous phyla and orders of animals (Table XV). Phylogenetic investigations on the concentra- tion 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 com- parison of the histamine contents of numerous tissues and organs in many species, orders, and phyla is now possible from the data pre- sented in this publication.

There are, however, also few evolutionary and phylogenetic studies on the pharma- cological 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 prac- tically 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 hist- amine in the gastric mucosa of the chordates.

As far as we know, only two authors per- formed phylogenedc studies on the localiza- tion of histamine in certain ceils (Reite, 1965; Takaya, Tsuneo, and Endo, I967; Takaya, I969). It seems ver 7 remarkable that in fishes and Amphibia histamine is not stored in mast ceils. In the evolution, beginning

~973, 4 HISTAMINE IN MAN AND ANIMALS ~'47

with reptiles and birds, histamine could be demons t ra ted in these cells, which are quant i ta t ively the most impor tan t stores o f histamine in mam m a l s (Riley and West, I953).

Unl ike the findings in most o f the m a m m a l s (H~kanson and others, ~97o), histamine in the gastro-intestinal tract of o ther classes o f vertebrates is therefore called ' non-mas t cell his tamine '.

REFERENCES ACK~RMA~N, D., and L~'r, P. H. (~957), ' Q b e r

das Vorkommen betr~chtlicher Mengen Hist- amin in der niederen Tierwelt ', Hoppe.Seyler's Z,. physiol. Chem., 3o8, ~74-~76 •

.~wrON, A. H., and SAV~, O. F. (I969), 'A modi- fied fluorometric procedure for tissue histamine and its distribution in various animals ', J . Pha~nac. exp. Ther., x(~, ~85-~92.

Aura.s, D., DAVmSON, W. D., and HAx.cNSON, R. (1969), 'Hisddine decarboxylase in gastric mucosa of various mammals ', Eur. J . Pharmac., 8, 1oo--1o6.

BAP.SOVM, G. S., and G~a~DUM,J. H. (1935) , ' The pharmacological estimation of adenosine and histamine in blood ', .7. Physiol., Lond., 85, I-~ 3.

BARTLET, A. L., and HASSA,'% T. (1968), 'Some actions of histamine and 5-hydroxyu'yptamine on isolated chicken oesophagus ', Br. jT. Pharm~., ~,~ ~56-163.

BEA~'M.ARIAGE, M. L., and L~coM'rx, J. (i955) , ' Teneur en histamine de quetques organes du coq ', C.r. Sean¢. Biol., 14~ ~7-~29.

BE~r~TT, A. (1965), 'A pharmacological investiga- tion of human isolated ileum ', )v'ature, Lond., 2o8, I~89-I~9~.

BE~.,~T'r, A., and Wm'rN~Y, B. (i966), 'A pharma- cological investigation of human isolated stomach ', Br. ".7. Pharmac., =7, ~86-298.

BERTACCINI, G. (r 96~), ' Discussion to H. H. Adam. Histamine in the central nervous system ', Regional Neurochemistry (ed. Kety and Elkes), p. 3o5 . Oxford: Pergamon.

BZRTACCZN~, G., NEvt~a~, D. E., and ROSEOHX,m, M. (~965), ' Occurrence ofbiogenic amines and other active substances in methanol extracts of beetle (Ludola italica)', J . Inject. Physiol., Ix, IO55-~o6o.

BEST, C. H., DALE, H. H., DUDLEY, H. W., and THORPE, W. V. (19~7), ' T h e nature of the vaso-dilator constituents of certain tissue ~x- tracts ', 7 . Physiol., Lond., 6"~, 397-417 .

BHOOL~, K. D., CAx.LE, J., and SCnACH'mR, M. (x961), 'Identification of acety.|choline, 5- hydroxyt .ryptamine, histamine and a new kinin in hornet venom', J . Physiol., Lond., x.5~ 167- x 74.

Bo~os'rr~T, H. H., Bz~j~m~, J. A., and EMMZL, V. M. (~962), 'Ro le of histamine in ureteral function ', aT. Pharmac. exp. Ther., 136 , 386-392.

CAma~i, E. A., and G!~EN, J. P. (1963), ' T h e measurement of histamine in brain and its dis- tribution ', Biochem. Pharmac.. x ~ I448-I449.

