124. TOLERATION OF THE DIURETIC ACTION OF CAFFEINE. BY

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418

[Vol. 4,

124.

Toleration

of the Diuretic By Gyokujo

Institute

of Pharmacology,

(Rec. June 28, 1928.Comm.

Action

of Caffeine.

KIHARA.

Tokyo Imperial

University.

by K. MIURA, M.I.A., July 12, 1928.)

It is a well known daily experience that customary use of tea, coffee or chocolate leadsvery often to an absence of diuretis and other symptoms due to caffeine. But an experimental study of this phenome non may be found only in the studies by Myers.1) In my experiments, therefore, in order to elucidate the relation between caffeine diuresis and caffeine tolerance, the changes in the renal and extrarenal responses in the rabbit following repeated administrations of the drug were minutelyobserved by various methods. The Minimal Effective Diuretic Doses of Cafeineand its Allies. As the diuretic effect of caffeine and its allies is strongly influenced by the water content in the animal body, an attempt was made to maintain the watercontent in the tissues of the animal used as uniform as possible. The water content in blood of normal animals under the usual feedingin our laboratory was 80-83 fo as determined by Bang's method.2) To observe the changes in the urine excretion, the urine dropsfrom the ureter-cannulae inserted into both sides were counted before and after the intravenous injection of the drugs. Under these circumstances, the minimal effective diuretic doses per kilogrambodyweight were found to be 0.8 mg. for caffeine, 2.0 mg. for diuretine (0.9 mg. as theobromine), and 0.5 mg.for theocine (0.325 mg. as theophylline) respectively. The Development of Toleration. When the administration of the drugs, either per so or subcutaneously had been daily repeated for 4-6 months without interruption, in gradually increasingdoses, the above mentioned minimal doses of the drugs became insufficient to cause diuresis. These facts to the diuretic administrations Changes

in

clearly show that in rabbits a decreased susceptibility actionof the drugs develops after long continued of caffeine or its allies. the

made on the extra-renal diuresis. In diuresis

Extra-Renal action with the

Response.

An

observation

was

first

of caffeine and its allies in producing minimal effective dose of caffeine the

1) H. B. Myers, Journ. Pharm. and Exp. Ther., 23 (1924), 465. 2) Bang, Mikromethode zur Blutuntersuchung. (1919).

No. 7.]

Toleration

number

of erythrocytes

decreased, marked

a sign hydraemia

Action of Caffeine .

and haemoglobin

content

419

in the blood

distinctly

hydraemia . Larger doses caused increasingly with pronounced diuresis . At the beginning of strong hydraemia appeared ; at the height of diuresis it had weakened; at the end of diuresis , the blood was more

diuresis already concentrated

than

of

normal.

Next, in the rabbit above mentioned induced sufficient to forthcoming. These long time

of the Diuretic

produce

tolerant toward caffeine , the minimal dose no diuresis ; even with larger doses generally

diuresis

in

such

an

animal

, no hydreamia

was

facts indicate that repeated administration of the drug for a first brings about the cessation of the extra-renal response .

Changes in the Renal Response. To observe the changes in the renal response, the rabbit's kidney was prepared and perfused according to NAGASAWA'Smethod.1) When the minimal effectivediuretic dose of caffeine was applied to the perfusion fluid of the kidney thus prepared, the urine outflow increased distinctly in a normal rabbit, but in the tolerant animal no diuresis followed. By sufficiently larger doses diuresis occurred in both, while the renal blood flow increased immediately after the injection, irrespective of diuresis. Changes in the Renal Circulation. The fact thata momentary renal vaso-dilation follows directly after an intravenous injection of caffeine, independent of diuresis, has already been ascertained by CUSHNY et al.2) and TAMURA et al.3) In the rabbit tolerant toward caffeine, prepared according to BARCROFT and BRODIE's method,4) the renal blood flow just asin normal rabbits, momentarily increased directly after the intravenous injection of caffeine, irrespective of diuresis. Cross bromine caffeine, any

Experiments. or theophylline no diuresis

one of them,

When

the

minimal

effective

was administered to the rabbit occurred ; but given a sufficiently

diuresis

appeared

without

dose tolerant large

of

theo

toward dose of

hydreamia.

Oxygen Consumption of the Kidney in the Tolerant Rabbit. TAMURA5)and his co-workers have recentlydemonstrated that the oxygen consumption of the rabbit's kidney is 0.04-0.079 c.c. per gramper minute and remainsunaltered by caffeine diuresis. According to my 1)

Nagasawa,

2)

Cushny

Mitt. d. med. Gesellschaft

and Lambie,

Journ.

Physiol..

zu Tokyo, 42 (1928), 377. 55 (1921), 276.

3) Tamura and Miwa, Mitt. med. Fak. Kais. Univ.Tokyo, 23 (1920), 317; Tamura, Watanabe, Shah, Komatsubara and Kihara, Proc. Imp. Acad.,2 (1926), 434. 4) Barcroft 5) Tamura,

and Brodie, Journ. Physiol., 32 (1905), 18. Watanabe and Kaburaki, Proc. Imp. Acad., 2 (1926), 431,

420

G. KIHARA.

[Vol. 4,

experiments, in the rabbit tolerant toward caffeine, the oxygen consumption of the kidney was the same as in the normal rabbit and remained unchanged after the injection of largedoses of caffeine sufficient to produce dieresis. The

following

1. Rabbits following upon of the drug. development of

conclusions

may

be put

forward

:

acquire a moderate degree of tolerance toward caffeine repeated administration of gradually increasingdoses It requires approximately 4-6 months for thefull toleration.

2. The development of a decreased susceptibility to the diuretic action of caffeine is shown at firstin the cessation of the extra-renal response (hydraemia), and next in that of the renal response. But the renal vasodilation to be seen immediately after theinjection of caffeine appears ina caffeine-tolerant animal as well as in a control animal. 3.

An

animal

philline manifests also to the other

tolerant

a decreased two.

toward

caffeine,

susceptibility

theobromine not

only

to

and the

one

theobut

4. In caffeine-tolerant rabbits, as in a control animal, no increase in the oxygen consumption of thekidney is produced by caffeine injection.