THE EFFECT OF HISTAMINE ON THE ACID-BASE BALANCE.*

BY ALMA HILLER.

(From the Hospital of The Rockefeller Institute for Medical Research, New York.)

(Received for publication, April 23, 1926.)

Dale and his collaborators (6, 14-18, 44) have shown that the more striking and clinically important effects following injection of histamine into cats and dogs resemble those of traumatic and surgical shock; viz., oligemia due to loss of plasma from the circu- lation through the capillary walls, relaxation of the capillary bed, fall of blood pressure, etc. The parallelism appears sufficient to make an understanding of the various effects of histamine injec- tion desirable as part of the general knowledge concerning the nature of shock.

We have accordingly studied one phase of the picture of hista- mine shock; viz., the acid-base balance, a factor which has been found to be severely disturbed in traumatic shock and in some conditions which simulate it.

Fall of the carbon dioxide content of the blood and plasma ap- pears to have been regularly observed in most of the types of shock that have been studied (6, S-12,21,24-26,30-33,37,38,40). Such a fall can be caused either by hyperpnea, with blowing off of CO2 from the blood, and a resultant H&O3 deficit, or by acidosis caused by decomposition of blood bicarbonate by invading acids. In the former case the alkalinity of the. blood, in terms of pH, is increased, in the latter it is usually diminished. Y. Henderson (30) at first considered the acid-base condition and chief causative factor in traumatic shock to be carbon dioxide deficit. Most other investigators have interpreted the condition as one of acido-

* Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Faculty of Pure Science of Columbia Uni- versity.

833

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834 Histamine and Acid-Base Bala‘nce

sis. In a few cases this interpretation has been confirmed by pH determinations in the blood plasma. Guthrie in traumatic shock caused in various ways (26), and Menten and Crile after manipula- tion of the intestines (39) observed a fall in plasma pH. Witt- kower (53) and Zunz and La Barre (54) reported lowered plasma pH in anaphylactic shock in guinea pigs. De Waele reported increased plasma pH in shock caused by peptone injections in dogs (20).

It appears that in traumatic shock there is a condition of true acidosis, with lowering of both bicarbonate and pH in the blood plasma. As Dale (14) has pointed out, the acidosis is a conse- quence rather than a cause of the shock symptoms; they do not result from acidosis of the degree observed. However, dislocation of the acid-base balance, even though it does not play a dominant rBle in producing the symptoms, forms a frequent, if not a constant part of the disturbances involved, and must be considered in any attempt to draw the entire picture.

Reports of the effect of histamine shock on the acid-base balance have been conflicting. Wallace and Pellini (51) found that histamine injected subcutaneously caused an increase in plasma bicarbonate, but when injected intravenously under ether anes- thesia caused a fall. Underhill and Ringer (45) concluded that the carbon dioxide content of the blood was not lowered as much by histamine as in other forms of shock. Hashimoto (27) found no consistent change in-the plasma COZ content during histamine intoxication.

EXPERIMENTAL.

Dogs weighing between 11 and 16 kilos were used. They were fasted for 24 hours before the injection of histamine. The bladder was emptied by catheterization and a sample of blood was drawn just before the injection. Histamine was then injected sub- cutaneously, in varying amounts, and the acid-base balance was studied over a period of 6 hours thereafter, by means of blood and urine analyses. Blood was drawn by venepuncture at intervals, and the urine was collected by catheterization at the end of the 6 hour period.

Control experiments were performed, in which the acid-base balance was studied during a similar 6 hour period after a 24 hour

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TABL

E I.

Cont

rol

Expe

rimen

ts.

6 Ho

ur

Perio

ds

follo

wing

2.

4 Ho

ur

Fasts

.

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d.

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e.

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ll 2

P1zY

cm

&t.

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lWS.

vol.

vol.

per

cent

pe

r ce

nt pe

r ce

nt

Begin

ning

of 6

hrs

. 29

.8

End

“ 6

“ 36

.8

Begin

ning

of 6

hrs

. 7.

25

35.0

En

d “

6 “

7.25

37

.5

Begin

ning

of 6

hrs

. En

d “

6 “

Begin

ning

of 6

hrs

. 7.

42

41.9

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(j “

7.40

44

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ning

of 6

hrs

. 7.

36

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43

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ning

of 6

hrs

. 7.

25

57.4

t 38

.5

End

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“ ,

7.33

63

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34.0

Begin

ning

of 6

hrs

. 7.

35

56.0

34

.0

End

“ 6

“ 7.

31

55.8

34

.3

Begin

ning

of 6

hrs

. 7.

32

58.6

27

.0

End

‘I 6

“ 7.

31

59.8

28

.0

- _ - .- - - -

cc.

72

36

67

85

56

81

61

97

Urine

.

Body

we

ight

.

kg.