Cm, J. M., ERaP.~,,mR, V., and RoseoHIm, M. (i967), ' Taxonomic and evolutionary signifi- cance of biogenic amines and polypepddes occuring in amphibian skin. I. Neotropical !eptodactylid ¢rogs ', System. ~ool., 16, 328-372.

COD~, C. F. (1956), 'Histamine and gastric secretion ', Ciba Found. Syrnp. on Hi~taraine, pp. I89-2 x 9. London : Churchill.

COHEN, S. G., SAPP, T. M., and Stt,~sxas, J. R. (I968), 'Histamine shock in the frog ', Am..7,. Physiol., '~14~ x 288-t 29o.

D.~s, N. P., LIM, H. S., and TE~, Y. F. (1971), ' Histamine and histamine-like substances in the marine sponge, Suberites inconstans ', Comp. gen. Pharmac., 2, 473-425 .

DAV~VSON, W. D., LEMm, C. A. E., and THOMSOn, .J.C. (1966), 'Action of gastrin on the isolated gastric mucosa of the bullfrog ', Proc. Soc. exp. BioL ~Vled., x~x, 545--547-

DRE'~R, N. B. (1946), 'Histamine and posterior pituitary, actions on elasmobranch and teleost smooth muscle ', Archs int. Pharraazodya. Th, r., 72, 44o-'443.

DtYYER, H., and I~RNOW, B. (196o~. ~ Histamine in man under physiological and pathological conditions '. Acta rr~d. stand., x(~ 3o7-323 .

ECKXRT, D., PAAso~r~, M., and V.~a~T.~mna~, A. (1951), ' O n histamine in the gnat (Cubx pipiens) ', A¢ta pharma¢, toxic., 7, I6-22.

ELLZ.'~ERGItR, W., and BAtrM, H. (1912), Hand- buch der verg~'¢henden Anatomic der Haustiere. Berlin : Hirschwald.

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ERS~AM~R, V., and BoRza-n, G. (~95~), ' Identifi- cation and characterization bv paper chromatography, of enteramine, octopamine, tyramine, histamine and allied substances in extracts of posterior salivary glands of octopoda and in other tissue extracts of vertebrates and invertebrates ', Ar¢hs int. Pharmacodyn. 77m'., 88,

EmP~a~R, G. F., and CEt, J. M. (~ 97o), ' Biogenic amines and active pol.~peptides in the skin of Leptodactylua ~ilarsi metin ', Biochem. Pharma~., x ~ 321-3~5.

ERSPAMm~, V., RosEogrm, M., and CEI, J. M. (~964), ' Indole-imidazole- and phenyl-alkyl- amines in the skin of thirteen leptodactylus species ', Bio~hem. Pharma¢. , 13~ xo83-xo93.

E~PAM~R, V., VrrAta, T., ROSEOHn'a, M., and C~x, J. M. (1963), ' Occurrence of new imi- dazole alkvlamines ( s p i n a c ~ e and 6-methvl- spinacaemine) in skin extracts of Leptoda¢tylus pentadactylus labyrinthicus ', ExpcHentia, t ~ 346- 347.

ERs~.~wm~, V., VrrAta, T., Ro~HX~n, M., and Cm, M. J. (i964), ' The identification of new

~48 LORENZ AND OTHERS Comp. gen. Pharmac.

histamine derivates in the skin of Leptodactylus ', Arrhs Biochem. Biophys., sos, 6ao-6~ 9.

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EvzREv'r, S. D., and MANN, S. P. (x967), ' Gate- cholamine release b.v histamine from the isolated intestine of the chick ', Ear. 07. Pharra~., x~ 3 ~o-3~o.

GA~, M. (~97I), ' Repartition des cellules hist- amincrgiqucs dam la paroi gastrique de quelques reptiles ', C. r. heM. S~an¢. Aoad. Sci., =73, ¢~87-~a89.

Guoozm-mi~, M., and L 6 ~ z g , W. (x9~6), 'Biologischer Nachwcis proteinogener .~nine in Organextrakten mad K6rperfliissigkeiten ', Biochtm. ~.., 7~ 303-3 ~ t.

