Angiotensin (ANG) II is a powerful and phylogenetically widespread stimulus to thirst and sodium appetite. When it is injected directly into sensitive areas of the brain, it causes an immediate increase in water intake followed by a slower increase in NaCl intake. Drinking is vigorous, highly motivated, and rapidly completed. The amounts of water taken within 15 min or so of injection can exceed what the animal would spontaneously drink in the course of its normal activities over 24 h. The increase in NaCl intake is slower in onset, more persistent, and affected by experience. Increases in circulating ANG II have similar effects on drinking, although these may be partly obscured by accompanying rises in blood pressure. The circumventricular organs, median preoptic nucleus, and tissue surrounding the anteroventral third ventricle in the lamina terminalis (AV3V region) provide the neuroanatomic focus for thirst, sodium appetite, and cardiovascular control, making extensive connections with the hypothalamus, limbic system, and brain stem. The AV3V region is well provided with angiotensinergic nerve endings and angiotensin AT1 receptors, the receptor type responsible for acute responses to ANG II, and it responds vigorously to the dipsogenic action of ANG II. The nucleus tractus solitarius and other structures in the brain stem form part of a negative-feedback system for blood volume control, responding to baroreceptor and volume receptor information from the circulation and sending ascending noradrenergic and other projections to the AV3V region. The subfornical organ, organum vasculosum of the lamina terminalis and area postrema contain ANG II-sensitive receptors that allow circulating ANG II to interact with central nervous structures involved in hypovolemic thirst and sodium appetite and blood pressure control. Angiotensin peptides generated inside the blood-brain barrier may act as conventional neurotransmitters or, in view of the many instances of anatomic separation between sites of production and receptors, they may act as paracrine agents at a distance from their point of release. An attractive speculation is that some are responsible for long-term changes in neuronal organization, especially of sodium appetite. Anatomic mismatches between sites of production and receptors are less evident in limbic and brain stem structures responsible for body fluid homeostasis and blood pressure control. Limbic structures are rich in other neuroactive peptides, some of which have powerful effects on drinking, and they and many of the classical nonpeptide neurotransmitters may interact with ANG II to augment or inhibit drinking behavior. Because ANG II immunoreactivity and binding are so widely distributed in the central nervous system, brain ANG II is unlikely to have a role as circumscribed as that of circulating ANG II. Angiotensin peptides generated from brain precursors may also be involved in functions that have little immediate effect on body fluid homeostasis and blood pressure control, such as cell differentiation...

SUMMARY1. When applied directly to the brain, angiotensin II amide, as either the valine5 or isoleucine5 octapeptide, causes rats in normal fluid balance to drink water.2. The drinking response to angiotensin injections is copious, rapid, repeatable within the same test session, and stable over months of testing in the same animal.3. The response is motivationally potent and specific. After injection the animals move directly to the source of water and drink. There is typically no preliminary hyperactivity or subsequent depression. The animals do not eat, gnaw or exhibit other behaviours that are not normally seen during spontaneous drinking. The injections rouse sleeping animals to drink and interrupt eating in animals deprived of food for two days.4. The region of the brain that is most sensitive to angiotensin includes the anterior hypothalamus, the preoptic region, and the septum including the nucleus accumbens.5. Intracranial renin elicited drinking. Bradykinin and vasopressin did not, nor did adrenaline, noradrenaline or aldosterone. In the most sensitive region, sites positive for angiotensin also yielded drinking to carbachol.6. Responses were obtained with 5 ng (ca. 5 p-mole) and occurred reliably with 50 ng angiotensin or more. The dose-response curve for amount drunk rose from 5 to 100 ng and levelled off thereafter. Angiotensin is therefore the most potent dipsogen known and is effective at doses that are reasonably within the concentration range for circulating endogenous angiotensin.

