Research in

Experimental Medicine

Res. Exp. Med. (Bed.) 175, 117--121 (1979)

© Springer-Verlag 1979

The Effects of Intra-arterially Administered Histamine on Vascular Permeability D. Engel Department of Physiology, University of Zurich, CH-8044 Zurich, Switzerland

Summary. The influence of intra-arterially administered histamine on the permeability of the articular barrier (synovial membrane plus vascular endothelium) was studied in cats. The dye penetration from the blood through the barrier was tested by perfusing the two knee joints with saline; the histamine solution was infused through one of the circumflex branches of the femoral artery. The dye content of the two perfusates was measured colorimetrically, the local blood supply of the two knee joints thermo-electrically. In the great majority of experiments it was found that the dye excretion was considerably reduced on the histamine-infused side, in spite of marked improvement of blood supply. Key words: Histamine - Vascular permeability Zusammenfassung. Die Wirkung von intraarteriell verabreichtem Histamin auf die Permeabilit/it der Gelenksbarriere (Synovialmembran + Geffil3endothel) wurde an Katzen untersucht. Die Penetration yon Farbstoffen aus dem Blut durch die Barriere wurde mittels Perfusion der beiden Kniegelenke mit normaler Kochsalz16sung gepriift; die Histaminl6sung wurde durch die A. circumflexa femoris verabreicht. Die Farbstoffkonzentration der beiden Perfusate wurde kolorimetrisch, die lokale Blutversorgung der Gelenke thermoelektrisch gemessen. Die tiberwiegende Mehrzahl der Versuche ergab, dab die Farbstoffausscheidung der mit Histamin behandelten Seite, trotz der bedeutend verbesserten Blutversorgung, stark herabgesetzt war. Schliisselwiirter: Histamin - vaskul~ire Permeabilit/it

The influence of the sympathetic nervous system on capillary permeability was studied in previous experiments (Engel, 1941, 1973, 1978). The dye filtration through the articular barrier (synovial membrane + capillary endothelium) was Offprint requests to: Dr. D. Engel M.D., F.R.C.S. (Edin.), Voltastr. 64, CH-8044 Zurich

0300-9130/79/0175/0117/$1.00

118

D. Engel

tested b y perfusing two knee joints, one o f which was d e p r i v e d o f its s y m p a t h e t i c nerve s u p p l y b y u n i l a t e r a l l u m b o s a c r a l s y m p a t h e c t o m y . D e s p i t e m a r k e d v a s o d i l a t a t i o n , the dye p e n e t r a t i o n into the perfusate was f o u n d to be c o n s i d e r a b l y r e d u c e d on the s y m p a t h e c t o m i z e d side. It was, therefore, t h o u g h t to be o f interest to investigate w h e t h e r vascular d i l a t a t i o n p r o d u c e d i n d e p e n d e n t l y o f the s y m p a t h e t i c nervous system is f o l l o w e d b y decreased p e r m e a b i l i t y . In the p r e s e n t experiments the v a s o d i l a t a t i o n was p r o d u c e d b y i.a. a d m i n i s t e r e d histamine.

Methods Adult male and female cats of 2--5 kg were anesthetized with Nembutal 50mg/kg. Operation. Through an incision of 10 cm the femoral artery and its lat. circumflex branch is dissected out and this branch is ligated 12--14 mm distal to its junction with the femoral a. After temporary compression of the main artery a fine plastic tube is introduced and ligated into the circumflex a., avoiding the lumen of the femoral a. The histamine is injected through this tube after the knee perfusion is started. The same procedure is followed on the other extremity with the difference that the circumflex a. is not intubated, but only ligated (no histamine infused). Measuring the Rate of Dye Filtration Through the Articular Barrier. A highly diffusible dye, acid fuchsin (20--50ml aq. sol.according to weight) was injected i.m. or i.v., 1 h before the perfusion. The two knee joints were perfused with normal saline. For this purpose an Unitas perfusor (Braun) was used. See details of perfusion in my previous papers (Engel, 1978). The perfusates were Separately collected from the two knees every 15--20min and their dye content measured by a Leitz colorimeter or a spectrophotometer (Varian, 635 UV-visible), after adding 1--2 drops of 2% acetic acid to the perfusates. Measuring the Muscular Temperature. This was done by inserting thermocouple needles of Labhart (Basel), 5--6cm deep into the two quadriceps muscles, avoiding entering into the joints. The muscular temperatures rose by 1 to 21/2°C within 1 min after the i.a. histamine injections. Drugs Used. Histamine dihydrochloride 1%0 (Gattiker) in dilution and quantities indicated in Table 1 was injected into the circumflex artery at intervals of 10--30min. The quantities of histamine injected varied between 30 and 250 ~tg (average 113.42 ~tg) in 19 cats; in only one cat it amounted to 1500~tg. The durations of the i.a. injections varied between 25 and 140rain (average 85 min) including the intervals. In three cats acetylcholine (BDH) 10 y/ml was injected i.a. in the same way as the histamine in the other animals.

