THE INFLUENCE OF MORPHINE AND PHENOBARBITAL ON THE BLOOD CONTENT OF ACETONE-BODIES IN NORMAL RABBITS*

Jap. J. Pharmacol. 1, 79 (1952) THE

INFLUENCE

BLOOD

OF MORPHINE

CONTENT

AND

PHENOBARBITAL

OF ACETONE-BODIES

IN NORMAL

ON

THE

RABBITS'

SHUBOKU KYO Department of Pharmacology, Kyoto Prefectural Medical College, Kyoto Received for publication September 4, 1951 It is led to the effect that of function

and intermediary

of hunger,

increase

avitaminostic

Acute chloroform

that

effect brings

of each kind are

mediary

run of metabolism.

I tried,

therefore,

butyric

about

acid in blood of rabbits,

the physiological

change

those

While, Quastel calls'

o` lactic

by

the case,

of the inter

an intermediate acid

and

in order

ma -phine

and

oxidation

Such being in.point

acid,

acetoacetic

of fat metabolim,

by giving

the function

of the past that

the cerebral functions.

of function

injure

reports

correlated

amount

as well as

metabolism.

inhibit

with acetone,

in case

in effect.

narcotics

to be much

the

together

public

on the various

considered

change

such as acetonuria

academic

in intermediary narcotics

to examine

metabolism,

of many

by many

physiological

in blood of diabetics

had been made

(1) and that

changes

narcotics

between

acid and lactic acid

poisoning

considerable

carbohydrate

of metabolism,

and it was shown

(2) have explained

which a special

substance

and such, which

of liver and kidney Wheatly

a correlation

of pyruvic

stage,

it produces

it makes

of

Q-hydroxy

to let me know

hydrochloride

and soluble

phenobarbital. EXPERIMENTS I used matured designed

to take

left jugular

male rabbits blood and also

side and cutting

a few days before. oxalate

made

about 2kg, whose car vein became a point

an operation

of N. auricularis

In case of taking

was employed

p-hydroxybutyric

weighing

to prevent

acid determination

its

blood,

ofi sympatheticotorny

inagnus an

coagulation.

morphine

chloride

and

pbenobarbital

were done according

and of sodium

were

bit

Acetone,

procedure (3), lactic acid by Clausen's (4). Therefore, bodies herein state;i is implied the sum of performed while

on the same

extremely

used as each

on the

one in advance of potassium

acetoacetic to Takahata

acid

of and

& Kume's

the total amount of acetore acetone and acetoacetic acid, aq•.xaous solutioi

of hydro

respectively. RESULTS OF THE EXPERIMENTS

Control exprrhnent I tried subcutaneous

to inject part

3.-c of sterilized of normal

*Director : Prof . I. Fujii

physiological

male rabbit,

and

saline

acetone

solution

q -tantity

into the

in its blood

dorsal is as

80

SHUBOKU KYO

shown in the first table, but the quantities of acetone and 0-hydroxybutyric acid in blood are divers depending upon kinds of animals together with determining method

as reported

by many

showed

to be about

the same as that

of the acetone,

after

seniors

the injection

little-by-little-bleeding

in hourly

in this field, and of Kozawa

in my

(5) and Asano

of the physiological system

also

was already

saline

experiment

(6).

The

solution,

indicative

it

increase

by means

of seniors'

of

reports

(7, 8) and my experiment showed as well that total quantity of the acetone increas es a little to a certain degree after the injection, even in passing five hours, and also in that

of Q-hydroxybutyric

hand,

lactic

acid in blood was seen to have decreased

range

of physiological

errors

acid

diately

I.

after

table

injection

value one

(0.52 0.57 mg%).

passes,

value is 0.60 mgr, after The

'Percentage after the injection; the injection. injection

(3-Hydroxybutyric

or acetone

value

hour

before

and

the amount

the injection

of decreas3 25.8% three

the percentage

after

On the other

the injection

within the

of morphine per 5 mg

and the average

As time

the same.

experiment

shows, the amount

0.85 mg%) and the lowest

acetone,

Control

In case of subcutaneous injection

As the second

to be about

(5). TABLE

2)

proves

half

in general injection after

of acetone

three hours;

decreases

imme

is 0.82 mg%

injection increases

0.63 mg% after

(0.78

is 0.59 mg% gradually;

injection

the

five hours.

is 28.1% against before injection one hour and half hours after the injection; and 23.2% five hours after acid

of decrease

shows is a little

is 0.82mg?% (0.65 -1.02 mg%).

