Histamine Release as Cause

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Naunyn-Schmiedebergs Arch. Pharmak. 267, 433--445 (1970) 9 by Springer-Verlag 1970

Histamine Release as Cause

of Acute Hypotension Following Rapid Colloid Infusion*

K . MEssM~I~, W . LORENZ, L. SUNDER-PLASSMANN, W . P. KLO]~VE~:OaN, a n d M. I-IUTZ]~L**

Institut fiir Experimentelle Chirurgie an der Chirurgischen Universit/~tsklinik un4 Institut fiir Klinische Chemic

und Klinische Biochemie der Universit~t Miinchen Received May 4, 1970

Summary. In a series of 133 dogs, 10--20 ml/kg arterial blood were removed and replaced by rapid intravenous infusion of an equivalent volume of various plasma substitutes. Following the infusion of gelatine solutions, an acute fall in arterial blood pressure was observed, but not following the infusion of equal quantities of Dextran 60 or of 0.90/0 NaC1 solution, lVieasurement of the blood histamine levels as well as the fact that the circulatory effects could be modified by the previous administration of anti-kistaminie drugs indicate that the hypotension observed following the rapid infusion of gelatine solutions is due to the release of histamine.

Since histamine liberation has also been shown in preliminary studies in man, rapid infusions of gelatine solutions should be avoided in clinical practice, or patients receiving them should be pre-treated with anti-histaminic drugs.

Key-Words: Gelatine -- Dextran 60 -- Hypotension -- Histamine Release.

Besides p l a s m a itself, colloidal s o l u t i o n s b a s e d on d e x t r a n a n d g e l a t i n e are t h e m o s t w i d e l y u s e d e r y t h r o c y t e - f r e e a g e n t s for v o l u m e r e p l a c e m e n t . I n emergencies t h e v o l u m e e x p a n d e r s m a y h a v e t o be a d m i n i s t e r e d r a p i d l y , for i n s t a n c e , i n t h e f o r m o f infusions u n d e r pressure, a n d i t is e s s e n t i a l t h a t such r a p i d infusions s h o u l d s t a b i l i z e t h e c i r c u l a t i o n , a n d t h a t t h e y s h o u l d in no case r e n d e r i t worse. I n a p r e l i m i n a r y s t u d y on a c u t e e x t r e m e h e m o d i l u t i o n p e r f o r m e d b y w i t h d r a w a l o f b l o o d followed b y i n f u s i o n of p l a s m a s u b s t i t u t e s , a c u t e a n d s o m e t i m e s d a n g e r o u s falls in a r t e r i a l b l o o d p r e s s u r e w i t h c o n c o m i t a n t release of h i s t a m i n e were o b s e r v e d in dogs a f t e r g e l a t i n e h a d b e e n i n f u s e d r a p i d l y (Messmer et al., 1969). T h e causes o f t h i s h y p o t e n s i v e r e a c t i o n h a v e n o w b e e n investi- g a t e d m o r e closely.

* A preliminary report was presented at the 4th Congress of the European Society for Experimental Surgery in Davos, Switzerland, April 1969.

** Supported by "Sonderforschungsbereich 37--Restitution und Substitu- tion innerer Organe".

30*

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434 K. Messmer et al. : Methods and Materials Preparation of Experimental A n i m a l s

133 mongrel dogs of both sexes, and of an average body weight of 15.2 • 0.5 kg, were anaesthetized by intravenous injection of pentobarbital (25 mg/kg body weight) without premedication, and a tracheal intubation was performed. Respiration was maintained in 79 of the animals, after relaxation with succinylcholine (4 mg/kg body weight), with a mixture of air and oxygen administered via a Starling pump.

The other 54 animals breathed atmospheric air spontaneously through the intubation catheter. The left femoral artery and vein were cannulated with a polyethylene catheter in all animals. The arterial catheter was advanced to the abdominal aorta, and the venous catheter to the inferior vena eava. The arterial blood pressure was measured by a Statham element (Statham Lab. Inc., Hate, Rey Puerto Rico) attached laterally to the arterial catheter, and continuously recorded (Physioscript, Schwarzer, Mfinchen-Pasing). The arterial catheter was also used to withdraw blood for histamine estimations. The catheter in the inferior vena cava was used for infusion of the volume substitutes.