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SUMMARY1. Rats in normal fluid balance drank water 1-2 hr after complete ligation of the inferior vena cava either above or below the renal veins. At the same time there was a fall in urine flow and excretion of electrolyte, especially after caval ligation above the renal veins, so that the animals ended the initial 6 hr period in positive fluid balance.2. Caval ligation was relatively ineffective as a stimulus to drinking after bilateral nephrectomy, but was effective in rats made anuric by ureteric ligation.3. Rats subjected to caval ligation and offered a choice between water and 1l8 % saline (w/v) drank water, despite the increasing hypotonicity of the body fluids thereby resulting. 4. During the secondary polydipsia, which generally occurred on about the third day after caval ligation as renal function was recovering, there was an increased preference for 18 % saline.5. Constriction of the aorta above the renal arteries, or constriction of both renal arteries, also caused drinking, oliguria and the development of positive fluid balance.6. Constriction of the aorta below the renal arteries, or after nephrectomy, was ineffective as a stimulus to drinking.7. Saline extracts of renal cortex caused rats in normal water balance to drink. Activity was destroyed by boiling the extract for 10 min. Renal medullary and hepatic extracts were without effect on drinking.8. It proved impossible to separate dipsogenic and pressor activities of renal extracts during the different stages of fractionation which lead to the production of renin; disappearance of one activity was invariably accompanied by disappearance of the other.9. Dipsogenic and pressor actions were greater in nephrectomized rats than in normal rats. J. T. FITZSIMONS 10. Both extractable dipsogenic factor and extractable pressor activity were reduced by treating the rat with DOCA and saline for several weeks beforehand.11. The renal dipsogen therefore has similar properties to renin. It may prove to be identical with renin, particularly in view of the fact that angiotensin also stimulates drinking.12. Adrenalectomy did not affect drinking induced by renin or by caval ligation.13. It is concluded that the renin angiotensin system may play a role in the genesis of the thirst which follows certain extracellular stimuli.

SUMMARY1. Intravenous infusion of angiotensin causes rats which are in water balance to drink water.2. The mean amount of angiotensin needed to initiate drinking was 291 + 4-6 jtg/kg (S.E. of mean) in twenty normal rats, and 15-7 + 241 ,g/kg in thirty-four nephrectomized rats.3. The nephrectomized rat is therefore more sensitive to this action of angiotensin than the rat with intact kidneys.4. The rates of infusion (0.05-3.0 jtg/kg-l min-) which cause drinking are comparable to those used to produce other effects in rats.5. Angiotensin restores the drinking response of the nephrectomized rat subjected to caval ligation to a value similar to that obtained in the uninfused normal rat subjected to caval ligation.6. The effects of angiotensin and hypertonic saline on drinking are additive when both substances are administered to nephrectomized rats.7. These experiments provide further support for the view that the renin-angiotensin system is concerned in extracellular thirst.

SUMMARY1. Prolonged exposure of the brain of the normal Na-replete rat to angiotensin II produced a marked and persistent Na appetite. In a first series of experiments, short-term, repeated systemic injections of isoprenaline or renin (both of which raise circulating angiotensin levels), and repeated intracranial injections of angiotensin II evoked increased ingestion of 2-7 % NaCl. In the second series of experiments, continuous infusions of angiotensin II directly into the brain evoked extremely large intakes of 3 % NaCl.2. In addition to large intakes of hypertonic NaCl some rats drank daily volumes of water that exceeded their body weight.3. Not only did the animals drink large volumes of 3 % NaCl during continuous angiotensin II infusion, but after termination of the infusion they continued to ingest NaCl at a rate comparable to that of the adrenalectomized rat. In most of the animals the persistent NaCl intake diminished over several days, but other animals continued to drink NaCl for as long as their intake was measured (up to 7 months).4. The response to continuous infusion of angiotensin II was dose-dependent.Both water and 3 % NaCl intake increased over a dose range of 6 ng h-1 to 6000 ng h-1.The persistence of the sodium appetite was also dose-dependent across the same range of doses. 5. Angiotensin-induced salt appetite is specific for Na. Animals did not drink 0.5 M-NH4CI and only occasionally drank minimal amounts of 0 5 M-KCl during continuous infusion. 6. The large water turnover was not responsible for the Na appetite. Rats given access to 3 % NaCl only during infusion of angiotensin drank copiously. Animals that were not infused but were given saccharine-flavoured water in order to increase their water intakes did not drink 3 % NaCl offered at the same time even though fluid intake was high. Rats that did not receive intracranial infusions but were infused intragastrically with volumes of water equal to or exceeding the amounts that were drunk during angiotensin infusion did not drink the 3 % NaCl but did drink some water.