Results The t o t a l results will be given in T a b l e 1 a n d one representative e x p e r i m e n t will be s h o w n in F i g u r e 1. O f 20 cats injected with histamine, 17 excreted less a n d three excreted more, o f the i.v. o r i.m. a d m i n i s t e r e d dye, f r o m the h i s t a m i n e - t r e a t e d side t h a n f r o m the c o n t r o l side. O f the 17 cats with d e c r e a s e d dye excretion, 13 h a d a higher q u a d r i c e p s t e m p e r a t u r e on the h i s t a m i n e - t r e a t e d side t h a n on the c o n t r o l side; in two there was no m a r k e d difference between the two sides a n d in two the t e m p e r a t u r e was n o t taken.

Intra-arterial Histamine and Vascular Permeability

119

Table 1. It is shown that the dye excretion through the synovial membrane of the histaminetreated side was less in 17 cats and more in 3, as compared to the control side (column 4}. At the same time, the quadriceps temperature of the histamine-treated side was unchanged only twice, and in all other cases it was higher than on the control side (column 6). The ratio of excreted dye quantity of the two sides shown in column 5 No.

Histamine gg injected

Duration of injection of histamine in min

Dye-excretion of histamineside compared with control

Ratio of dye excretion Histam Control ~, side ~

Quadriceps temperature of histamine side compared with control side

1

200

140

less

1

: 2

more - - 0.5°C

2 3 4 5

100 150 30 75

80 120 50 120

less less less less

1 1 1 1

: 2.55 : 1.9 : 3 : 4

more - - I°C more - - 1.4°C unchanged m o r e - - 0 . 5 °C

6 7 8 9

150 150 100 85

120 90 100 80

less more less less

I 2 1

: 2.66 : 1 : 2

more more - - I°C

10

100

110

less

1

: 2

11 12 13

75 175 75

70 90 140

less less less

1 1 1

: 2.5 : 2 : 1.5

m o r e - - 0 . 7 °C m o r e - - I°C

14 15 16 17

250 90 1500 50

100 45 1O0 25

less less more less

1 1

: 2 : 2

1

: 4

more - - 3.5°C m o r e - - 1.1°C no change m o r e - - 1 °C

18 19 20

100 200 100

30 60 30

less more less

1 2 1

: 2 : 1 : 2

more - - I°C less--0.5 °C more - - 1.5°C

bilateral more

O f the t h r e e cats w i t h i n c r e a s e d dye e x c r e t i o n o n the h i s t a m i n e - t r e a t e d side, t h e q u a d r i c e p s t e m p e r a t u r e was h i g h e r in o n e , l o w e r in o n e a n d e q u a l in o n e as c o m p a r e d to the c o n t r o l side. F r o m t h e s e figures it a p p e a r s t h a t in a s i g n i f i c a n t l y h i g h p r o p o r t i o n o f a n i m a l s the i.a. injection of histamine improved the blood supply and simultaneously

decreased the dye excretion through the articular barrier. Since the a d m i n i s t r a t i o n o f h i s t a m i n e in o u r e x p e r i m e n t s was n o t a p e r m a n e n t o n e , b u t was i n t e r r u p t e d by several i n t e r v a l s o f 1 0 - - 3 0 m i n , it was to s o m e e x t e n t p o s s i b l e to j u d g e t h e d u r a t i o n o f t h e h i s t a m i n e e f f e c t . T h i s l a s t e d m o s t l y 15--30 min and caused more temperature--than dye e x c r e t o r y c h a n g e s . O n e g a i n e d t h e i m p r e s s i o n t h a t t h e effect o n the l a t t e r h a d m o r e o f a c u m u l a t i v e c h a r a c t e r . A t y p i c a l e x p e r i m e n t is s h o w n in F i g u r e 1, i l l u s t r a t i n g the n o n c o n f o r m i t y o f the t w o f a c t o r s , the dye e x c r e t i o n o f the t w o k n e e j o i n t s o n the o n e h a n d a n d the q u a d r i c e p s m u s c l e t e m p e r a t u r e s o n the o t h e r ; viz. i n c r e a s e d

120

D. Engel 31 • -.

E-

m---m-_ n..

-m

"-.