Hemodilution Procedure

Following the cannulation of the abdominal aorta and inferior vena cava, and after keparinization with 330 I.U./kg of heparin, a control period of 30 rain was allowed to elapse. Then 10 or 20 ml/kg body weight of blood was removed through the aortic catheter and the same quantity of volume substitute immediately in- fused via the intravenous catheter. The volume substitute was warmed to 37~ in a waterbath and the average speed of infusion was 4 - - 6 ml/kg min (pressure infusion).

Histamine Estimation in Whole Blood o] Dog

For histamine estimation, 5 ml of whole blood was taken from the abdominal aorta via the arterial catheter, using a polyethylene syringe. Two samples were withdrawn during the control period and one sample at the time of the greatest fall in blood pressure, as well as 1,4,9 and 20 min after the beginning of the infusion.

The blood was mixed with an equal quantity of N HC104 and centrifuged at 1800 g for 10 rain. 5 ml of the supernatant fluid was used for histamine estimation using the method of Lorenz et al. (1970): Histamine was purified by cation-exchange chromatography on Dowex 50 W-X8, an4 estimated spectro-fluorometrically after condensation with o-phthaldialdehyde. The method of Lorenz et al. (1970, 1970a) was used for identification of histamine and assessment of the specifity of the procedure: a)thin-layer chromatography on MN-cellulose in six different sole vents; b) enzymatic breakdown by diaminoxidase from pig's kidney and histamine methyltransferase from guinea-pig's brain; c) biological tests on the isolated guinea- pig ileum and on the blood pressure of the anaesthetized cat; d) inhibition of the purified material by the anti-histaminic dimetinden maleate at low doses specific for anti-histaminic activity (Werle and Lorenz, 1969; Lorenz et al., 1970b). The histamine concentration in whole dog's blood was expressed in micrograms of histamine dihydrochloride per ml of blood.

Material

Plasma Substitutes. 0.9~ sodium chloride solution (Pharmacopoieal formula).

Dextran-60 (Macrodex | Knoll, Ludwigshafen). Gelatine, cross-linked by means of urea bridges (H~emaccel | Bohringwerko AG, 1Vfarburg). High mo'eeular weight cross-linked gelatine (Haemaeeel-H, Behringwerke AG, Marburg). 0xypolygelatine

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Histamine l~elease as Cause of Acute Hypotension 435

Fig. 1. Original record of the arterial blood pressure during the first step of isovolemic hcmodilution in the dog. a Withdrawal of 20 ml/kg blood via the aortic catheter;

b infusion of 20 ml/kg normothermic Haemaccel-solution. c and d withdrawal of 5 ml blood from the arterial line for histamine estimation

(OPG), Gelifundol | Biotest, Frankfurt). Modified fluid gelatine (Physiogel | SRC, Berne). High molecular weight gelatine for experimental purposes (FBb 4047- Bayer, Wuppertal-Elberfeld).

Reagents. Histamine dihydrochloridc (Fluka, Basle): o-phthaldialdchyde (recrystallized from ligroin B.P. 50--70~ Fluka, Basle). Dowex 50 W-XS, H +, 200--400 mesh (Serva, Heidelberg). Cellulose MI~ 300 for thin-layer chromatography (Macherey, Nagel and Co, Dfiren). Solvents were of Uvasol | grade (Merck, Darmstadt).

The results were evaluated statistically by Student's t-test.

Results

1. Frequency and Degree o/ the Hypotensive Reaction Following Rapid In/usion o/ Colloids

The tracing in Fig. 1 shows the typical behaviour of the arterial blood pressure following the rapid infusion of 20 ml/kg of Haemacce] solution at body temperature. During the steep fall in the blood pressure the pulse pressure first rises, but at the point of lowest blood pressure there is generally a reduction in the pulse pressure and bradycardia. I n some animals (2 out of 14 given Itaemaccel, 2 out of 6 given Haemaecel-I-I and 1 out of 6 given Gelifundol), cardiac arrest occurred after the infusion of 20 ml/kg of the gelatine solution, but could be controlled by extra- corporal cardiac massage. I n the majority of the experiments, however, the arterial pressure regained its initial value after 7 - - 9 min (Table 1).