Hkr, ANSON, R., Ovwt~ , CH., SJ6~ER~, N-O., and SPOR~ONO, B. (~97o), 'Amine mechanisms in enterochromaffm and enterochro~ike cells of gastric mucosa in various mammals': Histoclmni~try, =x, 18Q--RIO.

HOOaEN, C. A. M. (1967), 'Response of the isolated dog fish gastric mucosa to histamine ', Pro¢. 3o¢. exp. Biol. Med., xa 4, 89o-893.

Hot.s'rmN, B. (t97o), 'Metabolism of subcu- taneously injected ~*C-histamine in ]vlyxine gtutinosa ', Aeta physiol, seand., 8o, 433-437.

Huooms, A. K., and Woo~amn,, G. N. (I968), ' Histamine metabolim~ in invertebrates ', Comp. Bioehtra. Physiol., ~6, ~ ~o7-~ ~ ~ t.

JA~L~. lq.., and Sca^omzR, M. (~954), ' T h e presence of histamine, 5-hydro~'tryptamine and a potent, slow contracting substance in wasp venom ', Br. 07. Pharm~., 9* 53 "6~.

Jot-mso~, L. R. ('97~), 'Control of gastric secretion: no roo/'n for histamine?' , Goatro- enterolog),, 6x, m6--~ t8.

K A ~ , D. K. (I967), 'Studies of resting isolated frog gastric mucosa ', Pro~. Soc. exp. Biol. Msd., x=,~ ~67-277.

KAs~m¢.~m, D. K., KmL~V, H. A. and Fom'x,J. G. (;969), ' Pentagastrin and acetylcholine rela- tion to histamine in H ÷ secretion by gastric mucma ', Am. o7. Physiol., ',x6, 96~-965.

Kzmayr, G. A., and Pinch, M. A. (~96t), ' Hist- amine content of tissues from the crab Cardnus raaenas ', Comp. Biochem. Physiol., 3, 315-377 •

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KREMZN~R, L. T., and Pt, zWmZR, C. C. (t966), 'Identification of substances interfering with the fluorometric determination of brain hist- amine ', B/ochtm. Pharm~., x$, i97-2oo.

KOr~m-am., W., MAw'r~zs, E., and R.~m~zR, M. (I967) , Leitfadtn ff~r das Z.oologische Praktikarn. Stuttgart: Fischer.

K t ~ t ~ , V., L A ~ u , A. R., LAmm, P. K., and SA:¢YAL, R. I '2. (I968), ' T h e physiological levels of histamine in human tissues ', Int. Arch~ Allergy, 3~ ~33-~36.

Lo~Nz, W. (1969), ' Lokalisation, Stoffwechsel und Fragen einer physiologischen Funktion yon H~tamin in Speicheldrt~en, Schilddrt~ und Magen ', Thesis, University of Munich.

L o ~ z , W., BART-a, H., Kusct-m, j . , RZ~Nt¢, H. J., Scxm~a., A., M~Tzjg.~, E., MATataS, Ch., HLvrZEL, M., and WZm.E, E. (I97I), 'His t - amine in the pig: determination, distribution, release and pharmacological actions ', Ear. 07. Phamnat., x4~ r55-x75.

LORENZ, ~N., B,~Trt, H., and W~RLS, E, (I97o), ' H.ismmine and histamine methyltransferase in the gastric mucosa of man, pig, dog and cow ', Naunyn-Schmiedebergs Arch. Pharmak. exp. Path., =67, 42 z-432.

L~RENz, W.; BEN~SCH, L., BAZ~, H., MATZJZA, E., M.zvXR, g . , Kvscm~, J., HtrrZZL, IV[., and W E ~ , E. (197o) ' Fluoromeu-ic assay of hist- amine in tissues and body fluids. Choice of the purification procedure and identification in the nanogra~ range ', Z- atudyt. Chin., =5~, 94-98.

LOP.ZNZ, W., DOENmr,~, A., M~Y~R, K., RZIMANN, H. J., Kusct-m, J., BAR'r~t, H., GE~.StNG, H.; HtrrzzL, M., and WEtSmZNB^CX-mR, B. 097a), 'Histamine release in man by propanidid and thiopentone: pharmacological effects and clinical consequences ', Br. 07. Anaesth., 44, 355-370-

LORENz, W., Ht.a-mD, A., Kuscmz, J., B~a~a'R, H., H~uBzt~a¢, G., HUTZEL, M., SCFIMAL, A., GERAWr, M., WACHTER, A., MATlgJg.A, "[P.., HAsN, H., and WZRLZ, E. (I973), ' Histamine and saliva D" secretion '. XXV. Int. Cong. physiol. Sc/., Ldd~ (ed. Ma~lifiski), in the press.