11.7

5

11.7

5

11.5

11.5

11.5

15.5

15.7

15.7

-

r

_ .

-

l’itr$

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NHa

cc.

0.1

N

78.5

cc.

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N

104

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56

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-- -- __

27

P

-x 37

E %

31.4

32

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41

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34

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5.60

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TABL

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Ex

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of 6

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.

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re

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7.34

5

min.

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40

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29

6 hr

s. “

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re

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38

m

in.

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15 m

in.

afte

r. 45

“

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hr

s. “

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6 “

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7.27

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19

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7.

30

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PH

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ent

No

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e 2

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tent.

vol.

per

cent

65

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59.3

64

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60.9

58.4

51

.0

46.9

51

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55.8

39

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56.6

(45.

2).

(41.5

) (3

3.6)

(42.

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(50.4

) (4

5.7)

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r ce

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r ce

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r cm

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cc.

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34

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42

42

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33

33

246

246

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5 6

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838 Histamine and Acid-Base Balance

fast, when conditions were the same as on days when histamine was injected. In two of the control experiments the bladder was washed with boric acid (pH 5.2) after catheterization, as indicated in Table I. In all other experiments the bladder was washed with sterile 0.9 per cent saline solution. Precautions

-Y “” 5 z $50

2 E E?

40

s 30

FIG. 1. FIGS. 1 and 2. Variatio,ns in acid-base balance of plasma after hista-

mine injection. The numbers on the curves indicate the number of the experiment in Table II, and are placed at the site of the preinjection estima- tions. The arrows indicate the direction taken during the course of the 6 hour period of each experiment.

were taken with regard to asepsis in the process, in order to pre- vent bladder infection and its effect on the reaction of the urine. Control days were interspersed between injection days as a further check on this factor.

No anesthetics were used, because anesthesia increases ap-

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Alma Hiller 839

proximately ten-fold the shock produced by histamine on the organism (15) and also causes acidosis (3).

The acid-base balance was studied by determination of COz and pH in the blood plasma, and of pH, titratable acid, and am- monia in the urine.

Preparation of Histamine Solution for Injection.-A Burroughs Wellcome and Company product, “ergamine,” which is a prepara-

20 20

7x3 7x3 7.7 7.7 '1.6 '1.6 75 75 74 74 73 73 7.2 7.2 PH PH

FIG. FIG. 2. 2.

7.0

tion of histamine acid phosphate, was used. Analysis of this prod- uct indicated one-third of it to be histamine base. 0.4000 gm. of ergamine was dissolved in 0.9 per cent solution of sodium chloride, 0.128 gm. of sodium hydroxide was added to neutralize the phos- phoric acid, and the solution was diluted to a volume of 20 cc. The pH of the solution was determined and was usually found to be 7.4. If it was not, the reaction was adjusted to 7.4. This solution was freshly prepared for each injection. 1 cc. contained

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840 Histamine and Acid-Base Balance

6.66 mg. of histamine base. All data are given in mg. of histamine base injected per kilo of body weight.

Methods.

Blood.-Blood samples were drawn from the jugular vein and collected under oil. Samples were taken as soon as possible for analyses. The pH of the blood plasma was estimated by the method of Cullen (13j. The COz content of the blood or plasma was estimated by the method of Van Slyke (49, 50). In those cases in which the CO2 content of the plasma was not determined directly, it was calculated from the COz content of whole blood and the oxygen capacity by the formula of Peters, Bulger, and Eisenman (43). Hemoglobin was estimated by the calorimetric method of Palmer (41) and sometimes also by the gasometric method of Van Slyke (46). The cell volume was determined by means of the hematocrit.

Urine.-The pH of the urine was estimated by the method of Henderson and Palmer (29), with changes in the indicators used.’ The standard tubes were made up with ranges overlapping for the different indicators, as designated below.

pH range. Methyl red. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4-6.0 Brom-cresol purple.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2-6.8 Phenol red.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.8-8.4 Cresol “ . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,. . . . . . . . . . . . . ‘7.2-8.8

The titratable acidity of the urine was estimated by the method of Folin (22), the ammonia by the aeration technique of Van Slyke and Cullen (48).

DISCUSSION.

The control experiments, Table I, showed in only one case variations in plasma pH exceeding the limit of experimental error. In this animal there was an increase of 0.08 pH during the 6 hour period.

Injection of histamine (up to 3 mg. per kilo), Table II, caused a variable fall in both pH and COz content of the plasma, indicat-

1 The recent method of Hastings, Sendroy, and Robson (28) had not yet been devised.

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Alma Hiller

ing an uneampensated acidosis. The maximum drop in plasma CO, content was 16.5 volumes per cent in Experiment 3, Table II. The diminutions in pH and COz content did not always run paral- lel. In Experiment 6, Table II, the CO2 changes were slight, while the pH fell 0.20 but returned to the initial level more rapidly than some of the others. In Experiment 5 the CO2 fell 11.9 volumes per cent in the blood while the pH fell only 0.05. In Experiment 3 the falls in COz and pH were parallel, but the CO2 had returned to normal in 6 hours while the pH had not yet re- turned to the initial level.