Hypotensive reactions occurred following the rapid infusion of all the

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436 K. Messmer et al. :

Table 1. Hypotensive reactions after rapid intravenous inJusion o] di//erent colloids and sodium chloride solutions immediately a/ter withdrawal o/ identical amounts of

whole blood, ln/usion speed: 4--6 ml/kg rain

Plasma- ])osage Incidence of I)ecrease of Recovery

substitute hypotensive arterial time 9

reactions pressure a

(ml/kg) n/n ~ (ram tIg) (sec)

Gelifundol 10 1/4 25 3 --

tIaemaccel 10 20/32 63 71.0 -4- 7.2 195 ~ 42

Physiogel 10 1/6 17 6.3 --

I)extran 60 10 1/37 3 (10) --

Gelifnndol 20 4/6 67 19.7 • 9.0 213 :~ 99

]-taemacccl 20 13/14 93 79.0 -4- 11.2 539 :[: 120

Haemaccel-H 20 5/6 83 51.6 :f= 14.5 392 =j= 137

Physiogel 20 3/6 50 32.3 ~: 16.2 143 =J= 120

FB b 4047-Bayer 20 0/10 0 -- --

I)extran 60 20 0/6 0 -- --

NaC1 0.90/0 20 3/6 50 2.5 --

a mean values ~: S.I). from animals developing hypotensive reaction.

g e l a t i n e p r e p a r a t i o n s s t u d i e d (Table 1) w i t h t h e e x c e p t i o n o f t h e high- m o l e c u l a r w e i g h t g e l a t i n e s o l u t i o n ( F B b 4047, B a y e r ) . T h e l a s t - m e n t i o n e d s u b s t a n c e d i d n o t decrease t h e b l o o d p r e s s u r e in a n y case, b u t r a i s e d i t b y a b o u t 10 m m Hg. F o l l o w i n g t h e i n f u s i o n o f 20 m l / k g o f D e x t r a n 60 or o f 0.90/0 saline solution, t h e v a l u e s of t h e a r t e r i a l b l o o d p r e s s u r e p r e s e n t before b l e e d i n g were r e a c h e d i m m e d i a t e l y a f t e r t h e e n d o f t h e infusion. I t m a y be f u r t h e r seen f r o m T a b l e 1 t h a t i n c r e a s i n g t h e v o l u m e of t h e i n f u s i o n in t h e case o f all t h e g e l a t i n e p r e p a r a t i o n s led t o a h y p o - t e n s i v e r e a c t i o n in a h i g h e r p e r c e n t a g e o f a n i m a l s . I n t h e ease of P h y s i c - gel a clear d o s e - r e s p o n s e r e l a t i o n s h i p e x i s t s b e t w e e n b o t h t h e f r e q u e n c y a n d t h e degree o f t h e h y p o t e n s i v e r e a c t i o n s a n d t h e v o l u m e i n f u s e d ; in t h e ease o f H a e m a c e e l t h e r e l a t i o n s h i p b e t w e e n dose a n d h y p o t e n s i v e a c t i v i t y is n o t so c l e a r l y m a r k e d , since t h e dose u s e d was p e r h a p s a l r e a d y w i t h i n t h e u p p e r r a n g e of t h e d o s e - r e s p o n s e curve. T h e a p p e a r a n c e a n d degree of h y p o t e n s i o n is, h o w e v e r , c e r t a i n l y d e p e n d e n t on t h e s p e e d o f t h e infusion. I n f u s i o n r a t e s b e l o w 3 m l / k g m i n p r o d u c e fewer r e a c t i o n s , while r a t e s b e l o w 2 m ] / k g m i n cause no significant h y p o t e n s i v e r e a c t i o n s . W h e n t h e b l e e d i n g p r o c e d u r e a n d t h e infusion o f g e l a t i n e s o l u t i o n was r e p e a t e d i m m e d i a t e l y a f t e r t h e b l o o d p r e s s u r e h a d r e t u r n e d t o n o r m a l , a s e c o n d fall i n b l o o d p r e s s u r e was o b s e r v e d in 6 o u t o f 13 a n i m a l s (see T a b l e 3). F o l l o w i n g t h e t h i r d or f o u r t h e x c h a n g e of b l o o d b y m e a n s o f I t a e m a e c e l o n l y a few a n i m a l s s h o w e d a s l i g h t p r e s s u r e decrease o f