The

the

same great

average

tendency

as the

and the average value

after

mount

of

value before

they injection

is

INFLUENCE OF MORPHINE ETC. ON ACETONE-BODIES 26.8%,, 46.3%, 41.5% respectively.

It seems

acid

the

increases

value

after

hour

considerably

injection

five

and half after

mg%, five hours

after hours.

The

the injection

after

to increase

injection, value

the injection,

a little in five hours.

but,

it decreases

before

17.8 mg%,

three

10.0 mg%;

81

the

injection

hours

after

original

10.0 mg%,

ore

injection

14.1

the

the percentage

Lactic

to the

of increase

is 78%,

41% and 0% each. TABLE II.

3)

Example

The subcutaneous

of morphine

5mg per kilo body weight

of morphine when 10 mg per kilo was used

The rate of value shown that

injection

in the second

table.

in the third

The increase

table is large o

lactic acid

in change

as compared

and the decrease

are very conspicuous; the aver age value of lactic acid before one hour and half after injection shows the highest increase

with

of acetone

injection is 10.4 mg%%; which was 35.4 mg%

(240.4%); it begins to decrease in three acetone before the injection is 1.07 mg%;

and five hours. The average value one hour and half after the injection

0.63 mg% (41.1:?-,/); and three

the

percentage

hours

after

of d-_-crease shown 43.9%;

(27.1%), it shows

it takes

j3-Hydroxybutyric before the injection

injection

five hours

a long time to return

acid denotes a very is 0.75 mg%; ore hour

after

is 0.60 mg%; the

to the former

injection

the

of is

highest

is 0.78 mg?/,

value.

interesting aspect. Its average value and hall after the injection is 0.60 mg%

(20%) three hours after is 0.33 mg%; shows 52%; five hours after injection

the percentage of decrease is large and is 0.32 mg%; the percentage of decrease

it is

still higher

words,

to

decrease

; it shows 58.0%.

than

acetone

In other

and it is also slower

(3-hydroxybutyric to increase

than

acid the

is slower

latter.

Judging

82

SHUBOKU

from

the

above

acid

makes

fact,

Many

also proved Steward, experiment

the sauna result gland

that

adrenaline

intact blood

while

lactic

the change

the relation injected

the following

not

both

increase

on the

adrenaline

to the cat.

metabolism

in the suprarenal Kobayashi

amount

(10) and

on, rabbit;

they

of adrenaline

(14), Sato and Ohmi (15) proved after

They also stated increase

sides

after

ware cut.

in blood The

the

injection. secretion

that,

the

with

results

Endo ,

with morphine

ot , the cutting by giving morphine

administration

The same

experiment

of

morphine,

, as this were

(20).

adrenaline, and tie

Shibata,

by

in spite

still increased

(19;, and Watanabe

the acetone-b3lies

for a long time. table.

that

of epinephrine

b1o i 3 sugar

(18), Toda

of acetone between

of morphine

made the experiment

(13 , Hayashi

nerves.

did

per kilo weight

and the decreased

in blood increased

by Kato (17), Kikuna

About

in blood,

this.

on one side, the sugar

injection

was applied

when they

that the

splanchnic

when Nn. s_hlanchiici on

naline

besides

(16) stated

of Nn. s i1a a.h i

studied

acetone

(9) observed

of blood sugar

Rogoff (12), Hayama

and Nagakura

made

decrease

the influence

Elliott

when morphine

the increase

in the suprarenal

that

to

of 10mg morphine

concerning

of cat decreased

required

Examples

in the past.