If the COz is reduced primarily by overventilation the blood reaction swings to the alkaline side (19). Overventilation sufficient to cause an alkalosis from CO2 deficit can be brought about in man by hot baths (5) and by subjection to lowered barometric pressure (34). The urine in these conditions has a high pH, and the acid excretion and ammonia output are low.

An examination of the urine after histamine injection showed high pH, in all the cases above 7.0, accompanied by a diminished ammonia output and a low excretion of titratable acid, compared with that of the normal control periods (Tables I and II).

From the findings in the blood alone, the condition appears to be one of acidosis. From the findings in the urine alone, the condition would readily be pronounced an alkalosis.

Charting the acid-base findings in the blood according to the method of Van Slyke (47) indicates that histamine shock shows a tendency towards an uncompensated alkali deficit, with final return to the preinjection condition (Figs. 1 and 2). The direction of the arrows in the charts indicates metabolic acid formation rather than a primarily respiratory change. The overproduction of non-volatile acid would cause normally an increased excretion of titratable acid and ammonia. The fact that the reverse occurs indicates a failure of the kidneys to respond to the threat of acidosis in a normal manner.

Experiments 2 and 3, Table II, show a definite tendency to diuresis, as compared with the controls. It is known that hista- mine injection increases the flow of the salivary, gastric, and pancreatic secretions, but it has not yet been shown that it in- creases excretion by the kidney. The diuresis may be due to the increased concentration of urea in the blood which has been

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842 Histamine and Acid-Base Balance

shown as a result of histamine injection in the accompanying paper (35).

A factor which would influence the acid-base equilibrium in histamine shock is the effect of histamine on gastric secretion. Ackman (1) showed, by injection of very small quantities of hista- mine (0.5 mg.) in human subjects, a marked increase in acid secre- tion in the stomach accompanied by an increase in the pH of the urine. Hashimoto (27), who gave larger injections of histamine to dogs, found an increased COz capacity of the blood in only a few cases, despite the fact that his dogs all vomited as a result of the injection, and would therefore be expected to lose an even greater amount of HCl. He made no examination of the urine for acidity, but it is apparent that the kidney must have been excreting the excess alkali, or other metabolic changes were occurring to com- pensate the gastric effect. In the present report, dogs were used which showed a fairly good tolerance for histamine, and each was given a single small dose, so that in no case was there any vomiting, and the complications in acid-base balance of gastric origin were kept down as much as possible.

Another factor which might influence the acid-base balance in these experiments is exercise. Although the animals were kept as quiet as possible during the period of the experiment, there was in all cases a struggle just after the injection of histamine. A fall in CO2 capacity and pH of the blood after short vigorous exer- cise has been reported by Arborelius and Liljestrand (2), and by Barr, Himwich, and Green (4), and a lowered COz content has been found by Lundsgaard and Moller (36). Buell (7) found that when an animal struggled during an experiment the alkali reserve of the blood decreased. The urine during muscular exercise was found by Wilson, Long, Thompson, and Thurlow (52) to show an immediate increase in hydrogen ion concentration, acid, and ammonia excretion, with a return to normal values within 40 to 90 minutes after 1 or 2 minutes of exercise. The blood find- ings after histamine injection changed in the same direction, indicating acidification, as after exercise, but the urine examina- tion showed the opposite results. If exercise had an effect on the acid-base balance in these experiments, it was overshadowed by other factors simultaneously at work.

There was in some of our experiments a considerable loss of

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Alma Hiller 843

alkali in the urine. Gamble (23) has shown that the CO2 tension and H&O3 concentration of urine approximate those of the arterial blood plasma. Hence the bicarbonate content of the urine can be estimated by the Henderson-Hasselbalch equation,

BHC03 pH = 6.1 + log HCO. If the HzCOs concentration is taken as

4.2 volumes per ceit, in average normal value (23), the BHCOI would be 42 volumes per cent at pH 7.1, 84 volumes per cent at pH 7.4, 167 volumes per cent at pH 7.7, and 334 volumes per cent at pH 8.0. Doubtless the loss of bicarbonate through the urine was of some influence in creating the bicarbonate deficit in the plasma. However, the changes in the blood occurred so rapidly, reaching their maximum sometimes in a half hour, that excretion of alkali could hardly have been the main cause of the fall in plasma bicarbonate and pH. Even the bicarbonate output during the total period is not sufficient to account for much of the fall in plasma bicarbonate. In Experiment 4, Table II, the bi- carbonate output was highest, because of the combined high urinary volume (100 cc.) and high pH (7.9). The bicarbonate content of such a urine would be about 265 volumes per cent, and its loss would occasion a fall of 11.6 volumes per cent COz (that observed in plasma) in 2285 cc. of fluid. However, the fluid content of an animal of 11.5 kilos weight would be about 8 liters. Palmer and Van Slyke (42) have shown that bicarbonate changes in the body are distributed with some approximation to evenness throughout the body fluids. The observed bicarbonate output distributed over 8 liters, would cause a fall of only 3.3 volumes per cent COz compared with the 11.6 volumes per cent fall observed.