20 ~

~ 29

8 E ._o

5

i 1 i 2 i 3 i z,I

ix,,

Fig. 1. It is shown in a single, typical case the divergence of the two factors, blood supply and dye excretion: increased quadricepstemperature m--m with simultaneous low dye excretion rn----• of the histamine-treated side; and low temperature A---A with simultaneous high dye-excretion zx----zx of the control side. The dye excretion is measured in ram, as read by colorimeter, the arrows indicate time of histamine injection into one circumflex 5 i 6 I 7 I 8 I 9 I artery

Time in periods of 20 minutes

quadriceps temperature with simultaneous low dye excretion of the histaminetreated side, and decreased temperature with simultaneous high dye excretion of the control side. In the three cats, in which acetylcholine was injected, i.a. instead of histamine, the response with regard to dye excretion and quadriceps temperature was similar to that of the histamine cats, but was less pronounced.

Discussion

Histamine proved, in the present experiments, a powerful vasodilator, as manifested by the p r o m p t temperature increase of the muscles around the perftlsed knee joints. Measuring the blood supply by our thermocouples proved to be adequate, since the needles were separated only by a few millimeters from the suprapatellar bursa, quasi part of the knee joint. The experimental results concerning the histamine effect on vascular permeability were contradictory during the last few years. Richardson (1974) infused i.v. histamine in doses up to 10gg-lmin -1, producing a fall in capillary filtration coefficient (CFC) in cats intestines, and a rise in blood flow. He assumed that CFC is independent of blood flow, or regional vascular resistance. Marciniak et al. (1977) infused histamine base into the brachial artery of dogs and produced edema of the forelimb. In contrast, histamine by i.v. infusion caused fluid reabsorption. Grega et al. (1972) found with similar experimental arrangements an increase in vascular permeability after i.a. infused histamine (5 gg/min) and vascular fluid reabsorption on i.v. infusion of 40--60 lag/min histamine.

Intra-arterial Histamine and Vascular Permeability

121

The question as to w h e t h e r the m e c h a n i s m o f decreased v a s c u l a r p e r m e a b i l i t y c a u s e d b y s y m p a t h e c t o m y (Engel, 1941, 1978) a n d that caused b y h i s t a m i n e injected i.a. are identical, could n o t be answered. In b o t h cases it a p p e a r s that an i n c r e a s e d b l o o d s u p p l y is a s s o c i a t e d with decreased vascular p e r m e a b i l i t y .

Acknowledgements. Thanks are due to Prof. Dr. R. Hunsperger and Prof. Dr. E. A. Koller for their hospitality and interest taken in my work and to Dr. Kohl for her technical help.

References 1. Daugherty, R. M., Scott, J. B., Emerson, T. E., Haddy, F. J.: Comparison of intra-venous and intra-arterial infusion of vasoactive agents on dog forelimb bloodflow. Am. J. Physiol. 214, 611 (1968) 2. Deyrup, I. J.: Circulatory changes following s.c. injection of histamine in dogs. Am. J. Physiol. 142, 158--172 (1944) 3. Diana, J. N., Schwinghamer, J., Young, S.: Direct effect of histamine on arterial and venous reSistance in isolated dog hind limbs. 214, 494--505 (1968) 4. Engel, D.: The influence of sympathetic nervous system on capillary permeability. J. Physiol. 99, 161--181 (1941) 5. Engel, D.: Die Permeabilit~t der Synovialmembran entzfindeter Gelenke. Z. Rheumaforschung 32, 212--220 (1973) 6. Engel, D.: The influence of the sympathetic nervous system on capillary permeability. Res. exp. Med. 173, 1--8 (1978) 7. Grega, G. J., Dobbins, D. E., Parker, P. E., Haddy, F. J.: Effects of intravenous histamine on forelimb weight and vascular resistance. Am. J. Physiol. 223, 353--360 (1972) 8. Grega, G. J., Kline, R. L., Dobbins, D. E., Haddy, E. J.: Mechanism of edema formation by histamine administered locally into canine forelimb. Am. J. Physiol. 223, 1165--1171 (1972) 9. Haddy, F. J., Scott, J. B., Grega, G. J.: Effects of histamine on lymph protein concentration and flow in the dog forelimb. Am. J. Physiol. 223, 1172--1177 (1972) 10. Marciniak, D. L., Dobbins, D. A.: Effects of systematically infused histamine on transvascular fluid and protein transfer. Am. J. Physiol. 233, 148--153 (1977) 11. Richardson, P. D. I.: Drug-induced changes in capillary filtration coefficient and blood flow in innervated small intestine of anaesthetized cats. Br. J. Pharmacol. 52,481--498 (1974) 12. Rocha e Silva: Histamine chemistry, metabolism, pharmacological actions. Hdb. Pharmaco1., XVIII. Springer 1966 Received October 9, 1978 / Accepted February 2, 1979