Strauss (1958) said that: 'Thirst may occur in a variety of situations in which there is reason to believe that the volume of body fluids is contracted without concomitant change in osmolality.' As Strauss implies, the evidence is only suggestive. The present experiments were carried out in order to determine whether reduction in effective fluid volume without increase in crystalloid osmotic pressure, by peritoneal dialysis or by bleeding, would cause rats to drink. METHODSAlbino rats of both sexes weighing between 150 and 500 g were used. During the experiments they were housed in individual metabolism cages with water available from a drinking meter (Fitzsimons, 1958) but no food. Urine was collected and measured by weighing, the bladder being emptied by suprapubic pressure at the start and finish of the experiment.Effective fluid volume was reduced by peritoneal dialysis or by bleeding. Peritoneal dialysis was carried out in two ways; by intraperitoneal injection of hyperoncotic colloid dissolved in water or in 0*9 % sodium chloride, or by placing Visking cellulose sacs containing hyperoncotic colloid dissolved in 0-9 % sodium chloride in the peritoneal cavity. Gum acacia, polyvinyl pyrrolidone and polyethylene glycol in 25-50 % (w/v) solutions were used. The Visking cellulose sacs were to prevent systemic absorption of colloid from the peritoneal cavity. The sacs were well tolerated, though the depletions produced were smaller than when the colloid was introduced directly in the peritoneal cavity. Animals were bled by cutting off the tip of the tail.The experimental procedure was to inject a known weight of hyperoncotic solution, or insert a weighed Visking cellulose sac containing hyperoncotic solution through a small lumbar incision, or to bleed the animal a known amount, all procedures being carried out under ether anaesthesia. The rat was weighed to the nearest 0.1 g and placed in its metabolism cage, by which time it was recovering consciousness. Spontaneous drinking was recorded and urine collected for the next 6 hr. At the end of this time the rat was again anaesthetized and weighed and the change in weight of the rat was used as a measure of net fluid intake. The ascitic fluid or sac was recovered and weighed and the depletion produced in 6 hr obtained from the changes in weight. Some experiments were made on nephrectomized rats by essentially the same procedure, except that there was no urine to collect. Bilateral nephrectomy was carried out through a lumbar incision, the colloid or sac introduced and the wounds in the muscle wall sealed to prevent escape of fluid, or the animal was bled.The amount of water drunk, net fluid intake (i.e. change in body weight), depletion (i.e. increase in ascitic fluid or blood loss) and amount of urine were expressed as percentages of the initial body weight before the intraperitoneal procedures or bleeding.

1. Recently it has been shown that injection of angiotensin II into the anterior diencephalon causes the rat to drink water. In the present experiments the dipsogenic action of a number of other substances including substances related to angiotensin was tested.2. Injection of 0.001 Goldblatt u. renin into the angiotensin-sensitive region causes the water-replete rat to drink. Drinking is slower in onset and continues for longer than after injection of angiotensin II.3. Synthetic tetradecapeptide renin substrate and angiotensin I were as effective as angiotensin II at causing water-replete rats to drink.4. beta-aspartic acid(1)-valine(5)-angiotensin II was also fully effective; but the D-arginine substituted octapeptide was much less effective.5. The (2-8) heptapeptide retained about 50% of the dipsogenic activity of the octapeptide, whereas the absence of phenylalanine at the other end of the peptide chain in the (1-7) heptapeptide results in an inactive compound.6. The (3-8) hexapeptide and the (4-8) pentapeptide, both of which have phenylalanine at the end of the chain, and the (1-4) and (5-8) tetrapeptide fragments of angiotensin II showed only a slight action on intake of water.7. Kallikrein, bradykinin, adenosine-3'5-cyclic phosphate, vasopressin and oxytocin caused no drinking when injected into the angiotensin-sensitive region.8. It is concluded that the requirements for the dipsogenic activity of angiotensin are the same as those for its other biological actions with the qualification that the precursor peptides are also active, presumably because they give rise to angiotensin II locally.