Abe (11) obtained

and

III.

investigations

been made

gland

seems

it increase.

TABLE

have

morphine

KYO

Saji ,, and I (21) have arneant.s of adre

varioa3

of the study are summarily

stated

in

INFLUENCE

OF

MORPHINE

ETC. TABLE

N.

B.:

Figures

mean

ON ACETONE-BODIES

83

IV

percentage

of

variety.

When 0.15-0.8 mg of adrenaline are given per kilo, acetone and Q hydroxybutyric acid decrease in a certain degree. The time necessary to restore is proportional to the amount of administration. Lactic acid increases in proportion to the dose; its decrease is proportional as the same. Kozawa and Asano have given the same report of experiment though it was an investigation for a short time , having stated that acetone decreased and lactic acid increased when adrenaline was added. Through this experimental fact it is supposed that the decrease of acetone in blood by the amount of morphine which I have used is owing to the over-excretion of. adrenaline which is made by morphine use. . It is also thought that the influence of narcotic condition of morphine has not given an important effect on the de crease of acetone, because it seems to be proved by the following experiment of sodium phenobarbital. 4) Example ~ofphenobarbital sodium used I have injected subcutaneously 0.4cc of 10% solution per kilo . The result of this experiment is shown1 in the fifth table. The average value of acetone before

84

SHUBOKU KYO

the injection 0.99 mg%; tages

is 0.93 mg% '0.82-1.14 mg%) ; one hour three

hours

of increase

acid before

is 0.71 mg%;

injection

0.76 mg%;

one example and halt after

three

hours

the injection

enzyme

process

in tissues

stimulus

is added

appears

in the body.

before

are

0.72%; 2.9%,

after

the

V.

five hours 42%,

and

Harajima

by narcotics from

Keilin

was prevented

of

sodium

is 11.0 mg% ; one hour

hours

that

: so, tissues and this

(23) reported by narcotics.

that

the

10.1/0-05;and

after 9.6 mg/00' (12.8;0); the injection.

phenobarbital

(22) stated

outside;

after

the

the injection.

injection

(295.4%); three

Examples

is

of Q-hydroxybutyric

10.8 mg% ; and it is the same as before

of narcotics,

though

five hours

acid

is 8.1 mg%

TABLE

dehydr•ogenases

of increase

it increases of lactic

the injection

On the action

the injection

1.02 mg/'90/'; and the percen value

aft,:): the injection

the percentages

value

after

after

is 0.69 mg%, (0.48-0.65 mg/O-,)'; one hour and half after

shows that

The average

and hall after

0.99 mg°o ; five hours

are 3%, 3/96, and 5.8%0. The average

the injection

injection

five hours

after

the

chemical

change

can not make chemical is a

the

Reports

narcotic

reduction

by

reaction,

phenomenon

that

of cytochrorre

on the study of metabolism

by on

phenobarbital are very few. Tominaga (24) reported that basal metabolism slightly decreased when sodium phenobarbital was given, and morphine resembled as well as phen,)ba -bital. Koyama with various narcotics.

and Yoshida (25) investigated the iodic-acid They reported that it gave no considerable

value in blood change when

pher.,oba-bital0.2g per kilo was administered; and protein metabolism was increased with 0.5 g pe: kilo o chlo: alhydrate. Ishimaru (25) stated that he gave .0.1-0.3 g pe.r kilo pheenob4.:bitql

to a rabbit,

but the change

of blood sugar and, lactic

acid in.

INFLUENCE OF MORPHINE ETC. ON ACETONE-BODIES blood was very little ; and the small change variation

was only observed

Geelmuyden would take damaged

within

the physiological

in six hours.

(1) stated

place

o'," the amount

85

that

secondarily

acetonuria

which was caused

when carbohydrate

by chloroform

metabolism

was

narcosis

injured

by

the

livers.