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Histamine Release as Cause of Acute Hypotension 437 [pglml'l

o, Ic

o, oe

o, o2

t4r

I0C

6(:

2(

t ~ h i s t a m i n e c o n c e n t r a t i o n in a r t e r i a l b l o o d

I / I! / /

I -

~ /

S

m e a n a r t e r i a l b l o o d p r e s s u r e

i ,7 i ,~ i i i i .[~

C M 1 2 3 /-, 9 [mini

t i m e a f t e r m i n i m a l p r e s s u r e

Fig. 2. Behaviour of the histamine concentration in the arterial blood and of the arterial blood pressure in dogs following rapid infusion of 20 ml/kg Haemaecel after primary withdrawal of 20 ml/kg blood. C Mean value during the control

period; M $ime of maximum decrease of arterial blood pressure. (n = 8)

about 15 mm tIg, whereas most of the animals developed no further change in blood pressure. The hypotensive reaction described can thus be practically exhausted b y the second infusion (tachyphylaxis).

2. Changes in the Histamine Concentration in Arterial Blood after the Rapid In/usion o/Colloids

According to Anrep et al. (1935) and Emmelin et al. (1941), the plasma of the dog contains 50--80o/o of the histamine content of whole blood.

Previous experiments have shown t h a t the histamine concentration of canine blood is not influenced by rapid bleeding of 10--20 ml/kg from the aorta. No measurable amounts of histamine could be detected in a n y of the plasma substitutes used. Fig. 2 shows the changes in mean arterial pressure and histamine concentration in the arterial blood following the rapid infusion of Haemaccel solution in eight animals. Both values behave inversely, regaining their initial values 9 min after the maximal fall in blood pressure (M). Table 2 shows the histamine concentration in arterial blood before and after the infusion of the plasma substitutes investigated. The gelatine preparation F B b 4047 (Bayer),

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oo Table 2. Histamine concentration in arterial blood o/dogs after rapid in/usion o/20 ml/kg colloid resp. sodium chloride solutions (izg) histamine dihydrochloride/ml whole blood. M = maximal decrease o/arterial pressure: (Mean values :J= S.D.) Plasma ~umber Control M substitute of animals

Time after minimal pressure value was reached (rain) 1 4 9 20 Gelifundol v 6 0.0094 :~ 0.0007 0.0213 -4- 0.0062* 0.0181 :j: 0.0039 0.0150 -4- 0.0023 0.0130 • 0.0016 -- Haemaccel | 8 0.0149 ~: 0.0037 0.0991 :J: 0.0290** 0.0467 ~: 0.0140 0.0340 4- 0.0090 0.0317 4- 0.0087 0.0237 :~ 0.0041 Haemaccel-~ | 6 0.0116 4- 0.0010 0.0317 :J= 0.0095*** 0.0239 ~ 0.0052 0.0174 ~ 0.0027 0.0125 • 0.0024 -- Physiogel 6 0.0179 • 0.0025 0.0235 =~ 0.0049**** 0.0175 • 0.0018 0.0265 =t= 0.0013 0.0260 4- 0.0077 -- Fb 4047 6 0.0160 :]= 0.0010 0.0160 ~ 0.0020 + 0.016 4- 0.0010 0.015 =[= 0.0030 0.0120 i 0.0020 -- Macrodex | 6 0.0132 • 0.0023 0.0146 ~ 0.0016++ 0.0138 4- 0.0026 0.0142 • 0.0019 0.0139 4- 0.0027 -- NaC1 0.90/o 6 0.0114 ~ 0.0021 0.0114 :~ 0.0017 +++ 0.0109 • 0.0016 0.0115 ~ 0.0016 0.0123 • 0.0017 -- *p < 0.001; **p < 0.005; ***p < 0.001; ****p < 0.05; +p < 1; ++p < 0.3; +++p = 1.

