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.