My experimental carbohydrate

result

metabolism,

is similar

to the

above

mentioned

and ac tone is not generally

affected.

result

respecting

When this

result

with phenobarbital is compared with that with physiological saline solution, a tendency that acetone in blood will be decreased a little by phenobarbital is seen. But, it is not so striking difference

in action

as morphine

of both drugs

; and it is thought

with the acetone

there

is a fundamental

in blood.

SUMMARY 1.

The influence

adrenalinee; tyric

of morphine

it decreases

acid in blood.

made hitherto.

on the acetone

the amount

Lactic

of acetone,

acid shows the same

It increases

and

its change

has

a tendency

in blood shows similar acetoacetic result

acid, and

action

as

Q-hydroxybu

as that shown in the report

is in proportion

to the

amount

of

administration. 2.

Phenobarbital

sodium

acid, Q-hydrotiybutyric

of decreasing

acid and lactic acid extremely

acetone,

acetoacetic

little, and it is not so striking

as morphine. 3.

The action

of morphine

to have a fundamental I wish to thank

difference Prof.

and

phenobarbital

upon the acetone

in blood seems

each.

I. Fujii and Assist.

Prof.

S. Kozawa

for

their

direction

and help in this work. REFERENCES 1) GEELMUYDEN, H. C.: Ergeb. Pkysiol. 21, 274 (1'23). 2) QUASTEL,J. H. AND WHEATLY,A. H. M.: P:oc. Roy. Soc., London, s. B. 112, 60 (1nS2'. 3) TAKAHATA, T. AND KUME, J.: Referred tj KOZAA, S.: Folia p.'.armacol. japon. 58,27E.'(1943). 4) KAWAMURA,C.: Mitt. Med. Akad. Iioto 2, 161 (19:8). 5) 6) 7) 8) 9) 10) 11) 12)

KOZAWA,S.: Folia pharmacol. japon. 39, 25 (1943). ASANO, G.: Mitt. Med. Akad. Kioto 46, 803 (195)). HIRAYOSHI,Y.: Ibid. 24, 841 (1938). TARUMI, S.: Ibid. 13, 753 (1941). ELLIOTT, T. R.: J. Physiol. 44, 374 (1912). KOBAYASHI,K.: Keio Igaku 7, 1131 (1927) (Japanese). ABE, T.: Ibid. 7,1165 (1927). STEWARD,G. N. ANDROGO?F,J. M.: J. Pharmacol. & Exper. Therap. 19, 59, 87 and 97 (1F•22).

13) HAYAMA,D.: Folia pharmacol. japon. 7, 137 (19?8).

86 14)

SHUBOKU HAYASHI, A.:

J. Orient. Med. 9, 681 (1928).

15) SATO, H. AND OHMI, F.:

Tohoku J. Exper. Med. 21, 411 (1938).

16) SHIBATA, H., ENDO, K. AND NAGAKURA, G.: 17) KATO, K.:

ibid. 50, 1 (1:949).

J. Orient. Med. 9, 25 (1928).

18) KIKUNA, K.: 19) TODA, H.:

KYO

Mitt. Med. Gesells. Osaka 27, 2447 (1928). Tohoku J. Exper. Med. 19, 405, (19:.2).

20)

WATANABE, E.:

Mitt. Med. Akad. Kioto 19, 1781 (1937).

21)

KYO, S. AND SAJI, Y.:

Unpublished.

22) HARAJIMA, S. : Keio Igaku 9, 1251 (1929). 23)

KEILIN, D.:

24)

TOMINAGA, R.:

Proc. Roy. Soc. London, s. B. 104, 206 (1929). Die Zentralmedicin.

25) KOYAMA, H. AND YOSHIDA, T.: 23) ISHIMARU, S.:

10, 808 (1941).

Mitt. Med. Gesells. Osaka 34, 1931 (1935).

Mitt. Med. Akad. Kioto 23, 839 (1938).