Loa~xz, W., and I~t.ZOZR, K. ' ( I968) , ' Stoff- wechsel und ph.vsiologische Fun_krion yon Hist- amin im Magen ', Klin. Wsehr., 46, 57--7t-

LORENZ, W., PFLZGZR, K., and Wzm.z, E. (t967), ' Histamin und Histidindecarboxylasen im obe- ten Verdauungstrakt yon Mensch, Hund, Meer- schweinchen und Katte ', Waunyn-Schmiedtbergs' Arch. Pharmak. exp. Path., =Sg, 15o--z59.

LoRENz, W., ILZtMANN, H. J., BAgTH, H., KUSCHE, J., Mz~n~R, R., Dozmcg~, A., and Htrrzm., M. (I972), 'A sensitive and specific method for the determination of histamine in human whole blood and plasma ', Hoppe-Seyler's Z.. physiol. Chem., 353, 911-92o.

LoggNz, W., SC14AtmR, A., I - I ~ D , ST., MA~JZ, A, E., and WERLE, E. (1969), 'Bio- chemical and histochemical studies on histamine in the digestive tract: distribution in different chordates and cellular stores in the dog ', .Naunyn-Schmiedebergs Arch. Pharmak. exp. Path., =64, 274.

LORENZ, ~r., SCHMAL, A., REIMANN, H. J., TA~rsgz, K., UHLm, R., MAN"K, G., BA.RTtt, H., KUSCHE, J., SEmEL, W., DoeymRE, A., HAm~L- MANN, H., and Wzm.~, E. (~97a), ' Histamine release in man, dog and pig: problems of its determination and evaluation under various pharmacological and clinical conditions ', tst A.

~973, 4 HISTAMINE IN MAN AND ANIMALS ~49

3/Ieet. Eur. Branch Histamine Club, Paris ~97 .o, ft. Pharmac. (Paris), 3, 5~6.

L o ~ y z , W. and W~RLS, E. (~974), ' Occurrence. distribution and subcellular localization of hist- amine in man, animals and plants ', in Inter- national Encyclopedia of Pharmacology and Thera- p~tics (ed. Maxwell), section 74. Oxford: Pergamon. (In the press.)

~[ACINTOSH, 1". C., and PATON, W. D. M. (t949), ' The liberation of histamine by certain organic bases ', J . Physiol., Land., tog, ~9o-2~9 .

MATHIA$, A. P., Ross, D. M., and SCHACr~T~ta, M. (~ 958), ' Distribution of histamine, 5-hydroxy- t ryptamine, tetramethylammonium, and other substances in coelenterates possessing nemato- cysts ', .~. Physiol., Land., x4a, 56 P-57P.

MArinAS, A. P., Ross, D. M., and SCH:,CHT~, M. (~96o), ' T h e distribution of 5-hydroxyt .rypt- amine, tetramethylammonium, homarine, and other substances in sea anemones ', ./7. Physiol., Land., ~Sx, 296-3~ ~.

M~T'rmc~¢. D. F., and TELrORD, J. M. (~965). ' T h e histamine content and histidine decarb- oxvlase activity of some marine and terrestrial ammals from the West Indies ', Comp. Biochem. Physiol., r6, 547-559.

MXCH.k~LSON, I. A., and COrFMAN, P. Z. i~967), 'His tamine and spermidine in tissues of the guinea-pig ', Bioch~ra. Pharm~c., t6, ~636-~67x.

NhSaAHY, G. A. (t946), ' T h e metabolism of lust- amine and adenytic compounds in the embryo ', Am. J. Physiol., x47, 460-47o.

Na~.ajtM~, S.. Hmsczowt 'rz, B. I. , and S~CHS, G. (~97~), 'S tudies on adenyl-cyclase in Necturis gastric mucosa ', Archs Biocham. Biophys., x43, ~ 3 - t 2 6 .

