Department of Psychiatry,
Washington University School of
Medicine
St Louis, Missouri,
U.S.A.
1. Unilateral and bilateral injections of
1.0 pl. solutions of angiotensin II into
specific brain sites produced copious drinking
of water in the waterreplete rhesus monkey
(Mactwa mulatta).
2. Of six brain regions in seven monkeys
into which a total of 368 microinjections of
angiotensin II were made, three were sensitive
to angiotensin II. In decreasing order of
sensitivity, they were (i) a rostral zone that
included the septum, the anterior hypothalamus
and the preoptic region, (ii) a caudal zone
consisting of the mesencephalic central grey,
and (iii) the lateral and third ventricles near
the foramen of Monro. Of the regions tested,
those that were relatively inactive included (i)
the mid line thalmus, (ii) the mid-brain
reticular formation, and (iii) metencephalic
points in the cerebellum, the 4th ventricle and
the dorsal aspect of the pons.
3. Bilateral microinjections of angiotensin
II into the sensitive regions in doses as low as
0•75-6 ng were dipsogenic and, with
increasing doses, drinking occurred in a
dose-dependent fashion up to 500 ng, after which
the amount drunk levelled off or was reduced.
The dose-response curve for unilateral
microinjections began at 12•5 ng, and at
doses higher than 50 ng unilateral and bilateral
microinjections were equipotent.
4. The onset of drinking (without eating)
averaged 21-3•2 min following the end of
microinjections for all sensitive tissue sites.
Injections into the ventricles produced
significantly longer drinking latencies.
5. Angiotensin I elicited drinking in
amounts comparable to angiotensin II at a dose
of 100 ng whereas analogues of angiotensin II
were weak dipsogens. Of the three analogues
tested, Phe4, Tyr5-angiotensin II was the most
potent dipsogen, followed by 11e5-angiotensin
II. The 1-7 heptapeptide, des-Phe5-angiotensin
II was an ineffective dipsogen. Carbachol
mieroinjected into the most sensitive
angiotensin drinking sites had no dipsogenic
action in the water-replete monkey.
6. Tachyphylaxis to angiotensin II was
demonstrated as a reduction in mean water intake
of 55 and 74 per cent on the second and third
microinjections, respectively. This reduction
appeared to be due to dilutional inhibition or
signals from the amount of water ingested on the
first microinjection of angiotensin II.
7. Monkeys drank an amount equal to a normal
daily intake following two to three
microinjections of angiotensin II in doses of
100-250 ng into sensitive regions. This extra
water load caused no reductions in normal daily
water intake either for the remainder of the
experimental day or 24 hr later.
8. Pre-treatments with microinjections of an
angiotensin-converting enzyme inhibitor, SQ
20,881, did not reduce the dipsogenic action of
angiotensin I, suggesting that this and perhaps
other peptide precursors act directly on
receptor mechanisms to produce thinking.
Attempts to change the polydipsic effects of
angiotensin II were unsuccessful with
pre-treatments of intracranial microinjections
of either haloperidol, Jle8-angiotensin II or
carbachol.
9. Microinjections of angiotensin II
dissolved in hypertonic saline solutions had no
influence on water intake when compared with the
same dose dissolved in distilled water or
isotonic saline.
10. Yawning was the only response besides
drinking that appeared to be directly related to
intracranial injections of angiotensin II in the
monkey. The response appeared to be spontaneous,
reflexive and dose-related, but did not seem to
be related to the occurrence of sleep or to the
stimulation of active drinking sites. The onset
of yawning was within 5 min of the
microinjection if no drinking occurred, or if
non-drinking sites were stimulated with
angiotensin II. Inasmuch as other injected
substances have not elicited yawning, the
significance of the angiotensin-yawning relation
is unclear. In some instances, a hyperactive
state of the animal followed intraventricular
injections of angiotensin II. In other
instances, intracranial microinjections of
angiotensin II were followed by quietude or
e.e.g. and behavioural signs of light sleep.
11. This work further confirms the findings
of previous research which showed that
angiotensin II is the most potent dipsogen in
all species tested to date. This endogenous
peptide appears to participate in natural thirst
by acting on central mechanisms of extracellular
thirst.