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Histamine Release as Cause of Acute Hypotension 439

h i s t a m i n e c o n c e n t r a t i o n in a r t e r i a l b l o o d ~ug/m a 0,010

x j

\ 10 \

\\ n=6

20 I )=-I

n=6

,E, 30 I-- - I \ n=6

9 40 i ~ 9 - - - I

~ so

".- 60

"~ "/0

r = - 0 , 9 6 e~

~ 80 p< 0,005

90

100

0,050 0,100

x M a c r o d e x A 0,9% NaC[

o Ge[ifundo[

9 Physioge[

9 Haemaccet H 9 Haemacce[ + AH 9 H a e m a c c e L

\

' ^\^\_\ _I

l

_oⁿ⁼⁵ _I

' ^\^\_\

1

\

' l

^\_\ ⁿ⁼⁸

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'i

^{\ \}_\

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Fig.3. Correlation between maximal increase of histamine concentration in the arterial blood and maximum fall of the arterial blood pressure in dogs undergoing isovolemic hemodilution by means of different plasma substitutes. The datas from the animals pretreated with the antihistaminic Neclastinum (0.1 mg/kg) (ttaemaccel

+ AH) are not included for the calculation of ~he regression line

D e x t r a n 60 a n d 0.90/0 NaC1 s o l u t i o n p r o d u c e no significant changes w h e r e a s H a e m a c c e l , P h y s i o g e l a n d GeHfundol, g e l a t i n e p r e p a r a t i o n s w h i c h are u s e d clinically, cause a rise in t h e h i s t a m i n e level. A c o m p a r i s o n o f t h e i n c i d e n c e o f severe h y p o t e n s i v e r e a c t i o n s (Table 1) w i t h t h e increase in h i s t a m i n e levels in a r t e r i a l b l o o d following t h e infusion o f t h e different p l a s m a s u b s t i t u t e s (Table 2) shows a clear p a r a l l e l i s m b e t w e e n b o t h actions.

T h e r e is a significant c o r r e l a t i o n (r ~ --0.96, p < 0.005) b e t w e e n t h e fall in b l o o d p r e s s u r e a n d t h e rise in h i s t a m i n e c o n c e n t r a t i o n i n a r t e r i a l b l o o d following t h e infusion o f t h e different p l a s m a s u b s t i t u t e s (Fig. 3).

This c o r r e l a t i o n can be affected b y t h e ~ n t i h i s t a m i n i e N e c l a s t i n u m (Fig. 3). A c o r r e l a t i o n can also be shown b e t w e e n t h e rise in h i s t a m i n e levels a n d t h e fall in b l o o d pressure for e a c h i n d i v i d u a l g e l a t i n e p r e p a -

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r a t i o n . T h e c o r r e l a t i o n coefficient, r e l a t e d t o t h e n u m b e r of t e s t s per- f o r m e d , is for H a e m a c c e l , r = - - 0 . 7 6 (p > 0.05), for H a e m a e e e l - H , r ~- - - 0 . 9 7 (p < 0.01), for Gelifundol, r ~- - - 0 . 8 8 (p < 0.02) a n d for P h y s i o g e l , r ---- - - 0 . 7 2 (p < 0.2).

3. Inhibition o / t h e Hypolensive Reaction by Antihistaminies P r e - t r e a t m e n t o f t h e a n i m a l s w i t h t h e a n t i - h i s t a m i n i c N c e l a s t i n u m (0.1 m g / k g ) , while u n a b l e t o affect t h e f r e q u e n c y o f t h e h y p o t e n s i v e r e a c t i o n , d o e s r e d u c e t h e s e v e r i t y o f t h e fall in b l o o d pressure. T a b l e 3 shows t h e i n h i b i t o r y effect o f N e c l a s t i n u m on t h e H a e m a c c e l - i n d u c e d h y p o t e n s i o n . :

Table 3. Inhibitory effect o/Neclastinurs (0.1 rsg/kg) on the incidence and degree el hypotension ]ollowing the/irst and second step o/isovolemic hemodilution by 20 mg/kg Haersaccel. Hypotensive reaction: decrease el rsean arterial pressure > 10 mrs Hg.