PARSONS, J. (~ 962), ' Pharmacology of the poison gland of the locust, Poekiloceru~ bufonius Klug ', Proc. ont. Soc., ~7, °-~-22.

K.~Hm, S. (~97~), ' T h e nature of the para- sympathetic nerve fibres of the stomach of Rana temporaria ', Archs int. Pharmacodrn. Thor., x95, 247 -~5 x.

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335. l~ r r~ , O. B. (x969a), ' T h e evolution of vascular

smooth muscle responses to histamine and 5" hydroxytryptamine. L Occurrence of stimul- atory actions in fish ', Acta physiol, stand., 75, ~ ~-239-

K~rr~, O. B. (~969b), ' Phylogenetical persistance of the non-mast cell histamine stores in the digestive tract: a comparison with mast cell histamine ', Experientia, ~,5, ~76-277.

R~rr~, O. B. (~97a), ' Comparative physiology of histamine ', Physud. Rev., 52, 778--805.

l~ r r~ , O. B., and D.~,v~, W. H. (t97o), ' M a s t cells and hibernation: observations in the Indiana bat, 3/Iyotis sodalis ', Expmentia, 26, 745-746 •

Rm~v, J. F., and WEft, G. B. (x953), ' T h e presence of histamine in tissue mast cells ', ft. P/~iol., Lond., xao, 528-537.

ROCHA E SiLvA, M. (x966), ' Histamine and anti- histaminies '. in Handbook o.f Experimentai Pharma- cology red. Eichler and Farah), vol. t8, p. t. Heidelberg: Springer.

ROSEGHr~a, M., and KAMOaXNO, L. M. (I97o), 5" Hydroxvtryptamine, histamine and Ar-acetvl - histamine in the nervous system of Dosidi'ctu gigas ', .,7. Neurochem., zT, 489--49 .°.

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SCHAYEa, R. W. (I964), ' Histamine and hyper- aemia of muscular exercise ', Nature, Land., 2ox, I95-I96.

SCHmVZL~Em, H., VOO~L, R., LO~,ENZ, W., and SCHMAL, A. (i969), 'Contr ibut ions to the evolution of blood pressure regulation ', ~. klin. Chem. kiln. Biochem., 7, 461-465 •

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SXNGH, I., and SINOH, S. I. f~966) , ' Histaminergic transmission in a frog vagus stomach muscle preparation ', Archs int. Physiol. Biochera., 74~ 365-373.

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25o LORENZ AND OTHERS

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VtLLZOm, L. (1963), 'Action of histamine on the permeabili~, of the frog gastric mucosa to potassium and water ', Biochim. biophys. Aaa, 75, 377-385.

VO~EL, R., ScnmvEt.B~n% H., LomzNz, W., WERLZ, E., and SCHU.AL, A. (x969), ' Contribu- tiom to the evolution of blood pressure regula- tion, Part II ', Z. klin. Chem. klin. Biochem., 7, 464-468.

WA'roN, N. G. ( 1971 ), ' Histamine and the parietal cell ', Am. 3. dig. Di~., x6, 921--938.

WxR~z, E., and Gx~zmsnER, K. (i951) ' Ober die Herkunft des Histamins der Bienen' , Z. Vitarn.-, Horm.- u. Fcrmentforsch. 4, 45o-457 •

WERLE, E., and Lot~zNz, W. (197o), ' The anti- kinin action of some antihistaminic drugs on the isolated guinea-pig ileum, rat uterus and blood pressure of the anesthetized dog ', Int. Syrup. on Bradykinin and Related Substances, Fiesole. Adv. exp. Biol. Med., 8, 447-453. New York: Plenum.

WmGnT, R. D., FLOmZY, H. W., and SANDSm, A. G. (1957), 'Observations on the gastric mucosa of reptilia ', Q. ft. exp. Physiol., 4~ z- I4.

Wmonv K. D., and Tmza-h'zwm, E. R. (1956), ' Histamine of the reptilian stomach and lung ', Nature, Lond. , XT~ 546-545 .

WUR~mACn, H. (I97t) , Lehrbuch der Zoologic, vol. II . Stuttgart: Fischer.

Eey Word Index: Histamine, specific determina- tion, man, chordatcs, echinoderms, molluscs, crustace~"lns.