SUMMARY.

Injection of histamine into dogs, in doses of 1 to 3 mg. per kilo, caused a fall of 5 to 16.5 volumes per cent in plasma COa, and a fall of 0.05 to 0.20 in plasma pH. The result is therefore a mild uncompensated acidosis, due to invasion of acid or loss of base in the blood.

The alkalinity of the urine excreted after histamine injection, reaching pH 7.1 to 8.0, was high compared with 5.4 to 6.9 before the injections. The kidneys failed to respond normally to the

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Histamine and Acid-Base Balance

internal change towards acidosis by increasing their acid output. The increased output of bicarbonate in the urine was a factor, but not the main one, in depressing the bicarbonate content of the blood.

BIBLIOGRAPHY.

1. Ackman, F. D., Canad. Med. Assn. J., 1925, xv, 1099. 2. Arborelius, M., and Liljestrand, G., &and. Arch. Physiol., 1923, xliv,

215. 3. For a bibliography of the effect of anesthesia on acid-base balance see:

Atkinson, H. V., and Ets, H. N., J. Biol. Chem., 1922, lii, 5. Van Slyke, D. D., Austin, J. H., and Cullen, G. E., J. Biol. Chem., 1922, liii, 277. Collip, J. B., Brit. J. Exp. Path., 1920, i, 282. Raymund, B., Am. J. Physiol., 1920, liii, 109. Carter, W. S., Arch. Int. Med., 1920, xxvi, 319. Henderson, Y., and Haggard, H. W., J. Biol. Chem., 1918, xxxiii, 345. Leake, C. D., Leake, E. W., and Koehler, A. E., J. BioZ. Chem., 1923, lvi, 319. Koehler, A. E., J. BioZ. Chew, 1924-25, lxii, 435. Cullen, G. E., Austin, J. H., Kornblum, K., and Robinson, H. W., J. BioZ. Chem., 1923, lvi, 625. Stehle, R. L., and Bourne, W., J. BioZ. Chem., 1924, lx, 17.

4. Barr, D. P., Himwich, H. E., and Green, R. P., J. BioZ. Chem., 1923, Iv, 495.

5. Bazett, H. C., andHaldane, J. B. S., J. Physiol., 1921, Iv, p. iv. Cajori, F. A., Crouter, C. Y., and Pemberton, R., J. BioZ. Chem., 1923, lvii, 217. Koehler, A. E., Arch. Int. Med., 1923, xxxi, 590. Haggard, H. W., J. BioZ. Chem., 1920, xliv, 131.

6. Brit. Med. Research Comm., Special Rep. Series No. 65, 1919. ‘7. Buell, M. V., J. BioZ. Chem., 1919, xl, 29. 8. Cannon, W. B., J. Am. Med. Assn., 1918, lxx, 531, 611. 9. Cannon, W. B., Compt. rend. Sot. Biol., 1918, lxxxi, 850.

10. Cannon, W. B., Brit. Med. Research Comm., SpeciaZ Rep. Series No. 25, 1919, 85.

11. Cannon, W. B., Am. J. Physiol., 1918, XIV, 544; J. Am. Med. Assn., 1919, lxxiii, 174.

12. Cattell, McK., Arch. Surg., 1923, vii, 96. 13. Cullen, G. E., J. BioZ. Chem., 1922, Iii, 501. 14. Dale, H. H., The Harvey Lectures, 1919-20, xv, 26. 15. Dale, H. H., Brit. J. Ezp. Path., 1920, i, 103. 16. Dale, H. H., and Laidlaw, P. P., Brit. Med. J., 1917, i, 381. 17. Dale, H. H., and Laidlaw, P. P., J. Physiol., 1918-19, hi, 355. 18. Dale, H. H., Laidlaw, P. P., and Richards, A. N., Brit. Med. Research

Comm., Special Rep. Series No. $6, 1919, 8. 19. Davies, H. W., Haldane, J. B. S., and Kennaway, E. L., J. Physiol.,

1920, liv, 32. Collip, J. B., and Backus, P. L., Am. J. Physiol., 1920, li, 568. Grant, S. B., and Goldman, A., Am. J. Ph ysiol., 1920, hi, 209.

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