(Mean values 4. S.D. /rots animals developing hypotensive reaction) First step of Second step of hemodilution hemodilution No pretrea~ment Index of animals developing 13/14 6/13

Pretreatment with Neclastinum before the first step of hemodilution

Pretreatment withNeclastinum before the second step of

hemodilution

hypotensive reaction

Decrease of mean arterial blood pressure [mm Jig]

Time of recovery of arterial blood pressure [sec]

Index of animals developing 5/6 4/5

Decrease of mean arterial blood 65.0 d: 14.8

pressure [mm Hg] (n ~ 5)

Time of recovery of arterial blood 428 4. 144

pressure [sec] (n = 5)

Index of animals developing 8/9 2/8

Decrease of mean arterial blood pressure [ram Hg]

Time of recovery of arterial blood pressure [see]

79.04.11.2 66.04-8.8 (n = 13) ( n = 6) 4 3 4 4 . 4 0 3 4 3 4 . 7 1 ( n = 13) (n = 6 )

21.34.4-4.3 ( n = 4 ) 1 8 0 4 . 6 4 ( n ~ 4 )

93.14.11.5 30.04.5.0 (n ⁼ 8) ( n = 2 ) 6764.t-165 1154.65

( n = 8) (n = 2 )

1. W i t h o u t p r e - t r c a t m e n t w i t h a n t i h i s t a m i n i c s 13 o u t o f 14 a n i m a l s d e v e l o p e d h y p o t e n s i o n w i t h a m e a n d e c r e a s e o f a r t e r i a l b l o o d p r e s s u r e o f 79.0 :J: 11.2 m m H g a f t e r t h e first d i l u t i o n . T h i s d r o p in b l o o d pressure was d i m i n i s h e d t o 66.0 :J: 8.8 m m t t g a f t e r t h e s e c o n d d i l u t i o n .

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Histamine Release as Cause of Acute Hypotension 441 P r e - t r e a t m e n t with the antihistaminic before the first step of dilution reduced the pressure drop observed after the first dilution from 79.0 ~: 11.2 only to 65.0-~ 1 4 . 8 m m H g , whereas there was a significant inhibition after the second dilution from 65.0 :j: 14.8 in the untreated to 21.3 :~ 4.3 m m Hg in the pre-treated animals (p < 0.01).

2. The fact t h a t this significant difference exists in spite of the small n u m b e r of animals in the different groups emphazises the activity of Nec]astinum at the dose used. P r e t r e a t m e n t with promethazine (0.5 mg/

kg) 10 rain before the exchange of blood b y Haemaccel reduced the fall in blood pressure b y an average of 20O/o in 4 out of 5 animals.

Discussion

The plasma substitutes in use today, based on gelatine or dextran, are pharmacologically investigated mainly in dogs. The use of gelatine solutions for infusion is particularly recommended b y some authors on the grounds t h a t their side effects are particularly few, and theft- thera- peutic index therefore very high (see Lundsgaard-Hansen et al., 1969).

However, the appearance of massive falls in blood pressure following the administration of the gelatine solutions in clinical use has been re- ported (Meise] and Zoeck]er, 1970; Schmidt, 1970).

Severe circulatory disturbances are known to have occurred following the administration of the earlier macromolecular polymers (Giertz and Hahn, 1966; H a h n and Wellmann, 1952; Walton et al., 1959); we sought to elucidate in this series of experiments the cause of the severe depression of blood pessure observed following the administration of gelatine, and to ascertain whether such reactions have a n y consequences for the clinical use of the gelatine preparations investigated.

The reactions following the infusion of the macromolecular polymers are usually attributed to antigen-antibody reactions, which can result in a fall of blood pressure due to liberation of histamine, serotonin and or kinins. Since modern gelatine preparations are free from antigenicity (see Lundsgaard-Hansen et al., 1969; Schwick and Heide, 1969), and since this series of experiments has demonstrated a dose-response rela- tionship, the circulatory disturbances observed in the dogs cannot be attributed to anaphylactic reactions. Since, again, in some tests there was neither a fall in the blood kininogen levels nor a rise in free kinins in the blood, nor did the infusion of soyabean inhibitor exert a n y effect on the hypotension (Messmer et al., 1969), the fall in blood pressure seen following the infusion of gelatine solutions p r o b a b l y cannot be inter- preted as the result of the liberation of kinins b y hemodihition.

Walton et al. (1959) showed a rise in histamine in the blood following the infusion of a n u m b e r of the older plasma substitutes, including a 3.5 ~ gelatine solution (p]asmoid, Upjohn) ; therefore the question must

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be investigated as to whether modern gelatine preparations also liberate endogenous histamine.

The results obtained in this study indicate t h a t oxypolygelatine, reticulated gelatine and modified fluid gelatine are chemical liberators of mast cell histamine. The points which support this are: 1. following the rapid infusion of these solutions--though not fo]lowing infusions of Dextran 60 and NaC1 solution--the blood histamine level rises signifi- cantly. The specificity of the method used for the estimation of histamine cannot be questioned, since both qualitative and quantitative identification of histamine was carried out by thin-layer chromatography, enzymatic breakdown, biological tests and the inhibition of biological activity by antihistaminics (Lorenz et al., 1970, 1970a). Furthermore, histamine release from non-mast cell stores does not result in highly elevated histamine concentrations in the blood (Ivy and Bachraeh, 1966).

2. The increase in the histamine concentration in the whole blood of dogs was observed only when a hypotensive reaction took place;

thus, the taehyphylaxis against the hypotensive reaction due to gelatine also favorizes the concept of a liberation of mast cell histamine. Tachy- phylaxis is regarded as characteristic for liberators of mast cell histamine (Feldberg and Talesnik, 1953).

3. Finally, the circulatory effect can be counteracted by anti-hist- aminics. At the dose employed, the anti-histaminic counteracted the hypotensive effect, but not the histamine-liberating effect (see Fig.3);

this is best explained as a blockade of histamine receptors whereas histamine liberation is remaining unaffected.

The histamine-liberating effect of gelatine solutions appears to be independent of the concentration and molecular weight distribution of the gelatine solution. Following infusions of F B b 4047 (Bayer), the solution with the highest concentration of gelatine and the highest average molecular weight, no increase in blood histamine levels was observed;

on the other hand, significant differences in histamine-releasing activity exist between different gelatine preparations with a lower average molecular weight. T h e y present, however, differences in their chemical structure (oxypolygelatine, modified fluid gelatine, gelatine cross-linked by urea-bridges). The circulatory changes observed following the rapid infusion of gelatine solutions cannot be quantitatively induced by equivalent doses of exogenous histamine, since the hemodynamic activity of endogenous histamine exceeds t h a t of equivalent doses of exogenous histamine (Baker, 1966). The analogous behaviour of the blood histamine levels and the arterial blood pressure, and the ability of anti-histaminies to inhibit the reaction, however, suggest a direct action of histamine on the circulation. This interpretation is supported b y the following facts:

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Histamine Release as Cause of Acute Hypotension 443 1. The coincidence in time of maximal fall in blood pressure and maximal histamine concentration;

2. the highly significant correlation between the degree of fall in blood pressure and the rise in histamine concentration; and

3. the observation of comparable circulatory changes following the use of other chemical histamine liberators, such as compound 48/80, P V P and Tween 20, in the dog (Brashear et al., 1969; Goth et al., 1951).

For these reasons, the hypotensive reaction observed following the infusion of gelatine solutions in the dog must be attributed to the circulatory effect of liberated endogenous histamine. Histamine causes a dilatation of the precapillary sphincters and arterioles (Baker, 1966;

Diana et al., 1968; I t a d d y , 1960), and a constriction of post-capillary veins, and in the dog affects particularly the hepatic and the lungs circulation (Baker, i966; Brody and Stemmler, 1968; Storstein et al., 1959).

The resulting reduction in venous return (Deyrup and Root, 1947;

Emerson, 1968; Messmer, 1970; Storstein et al., 1959), together with a simultaneous reduction in cardiac output, will intensify the fall in blood pressure recorded in the experiments in this series.

Various chemical liberators are known to possess a strong species specificity (Giertz and Hahn, 1966; Masson et al., 1958), and it must therefore be shown whether the gelatine preparations investigated cause a liberation of histamine in other species, too. Because of its clinical implications, this investigation was carried out in h u m a n volunteers, and following the infusion of Haemaecel a significant increase in plasma histamine levels was observed (Lorenz et al., 1970c). This shows t h a t the histamine-liberating effect of gelatine is not specific for the dog. This findings has clinical consequences for man, which will be dealt with in a further communication (Lorenz et al., in preparation).

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Priv.-Doz. Dr. Konrad Mel]mer Institut fiir Experimentelle Chirurgie an dcr Chir. Univ. Klinik D-8000 l~f/inehen 15, NuBbaumstr. 20